Patra et al. J Nanobiotechnol (2018) 16:71 https://doi.org/10.1186/s12951-018-0392-8 Journal of Nanobiotechnology

REVIEW Open Access Nano based drug delivery systems: recent developments and future prospects Jayanta Kumar Patra1 , Gitishree Das1, Leonardo Fernandes Fraceto2,3, Estefania Vangelie Ramos Campos2,3, Maria del Pilar Rodriguez‑Torres4 , Laura Susana Acosta‑Torres4 , Luis Armando Diaz‑Torres5 , Renato Grillo6, Mallappa Kumara Swamy7, Shivesh Sharma8, Solomon Habtemariam9 and Han‑Seung Shin10*

Abstract Nanomedicine and nano delivery systems are a relatively new but rapidly developing science where materials in the nanoscale range are employed to serve as means of diagnostic tools or to deliver therapeutic agents to specifc targeted sites in a controlled manner. Nanotechnology ofers multiple benefts in treating chronic human diseases by site-specifc, and target-oriented delivery of precise medicines. Recently, there are a number of outstanding appli‑ cations of the nanomedicine (chemotherapeutic agents, biological agents, immunotherapeutic agents etc.) in the treatment of various diseases. The current review, presents an updated summary of recent advances in the feld of nanomedicines and nano based drug delivery systems through comprehensive scrutiny of the discovery and appli‑ cation of nanomaterials in improving both the efcacy of novel and old drugs (e.g., natural products) and selective diagnosis through disease marker molecules. The opportunities and challenges of nanomedicines in drug delivery from synthetic/natural sources to their clinical applications are also discussed. In addition, we have included informa‑ tion regarding the trends and perspectives in nanomedicine area. Keywords: Nanomedicine, Nanomaterials, Drug delivery, Drug targeting, Natural products

Background make them favorable leads in the discovery of novel drugs Since ancient times, humans have widely used plant- [4]. Further, computational studies have helped envisage based natural products as medicines against various dis- molecular interactions of drugs and develop next-genera- eases. Modern medicines are mainly derived from herbs tion drug inventions such as target-based drug discovery on the basis of traditional knowledge and practices. and drug delivery. Nearly, 25% of the major pharmaceutical compounds and Despite several advantages, pharmaceutical compa- their derivatives available today are obtained from natu- nies are hesitant to invest more in natural product-based ral resources [1, 2]. Natural compounds with diferent drug discovery and drug delivery systems [5] and instead molecular backgrounds present a basis for the discovery explore the available chemical compounds libraries to of novel drugs. A recent trend in the natural product- discover novel drugs. However, natural compounds are based drug discovery has been the interest in designing now being screened for treating several major diseases, synthetically amenable lead molecules, which mimic including cancer, diabetes, cardiovascular, infammatory, their counterpart’s chemistry [3]. Natural products and microbial diseases. Tis is mainly because natural exhibit remarkable characteristics such as extraordinary drugs possess unique advantages, such as lower toxicity chemical diversity, chemical and biological properties and side efects, low-price, and good therapeutic poten- with macromolecular specifcity and less toxicity. Tese tial. However, concerns associated with the biocom- patibility, and toxicity of natural compounds presents a greater challenge of using them as medicine. Conse- *Correspondence: [email protected] 10 Department of Food Science and Biotechnology, Dongguk University, quently, many natural compounds are not clearing the Ilsandong‑gu, Goyang, Gyeonggi‑do 10326, Republic of Korea clinical trial phases because of these problems [6–8]. Te Full list of author information is available at the end of the article use of large sized materials in drug delivery poses major

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Patra et al. J Nanobiotechnol (2018) 16:71 Page 2 of 33

challenges, including in vivo instability, poor bioavail- well appreciated in recent times due to the fact that ability, and poor solubility, poor absorption in the body, nanostructures could be utilized as delivery agents by issues with target-specifc delivery, and tonic efective- encapsulating drugs or attaching therapeutic drugs ness, and probable adverse efects of drugs. Terefore, and deliver them to target tissues more precisely with a using new drug delivery systems for targeting drugs to controlled release [10, 19]. Nanomedicine, is an emerg- specifc body parts could be an option that might solve ing feld implementing the use of knowledge and tech- these critical issues [9, 10]. Hence, nanotechnology plays niques of nanoscience in medical biology and disease a signifcant role in advanced medicine/drug formula- prevention and remediation. It implicates the utiliza- tions, targeting arena and their controlled drug release tion of nanodimensional materials including nanoro- and delivery with immense success. bots, nanosensors for diagnosis, delivery, and sensory Nanotechnology is shown to bridge the barrier of purposes, and actuate materials in live cells (Fig. 1). For biological and physical sciences by applying nanostruc- example, a nanoparticle-based method has been devel- tures and nanophases at various felds of science [11]; oped which combined both the treatment and imaging specially in nanomedicine and nano based drug deliv- modalities of cancer diagnosis [20]. Te very frst gen- ery systems, where such particles are of major interest eration of nanoparticle-based therapy included lipid [12, 13]. Nanomaterials can be well-defned as a mate- systems like liposomes and micelles, which are now rial with sizes ranged between 1 and 100 nm, which FDA-approved [21]. Tese liposomes and micelles can infuences the frontiers of nanomedicine starting from contain inorganic nanoparticles like gold or magnetic biosensors, microfuidics, drug delivery, and microar- nanoparticles [22]. Tese properties let to an increase ray tests to tissue engineering [14–16]. Nanotechnol- in the use of inorganic nanoparticles with an emphasis ogy employs curative agents at the nanoscale level to on drug delivery, imaging and therapeutics functions. develop nanomedicines. Te feld of biomedicine com- In addition, nanostructures reportedly aid in prevent- prising nanobiotechnology, drug delivery, biosensors, ing drugs from being tarnished in the gastrointestinal and tissue engineering has been powered by nanoparti- region and help the delivery of sparingly water-soluble cles [17]. As nanoparticles comprise materials designed drugs to their target location. Nanodrugs show higher at the atomic or molecular level, they are usually small oral bioavailability because they exhibit typical uptake sized nanospheres [18]. Hence, they can move more mechanisms of absorptive endocytosis. freely in the human body as compared to bigger mate- Nanostructures stay in the blood circulatory system rials. Nanoscale sized particles exhibit unique struc- for a prolonged period and enable the release of amalga- tural, chemical, mechanical, magnetic, electrical, and mated drugs as per the specifed dose. Tus, they cause biological properties. Nanomedicines have become fewer plasma fuctuations with reduced adverse efects

Fig. 1 Application and goals of nanomedicine in diferent sphere of biomedical research Patra et al. J Nanobiotechnol (2018) 16:71 Page 3 of 33

[23]. Being nanosized, these structures penetrate in the polymers such as polyvinyl alcohol, poly-l-lactic acid, tissue system, facilitate easy uptake of the drug by cells, polyethylene glycol, and poly(lactic-co-glycolic acid), permit an efcient drug delivery, and ensure action at the and natural polymers, such as alginate and chitosan, are targeted location. Te uptake of nanostructures by cells is extensively used in the nanofabrication of nanoparticles much higher than that of large particles with size ranging [8, 30–32]. Polymeric nanoparticles can be categorized between 1 and 10 µm [17, 24]. Hence, they directly inter- into nanospheres and nanocapsules both of which are act to treat the diseased cells with improved efciency excellent drug delivery systems. Likewise, compact lipid and reduced or negligible side efects. nanostructures and phospholipids including liposomes At all stages of clinical practices, nanoparticles have and micelles are very useful in targeted drug delivery. been found to be useful in acquiring information owing Te use of ideal nano-drug delivery system is decided to their use in numerous novel assays to treat and diag- primarily based on the biophysical and biochemical prop- nose diseases. Te main benefts of these nanoparticles erties of the targeted drugs being selected for the treat- are associated with their surface properties; as various ment [8]. However, problems such as toxicity exhibited proteins can be afxed to the surface. For instance, gold by nanoparticles cannot be ignored when considering the nanoparticles are used as biomarkers and tumor labels use of nanomedicine. More recently, nanoparticles have for various biomolecule detection procedural assays. mostly been used in combination with natural products Regarding the use of nanomaterials in drug delivery, to lower the toxicity issues. Te green chemistry route the selection of the nanoparticle is based on the physico- of designing nanoparticles loaded with drugs is widely chemical features of drugs. Te combined use of nano- encouraged as it minimises the hazardous constituents in science along with bioactive natural compounds is very the biosynthetic process. Tus, using green nanoparticles attractive, and growing very rapidly in recent times. It for drug delivery can lessen the side-efects of the medi- presents several advantages when it comes to the delivery cations [19]. Moreover, adjustments in nanostructures of natural products for treating cancer and many other size, shape, hydrophobicity, and surface changes can fur- diseases. Natural compounds have been comprehensively ther enhance the bioactivity of these nanomaterials. studied in curing diseases owing to their various char- Tus, nanotechnology ofers multiple benefts in treat- acteristic activities, such as inducing tumor-suppressing ing chronic human diseases by site-specifc, and target- autophagy and acting as antimicrobial agents. Autophagy oriented delivery of medicines. However, inadequate has been observed in curcumin and cafeine [25], knowledge about nanostructures toxicity is a major whereas antimicrobial efects have been shown by cin- worry and undoubtedly warrants further research to namaldehyde, carvacrol, curcumin and eugenol [26, 27]. improve the efcacy with higher safety to enable safer Te enrichment of their properties, such as bioavailabil- practical implementation of these medicines. Terefore, ity, targeting and controlled release were made by incor- cautiously designing these nanoparticles could be help- porating nanoparticles. For instance, thymoquinone, a ful in tackling the problems associated with their use. bioactive compound in Nigella sativa, is studied after its Considering the above facts, this review aims to report encapsulation in lipid nanocarrier. After encapsulation, it diferent nano based drug delivery systems, signifcant showed sixfold increase in bioavailability in comparison applications of natural compound-based nanomedicines, to free thymoquinone and thus protects the gastrointes- and bioavailability, targeting sites, and controlled release tinal stufs [28]. It also increased the pharmacokinetic of nano-drugs, as well as other challenges associated with characteristics of the natural product resulting in better nanomaterials in medicines. therapeutic efects. Metallic, organic, inorganic and polymeric nanostruc- Nano based drug delivery systems tures, including dendrimers, micelles, and liposomes are Recently, there has been enormous developments in the frequently considered in designing the target-specifc feld of delivery systems to provide therapeutic agents or drug delivery systems. In particular, those drugs having natural based active compounds to its target location for poor solubility with less absorption ability are tagged treatment of various aliments [33, 34]. Tere are a num- with these nanoparticles [17, 29]. However, the efcacy ber of drug delivery systems successfully employed in the of these nanostructures as drug delivery vehicles varies recent times, however there are still certain challenges depending on the size, shape, and other inherent bio- that need to be addresses and an advanced technology physical/chemical characteristics. For instance, poly- need to be developed for successful delivery of drugs to meric nanomaterials with diameters ranging from 10 its target sites. Hence the nano based drug delivery sys- to 1000 nm, exhibit characteristics ideal for an efcient tems are currently been studied that will facilitate the delivery vehicle [7]. Because of their high biocompat- advanced system of drug delivery. ibility and biodegradability properties, various synthetic Patra et al. J Nanobiotechnol (2018) 16:71 Page 4 of 33

Fundamentals of nanotechnology based techniques with drug delivery system to anchor them to the receptor in designing of drug structures expressed at the target site. In passive target- Nanomedicine is the branch of medicine that utilizes the ing, the prepared drug carrier complex circulates through science of nanotechnology in the preclusion and cure of the bloodstream and is driven to the target site by afnity various diseases using the nanoscale materials, such as or binding infuenced by properties like pH, temperature, biocompatible nanoparticles [35] and nanorobots [36], molecular site and shape. Te main targets in the body for various applications including, diagnosis [37], deliv- are the receptors on cell membranes, lipid components ery [38], sensory [39], or actuation purposes in a living of the cell membrane and antigens or proteins on the cell organism [40]. Drugs with very low solubility possess surfaces [43]. Currently, most nanotechnology-mediated various biopharmaceutical delivery issues including lim- drug delivery system are targeted towards the cancer dis- ited bio accessibility after intake through mouth, less dif- ease and its cure. fusion capacity into the outer membrane, require more quantity for intravenous intake and unwanted after- Biopolymeric nanoparticles in diagnosis, detection efects preceding traditional formulated vaccination pro- and imaging cess. However all these limitations could be overcome Te integration of therapy and diagnosis is defned as by the application of nanotechnology approaches in the theranostic and is being extensively utilized for cancer drug delivery mechanism. treatment [44, 45]. Teranostic nanoparticles can help Drug designing at the nanoscale has been studied diagnose the disease, report the location, identify the extensively and is by far, the most advanced technology stage of the disease, and provide information about the in the area of nanoparticle applications because of its treatment response. In addition, such nanoparticles can potential advantages such as the possibility to modify carry a therapeutic agent for the tumor, which can pro- properties like solubility, drug release profles, difusiv- vide the necessary concentrations of the therapeutic ity, bioavailability and immunogenicity. Tis, can con- agent via molecular and/or external stimuli [44, 45]. Chi- sequently lead to the improvement and development of tosan is a biopolymer which possesses distinctive prop- convenient administration routes, lower toxicity, fewer erties with biocompatibility and presence of functional side efects, improved biodistribution and extended drug groups [45–47]. It is used in the encapsulation or coating life cycle [17]. Te engineered drug delivery systems are of various types of nanoparticles, thus producing difer- either targeted to a particular location or are intended ent particles with multiple functions for their potential for the controlled release of therapeutic agents at a par- uses in the detection and diagnosis of diferent types of ticular site. Teir formation involves self-assembly where diseases [45, 47]. in well-defned structures or patterns spontaneously are Lee et al. [48] encapsulated oleic acid-coated FeO nan- formed from building blocks [41]. Additionally they need oparticles in oleic acid-conjugated chitosan (oleyl-chi- to overcome barriers like opsonization/sequestration by tosan) to examine the accretion of these nanoparticles in the mononuclear phagocyte system [42]. tumor cells through the penetrability and holding (EPR) Tere are two ways through which nanostructures consequence under the in vivo state for analytical uses by deliver drugs: passive and self-delivery. In the former, the near-infrared and magnetic resonance imaging (MRI) drugs are incorporated in the inner cavity of the struc- mechanisms. By the in vivo evaluations, both techniques ture mainly via the hydrophobic efect. When the nano- showed noticeable signal strength and improvement in structure materials are targeted to a particular sites, the tumor tissues through a higher EPR consequence the intended amount of the drug is released because of after the injection of cyanine-5-attached oleyl-chitosan the low content of the drugs which is encapsulated in a nanoparticles intravenously (Cyanine 5). hydrophobic environment [41]. Conversely, in the latter, Yang et al. [49] prepared highly efective nanoparti- the drugs intended for release are directly conjugated to cles for revealing colorectal cancer (CC) cells via a light- the carrier nanostructure material for easy delivery. In mediated mechanism; these cells are visible owing to the this approach, the timing of release is crucial as the drug physical conjugation of alginate with folic acid-modifed will not reach the target site and it dissociates from the chitosan leading to the formation of nanoparticles with carrier very quickly, and conversely, its bioactivity and enhanced 5-aminolevulinic (5-ALA) release in the cell efcacy will be decreased if it is released from its nano- lysosome. Te results displayed that the engineered nan- carrier system at the right time [41]. Targeting of drugs oparticles were voluntarily endocytosed by the CC cells is another signifcant aspect that uses nanomaterials by the folate receptor-based endocytosis process. Subse- or nanoformulations as the drug delivery systems and, quently, the charged 5-ALA was dispersed into the lyso- is classifed into active and passive. In active targeting, some which was triggered by less desirability strength moieties, such as antibodies and peptides are coupled between the 5-ALA and chitosan through deprotonated Patra et al. J Nanobiotechnol (2018) 16:71 Page 5 of 33

alginate that gave rise to the gathering of protoporphy- therapeutic potential of P-HA-NP was then investigated rin IX (PpIX) for photodynamic detection within the in diferent systems of the mice colon cancer. Trough cells. As per this research, chitosan-based nanoparticles the intravenous injection of the fuorescent dye attached in combination with alginate and folic acid are tremen- nanoparticles (Cy 5.5-P-HA-NPs), minute and initial- dous vectors for the defnite delivery of 5-ALA to the CC stage tumors as well as liver-embedded colon tumors cells to enable endoscopic fuorescent detection. Cath- were efciently pictured using an NIRF imaging method. epsin B (CB) is strongly associated with the metastatic Due to their extraordinary capability to target tumors, process and is available in surplus in the pericellular drug-containing nanoparticles (IRT-P-HA-NP) showed areas where this process occurs; thus, CB is important markedly decreased tumor development with decreased for the detection of metastasis. Ryu et al. [50] designed systemic harmfulness. In addition, healing efects could a CB-sensitive nanoprobe (CB-CNP) comprising a self- be examined concurrently with Cy 5.5-P-HA-NPs [57]. satisfed CB-CNP with a fuorogenic peptide attached to Another option that can be used is alginate, which is the tumor-targeting glycol chitosan nanoparticles (CNPs) a natural polymer derived from the brown seaweed and on its surface. Te designed nanoprobe is a sphere with has been expansively scrutinized for its potential uses in a diameter of 280 nm, with spherical structure and its the biomedical feld because of its several favorable char- fuorescence capacity was completely extinguished under acteristics, such as low cost of manufacture, harmonious the biological condition. Te evaluation of the usability nature, less harmfulness, and easy gelling in response to of CB-sensitive nanoprobe in three rat metastatic models the addition of divalent cations [58, 59]. Baghbani et al. demonstrated the potential of these nonoprobes in dis- [60] prepared perfuorohexane (PFH) nanodroplets stabi- criminating metastatic cells from healthy ones through lized with alginate to drive doxorubicin and then evalu- non-invasive imaging. Hyaluronic acid (HA) is another ated their sensitivity to ultrasound and imaging as well biopolymeric material. Tis is a biocompatible, nega- as their therapeutic properties. Further found that the tively charged glycosaminoglycan, and is one of the main ultrasound-facilitated treatment with PFH nanodroplets constituents of the extracellular matrix [51, 52]. HA can loaded with doxorubicin exhibited promising positive bind to the CD44 receptor, which is mostly over articu- responses in the breast cancer rat models. Te efcacy lated in various cancerous cells, through the receptor- was characterized by the deterioration of the tumor [60]. linker interaction. Tus, HA-modifed nanoparticles are In another study, Podgorna et al. [61] prepared gadolin- intriguing for their use in the detection and cure of can- ium (GdNG) containing nanogels for hydrophilic drug cer [53–55]. Wang et al. [56], coated the surface of iron loading and to enable screening by MRI. Te gadolinium oxide nanoparticles (IONP) with dopamine-modifed alginate nanogels had an average diameter of 110 nm HA. Tese nanoparticles have a hydrophilic exterior with stability duration of 60 days. Because of their para- and a hydrophobic interior where the chemotherapeutic magnetic behavior, the gadolinium mixtures are normally homocamptothecin is encapsulated [56]. Te biopoten- used as positive contrast agents (T1) in the MRI images. tial of this process was investigated in both laboratory Gadolinium nanogels signifcantly reduce the relaxa- and in the live cells. Increased uptake of nanoparticles tion time (T1) compared to controls. Terefore, alginate by tumor cells was observed by MRI when an external nanogels act as contrast-enhancing agents and can be magnetic feld was employed [56]. After the intravenous assumed as an appropriate material for pharmacological administration of the nano-vehicle in 3 mg/kg (relative to application. the free drug) rats, a large tumor ablation was observed Also, the polymeric material dextran is a neutral poly- and after treatment, the tumors almost disappeared [56]. mer and is assumed as the frst notable example of micro- Choi et al. [53] also synthesized nanoparticles of hya- bial exopolysaccharides used in medical applications. luronic acid with diferent diameters by changing the A remarkable advantage of using dextran is that it is degree of hydrophobic replacement of HA. Te nano- well-tolerated, non-toxic, and biodegradable in humans, particles were systemically administered in the mice with no reactions in the body [62]. Photodynamic ther- with tumor, and then, its efect was studied. Tis same apy is a site-specifc cancer cure with less damage to research group developed a versatile thermostatic sys- non-cancerous cells. Ding et al. [63] prepared a nano- tem using poly (ethylene glycol) conjugated hyaluronic particulate multifunctional composite system by encap- acid (P-HA-NPs) nanoparticles for the early detection of sulating ­Fe3O4 nanoparticles in dextran nanoparticles colon cancer and targeted therapy. To assess the efec- conjugated to redox-responsive chlorine 6 (C6) for near tiveness of the nanoparticles, they were frst attached infrared (NIR) and magnetic resonance (MR) imaging. to the near-infrared fuorescent dye (Cy 5.5) by chemi- Te nanoparticles exhibited an “of/on” behavior of the cal conjugation, and then, the irinotecan anticancer redox cellular response of the fuorescence signal, thus drug (IRT) was encapsulated within these systems. Te resulting in accurate imaging of the tumor. In addition, Patra et al. J Nanobiotechnol (2018) 16:71 Page 6 of 33

excellent in vitro and in vivo magnetic targeting ability addition, Pelaz et al. [71] provided an up-to-date over- was observed, contributing to the efcacy of enhanced view of several applications of nanocarriers to nanomedi- photodynamic therapy. Hong et al. [64] prepared thera- cine and discussed new opportunities and challenges for nostic nanoparticles or glioma cells of C6 mice. Tese this sector. particles comprised of gadolinium oxide nanoparticles Interestingly, each of these drug delivery systems has coated with folic acid-conjugated dextran (FA) or pacli- its own chemical, physical and morphological character- taxel (PTX). Te bioprotective efects of dextran coating istics, and may have afnity for diferent drugs polarities and the chemotherapeutic efect of PTX on the C6 gli- through chemical interactions (e.g., covalent bonds and oma cells were evaluated by the MTT assay. Te synthe- hydrogen bonds) or physical interactions (e.g., electro- sized nanoparticles have been shown to enter C6 tumor static and van der Waals interactions). As an example, cells by receptor-mediated endocytosis and provide Mattos et al. [72] demonstrated that, the release profle enhanced contrast (MR) concentration-dependent activ- of neem bark extract-grafted biogenic silica nanoparti- ity due to the paramagnetic property of the gadolinium cles (chemical interactions) was lower than neem bark nanoparticle. Multifunctional nanoparticles were more extract-loaded biogenic silica nanoparticles. Hence, all efective in reducing cell viability than uncoated gado- these factors infuence the interaction of nanocarriers linium nanoparticles. Terefore, FA and PTX conjugated with biological systems [73], as well as the release kinetics nanoparticles can be used as theranostic agents with par- of the active ingredient in the organism [68]. In addition, amagnetic and chemotherapeutic properties. Sethi et al. [74] designed a crosslinkable lipid shell (CLS) containing docetaxel and wortmannin as the prototypi- Drug designing and drug delivery process cal drugs used for controlling the drug discharge kinetics; and mechanism then, they studied, its discharge profle, which was found With the progression of nanomedicine and, due to the to be afected in both in vivo and in vitro conditions. advancement of drug discovery/design and drug deliv- Apart from this, other parameters, such as the compo- ery systems, numerous therapeutic procedures have been sition of the nanocarriers (e.g., organic, inorganic, and proposed and traditional clinical diagnostic methods hybrid materials) and the form in which drugs are associ- have been studied, to increase the drug specifcity and ated with them (such as core–shell system or matrix sys- diagnostic accuracy. For instance, new routes of drug tem) are also fundamental for understanding their drug administration are being explored, and there is focus on delivery profle [75, 76]. Taken together, several studies ensuring their targeted action in specifc regions, thus regarding release mechanisms of drugs in nanocarriers reducing their toxicity and increasing their bioavailability have been conducted. Difusion, solvent, chemical reac- in the organism [65]. tion, and stimuli-controlled release are a few mechanisms In this context, drug designing has been a promising that can represent the release of drugs in nanocarriers feature that characterizes the discovery of novel lead as shown in Fig. 2 [77, 78]. Kamaly et al. [79] provided drugs based on the knowledge of a biological target. Te a widespread review of controlled-release systems with a advancements in computer sciences, and the progression focus on studies related to controlling drug release from of experimental procedures for the categorization and polymeric nanocarriers. purifcation of proteins, peptides, and biological targets Although there are several nanocarriers with diferent are essential for the growth and development of this sec- drug release profles, strategies are currently being for- tor [66, 67]. In addition, several studies and reviews have mulated to improve the specifcity of the nanostructures been found in this area; they focus on the rational design to target regions of the organism [80], and to reduce the of diferent molecules and show the importance of study- immunogenicity through their coating or chemical func- ing diferent mechanisms of drug release [68]. Moreover, tionalization with several substances, such as polymers natural products can provide feasible and interesting [81], natural polysaccharides [82, 83], antibodies [84], solutions to address the drug design challenges, and can cell-membrane [85], and tunable surfactants [86], pep- serve as an inspiration for drug discovery with desired tides [87], etc. In some cases where drugs do not display physicochemical properties [3, 69, 70]. binding and afnity with a specifc target or do not cross Also, the drug delivery systems have been gaining certain barriers (e.g. blood–brain barrier or the blood– importance in the last few years. Such systems can be cerebrospinal fuid barrier) [88], these ligand-modifed easily developed and are capable of promoting the modi- nanocarriers have been used to pass through the cell fed release of the active ingredients in the body. For membrane and allow a programmed drug delivery in a example, Chen et al. [70] described an interesting review particular environment. For example, hyaluronic acid using nanocarriers for imaging and sensory applications (a polysaccharide found in the extracellular matrix) has and discussed the, therapy efect of these systems. In been used as a ligand-appended in several nanocarriers, Patra et al. J Nanobiotechnol (2018) 16:71 Page 7 of 33

Fig. 2 Mechanisms for controlled release of drugs using diferent types of nanocarriers

showing promising results to boost antitumor action [93, 94], meanwhile due some particular physicochemi- against the melanoma stem-like cells [89], breast cancer cal characteristics of each delivery systems have been cells [90], pulmonary adenocarcinoma cells [91], as well difcult to standardize the mechanism of action/inter- as to facilitate intravitreal drug delivery for retinal gene action of these systems in the cells. For example, Salatin therapy [83] and to reduce the immunogenicity of the and Khosroushahi [95], in a review highlighted the main formed protein corona [82]. However, the construction of endocytosis mechanisms responsible for the cellular the ligand-appended drug delivery systems is labor-inten- uptake of polysaccharide nanoparticles containing active sive, and several targeting designs must be performed compounds. previously, taking into account the physiological variables On the other hand, stimuli-responsive nanocarriers of blood fow, disease status, and tissue architecture [92]. have shown the ability to control the release profle of Moreover, few studies have been performed to evaluate drugs (as a triggered release) using external factors such the interaction of the ligand-appended in nanocarriers as ultrasound [96], heat [97–99], magnetism [100, 101], with cell membranes, and also their uptake mechanism light [102], pH [103], and ionic strength [104], which is still unclear. Furthermore, has been known that the can improve the targeting and allow greater dosage con- uptake of the nanoparticles by the cells occurs via phago- trol (Fig. 2). For example, superparamagnetic iron oxide cytic or non-phagocytic pathways (e.x. clathrin-mediated nanoparticles are associated with polymeric nanocarri- endocytosis, caveolae-mediated endocytosis, and others) ers [105] or lipids [106] to initially stimulate a controlled Patra et al. J Nanobiotechnol (2018) 16:71 Page 8 of 33

release system by the application of external magnetic administration of drugs into the oral cavity. Te biocom- feld. In addition, Ulbrich et al. [107] revised recent patibility of the formulations was estimated based on the achievements of drug delivery systems, in particular, on solubility of the nanoparticles in a salivary environment the basis of polymeric and magnetic nanoparticles, and and its cytotoxicity potential was estimated in an oral also addressed the efect of covalently or noncovalently cell line. Alginate nanoparticles were the most unwaver- attached drugs for cancer cure [107]. Moreover, Au/ ing in the artifcial saliva for at least 2 h, whereas pec- Fe3O4@polymer nanoparticles have also been synthe- tin and especially chitosan nanoparticles were unstable. sized for the use in NIR-triggered chemo-photothermal However, the chitosan nanoparticles were the most cyto- therapy [108]. Terefore, hybrid nanocarriers are cur- competitive, whereas alginate and pectin nanoparticles rently among the most promising tools for nanomedi- showed cytotoxicity under all tested conditions (concen- cine as they present a mixture of properties of diferent tration and time). Te presence of Zn­ 2+ (cross-linking systems in a single system, thus ensuring materials with agent) may be the cause of the observed cytotoxicity. enhanced performance for both therapeutic and diagnos- Each formulation presented advantage and limitations tic applications (i.e., theranostic systems). Despite this, for release into the oral cavity, thus necessitating their little is known about the real mechanisms of action and further refnement. toxicity of drug delivery systems, which open opportu- In addition, Liu et al. [116] prepared nanoparticles of nity for new studies. In addition, studies focusing on the carboxymethyl chitosan for the release of intra-nasal synthesis of nanocarriers based on environmentally safe carbamazepine (CBZ) to bypass the blood–brain barrier chemical reactions by implementing plant extracts and membrane, thus increasing the amount of the medication microorganisms have increased [10]. in the brain and refning the treatment efcacy, thereby reducing the systemic drug exposure. Te nanoparticles Nanoparticles used in drug delivery system had a mean diameter of 218.76 ± 2.41 nm, encapsulation Biopolymeric nanoparticles efciency of 80% and drug loading of 35%. Concentra- Tere are numerous biopolymeric materials that are uti- tions of CBZ remained higher (P < 0.05) in the brain than lized in the drug delivery systems. Tese materials and the plasma over 240 min. their properties are discussed below. In another example, Jain and Jain [117] investigated the discharge profle of 5-fuorouracil (5-FU) from hyaluronic Chitosan Chitosan exhibits muco-adhesive properties acid-coated chitosan nanoparticles into the gut, via oral and can be used to act in the tight epithelial junctions. administration. Release assays in conditions mimicking Tus, chitosan-based nanomaterials are widely used for the transit from the stomach to the colon indicated the continued drug release systems for various types of epi- release profle of 5-FU which was protected against dis- thelia, including buccal [109], intestinal [110], nasal [111], charge in the stomach and small intestine. Also, the high eye [112] and pulmonary [113]. Silva et al. [114] prepared local concentration of drugs would be able to increase the and evaluated the efcacy of a 0.75% w/w isotonic solu- exposure time and thus, enhance the capacity for anti- tion of hydroxypropyl methylcellulose (HPMC) contain- tumor efcacy and decrease the systemic toxicity in the ing chitosan/sodium tripolyphosphate/hyaluronic acid treatment of colon cancer. nanoparticles to deliver the antibiotic ceftazidime to the eye. Te rheological synergism parameter was calculated Alginate Another biopolymeric material that has been by calculating the viscosity of the nanoparticles in contact used as a drug delivery is alginate. Tis biopolymer pre- with mucin in diferent mass proportions. A minimum sents fnal carboxyl groups, being classifed as anionic viscosity was observed when chitosan nanoparticles were mucoadhesive polymer and presents greater mucoadhe- placed in contact with mucin. However, the nanoparticles sive strength when compared with cationic and neutral presented mucoadhesion which resulted in good interac- polymers [59, 118]. Patil and Devarajan [119] developed tion with the ocular mucosa and prolonged release of the insulin-containing alginate nanoparticles with nicotina- antibiotic, and therefore, the nanoparticles can enhance mide as a permeation agent in order to lower the serum the life span of the drug in the eyes. Te nanoparticles did glucose levels and raise serum insulin levels in diabetic not show cytotoxicity for two cell lines tested (ARPE-19 rats. Nanoparticles administered sublingually (5 IU/kg) and HEK 239T). Te nanoparticles were also able to pre- in the presence of nicotinamide showed high availability serve the antibacterial activity, thus making them a prom- pharmacology (> 100%) and bioavailability (> 80%). Te ising formulations for the administration of ocular drugs fact that NPs are promising carriers of insulin via the sub- with improved mucoadhesive properties. lingual route have been proved in case of the streptozo- Pistone et al. [115] prepared nanoparticles of chi- tocin-induced diabetic mouse model by achieving a phar- tosan, alginate and pectin as potential candidates for the macological high potential of 20.2% and bio-availability of Patra et al. J Nanobiotechnol (2018) 16:71 Page 9 of 33

24.1% compared to the subcutaneous injection at 1 IU/kg release tannin in the buccal mucosa to treat sialorrhea. [119]. Tiolation of xanthan gum resulted in increased adhe- Also, Haque et al. [120] prepared alginate nanoparticles sion on the buccal mucosa when compared to native xan- to release venlafaxine (VLF) via intranasal for treatment than gum. In addition, xanthan gum thiolate has a higher of depression. Te higher blood/brain ratios of the VLF uptake of saliva whereas tannic acid ad-string and dry the concentration to the alginate nanoparticles administered oral mucosa. In this way, this system would be an efcient intra-nasally when compared to the intranasal VLF and way of reducing the salivary fow of patients with sialor- VLF solution intravenously indicated the superiority of rhea. Angiogenesis is an important feature in regenera- the nano-formulation in directly transporting the VLF tion of soft tissues. to the brain. In this way, these nanoparticles are prom- Huang et al. [126] prepared injectable hydrogels com- ising for the treatment of depression. In another exam- posed of aldehyde-modifed xanthan and carboxyme- ple, Román et al. [121] prepared alginate microcapsules thyl-modifed chitosan containing potent angiogenic containing epidermal growth factor bound on its exte- factor (antivascular endothelial growth factor, VEGF) rior part to target the non-small cell lung cancer cells. to improve abdominal wall reconstruction. Te hydro- Cisplatin (carcinogen drug) was also loaded in the nan- gel presented release properties mainly in tissues like oparticles. Te addition of EGF signifcantly increased digestive tract and open wounds. Te hydrogel contain- specifcity of carrier systems and presented kinetics of ing VEGF was able to accelerate the angiogenesis pro- cell death (H460-lung cancer strain) faster than the free cess and rebuild the abdominal wall. Menzel et al. [127] drug. studied a new excipient aiming the use as nasal release In addition, Garrait et al. [122] prepared nanopar- system. Xanthan gum was used as a major polymer in ticles of chitosan containing Amaranth red (AR) and which the-((2-amino-2-carboxyethyl) disulfanyl) nico- subsequently microencapsulated these nanoparticles in tinic acid (Cys-MNA) was coupled. Characteristics, alginate microparticles and studied the release kinetics of such as amount of the associated binder, mucoadhe- this new system in simulated gastric and intestinal fuids. sive properties and stability against degradation, were Te microparticles had a mean diameter of 285 μm with analyzed in the resulting conjugate. Each gram of poly- a homogeneous distribution; it was observed that there mer was ligated with 252.52 ± 20.54 μmol of the binder. was a release of less than 5% of the AR contained in the Te muco-adhesion of the grafted polymer was 1.7 fold systems in the gastric pH conditions, whereas the dis- greater than that of thiolated xanthan and 2.5 fold greater charge was fast and comprehensive in the intestinal pH than, that of native xanthan. In addition, the frequency of conditions. Tus, the carrier showed promise to protect ciliary beating of nasal epithelial cells was poorly afected molecules for intestinal release after oral administration. and was reversible only upon the removal of the polymer Costa et al. [123] prepared chitosan-coated alginate from the mucosa. nanoparticles to enhance the permeation of daptomycin into the ocular epithelium aiming for an antibacterial Cellulose Cellulose and its derivatives are extensively efect. In vitro permeability was assessed using ocular utilized in the drug delivery systems basically for modi- epithelial cell culture models. Te antimicrobial activ- fcation of the solubility and gelation of the drugs that ity of nanoencapsulated daptomycin showed potential resulted in the control of the release profle of the same over the pathogens engaged in bacterial endophthalmitis. [128]. Elseoud et al. [129] investigated the utilization of Also, the ocular permeability studies demonstrated that cellulose nanocrystals and chitosan nanoparticles for with 4 h of treatment from 9 to 12% in total of daptomy- the oral releasing of repaglinide (an anti-hyperglyce- cin encapsulated in chitosan/alginate nanoparticles, these mic—RPG). Te chitosan nanoparticles showed a mean were able to cross the HCE and ARPE-19 cells. Tese size distribution of 197 nm while the hybrid nanoparti- results indicated that with this system an increasing in cles of chitosan and cellulose nanocrystals containing the drug retention in the ocular epithelium has occurred. RPG. Chitosan hybrid nanoparticles and oxidized cellu- lose nanocrystals containing RPG had a mean diameter Xanthan gum Xanthan gum (XG) is a high molecular of 251–310 nm. Te presence of the hydrogen bonds weight heteropolysaccharide produced by Xanthomonas between the cellulose nanocrystals and the drug, resulted campestris. It is a polyanionic polysaccharide and has in sustained release of the same, and subsequently the good bioadhesive properties. Because it is considered nanoparticles made with oxidized cellulose nanocrystals non-toxic and non-irritating, xanthan gum is widely used presented lower release when compared to the nanoparti- as a pharmaceutical excipient [124]. cles produced with native cellulose nanocrystals. Lafeur and Michalek [125] have prepared a carrier Agarwal et al. [130] have developed a drug target- composed of xanthan gum thiolated with l-cysteine to ing mechanism which is based on the conjugation of Patra et al. J Nanobiotechnol (2018) 16:71 Page 10 of 33

calcium alginate beads with carboxymethylcellulose generally consists of a nanoparticle along with a targeting, (CMC) loaded 5-fuoroacyl (5-FU) and is targeted to the imaging and a therapeutic element [133]. colon. Te beads with lower CMC proportions presented Te typical synthesis procedure for liposomes are as greater swelling and muco-adhesiveness in the simu- follows, thin layer hydration, mechanical agitation, sol- lated colonic environment. With existence of colonic vent evaporation, solvent injection and the surfactant sol- enzymes there was a 90% release of 5-FU encapsulated ubilization [134]. One aspect to point out on liposomes is in the beads. Hansen et al. [131] investigated four cellu- that the drugs that are trapped within them are not bio- lose derivatives, including, meteylcellulose, hydroxypro- available until they are released. Terefore, their accu- pyl methylcellulose, sodium carboxymethylcellulose and mulation in particular sites is very important to increase cationic hydroxyethyl cellulose for application in drug drug bioavailability within the therapeutic window at release into the nasal mucosa. Te association of these the right rates and times. Drug loading in liposomes is cellulose derivatives with an additional excipient, was attained by active (drug encapsulated after liposome for- also evaluated. Te drug model employed in this process mation) and passive (drug encapsulated during liposome was acyclovir. Te viability of the polymers as excipients formation) approaches [135]. Hydrophilic drugs such for nasal release applications was also scrutinized for its as ampicillin and, 5-fuoro-deoxyuridine are typically ciliary beat frequency (CBF) and its infusion through the confned in the aqueous core of the liposome and thus, tissue system of the nostril cavity. An increase in ther- their encapsulation does not depend on any modifcation mally induced viscosity was observed when the cellulose in the drug/lipid ratio. However, the hydrophobic ones derivatives were mixed with polymer graft copolymer. such as Amphotericin B, Indomethacin were found in the Further an increased permeation of acyclovir into the acyl hydrocarbon chain of the liposome and thus their nasal mucosa was detected when it was combined with engulfng are subjected to the characteristics of the acyl cationic hydroxyethylcellulose. None of the cellulose chain [136]. Among the passive loading approaches the derivatives caused negative efects on tissues and cells of mechanical and the solvent dispersion method as well as the nasal mucosa, as assessed by CBF. the detergent removal method can be mentioned [135]. Tere are obstacles with the use of liposomes for drug Liposomes Tey were discovered by Alec Bangham delivery purposes in the form of the RES (reticuloen- in 1960. Liposomes are used in the pharmaceutical and dothelial system), opsonization and immunogenicity cosmetics industry for the transportation of diverse mol- although there are factors like enhanced permeability ecules and are among the most studied carrier system for and EPR (retention efect) that can be utilized in order drug delivery. Liposomes are an engrained formulation to boost the drug delivery efciency of the liposomes strategy to improve the drug delivery. Tey are vesicles [133, 135]. Once liposomes get into the body, they run of spherical form composed of phospholipids and ster- into opsonins and high density lipoproteins (HDLs) and oids usually in the 50–450 nm size range [132]. Tese are low density lipoproteins (LDLs) while circulating in the considered as a better drug delivery vehicles since their bloodstream by themselves. Opsonins (immunoglobu- membrane structure is analogous to the cell membranes lins and fbronectin, for example) assist RES on recog- and because they facilitate incorporation of drugs in them nizing and eliminating liposomes. HDLs and LDLs have [132]. It has also been proved that they make therapeu- interactions with liposomes and decrease their stability. tic compounds stable, improve their biodistribution, can Liposomes tends to gather more in the sites like the liver be used with hydrophilic and hydrophobic drugs and are and the spleen, this is an advantage because then a high also biocompatible and biodegradable. Liposomes are concentration of liposomes can help treat pathogenic dis- divided into four types: (1) conventional type liposomes: eases, although in the case of cancers this can lead to a these consists of a lipid bilayer which can make either ani- delay in the removal of lipophilic anticancer drugs. Tis onic, cationic, or neutral cholesterol and phospholipids, is the reason why as mentioned at the beginning, difer- which surrounds an aqueous core material. In this case, ent types of liposomes have been developed, in this case both the lipid bilayer and the aqueous space can be flled PEGylated ones. Dimov et al. [137] reported an incessant with hydrophobic or hydrophilic materials, respectively. procedure of fow system for the synthesis, functionali- (2) PEGylated types: polyethylene glycol (PEG) is incor- zation and cleansing of liposomes. Tis research consists porated to the surface of liposome to achieve steric equi- of vesicles under 300 nm in a lab-on-chip that are use- librium, (3) ligand-targeted type: ligands like antibodies, ful and potential candidates for cost-intensive drugs or carbohydrates and peptides, are linked to the surface of protein encapsulation development [137]. Tis is very the liposome or to the end of previously attached PEG important because costs of production also determine chains and (4) theranostic liposome type: it is an amalga- whether or not a specifc drug can be commercialized. mation kind of the previous three types of liposomes and Patra et al. J Nanobiotechnol (2018) 16:71 Page 11 of 33

Liposome-based systems have now been permitted by known as the critical micelle concentration (CMC) is the FDA [133, 135, 138–140]. reached by the amphiphilic molecules [143]. At lower concentrations, the amphiphilic molecules are indeed Polymeric micelles Polymeric micelles are nanostruc- small and occur independently [143]. Drugs are loaded tures made of amphiphilic block copolymers that gather within polymeric micelles by three common methodolo- by itself to form a core shell structure in the aqueous solu- gies such as direct dissolution process, solvent evapora- tion. Te hydrophobic core can be loaded with hydropho- tion process, and the dialysis process. As of the direct bic drugs (e.g. camptothecin, docetaxel, paclitaxel), at the dissolution process, the copolymer and the drugs com- same time the hydrophilic shell makes the whole system bine with each other by themselves in the water medium soluble in water and stabilizes the core. Polymeric micelles and forms a drug loaded with the micelles. While in are under 100 nm in size and normally have a narrow dis- the solvent evaporation process, the copolymer and the tribution to avoid fast renal excretion, thus permitting intended drug is dissolved using a volatile organic solvent their accumulation in tumor tissues through the EPR and fnally, in case of the dialysis process, both the drug efect. In addition, their polymeric shell restrains non- in solution and the copolymer in the organic solvent are specifc interactions with biological components. Tese combined in the dialysis bag and then dialyzed with the nanostructures have a strong prospective for hydropho- formation of the micelle [145]. bic drug delivery since their interior core structure per- Te targeting of the drugs using diferent polymeric mits the assimilation of these kind of drugs resulting in micelles as established by various mechanism of action enhancement of stability and bioavailability [141, 142]. including the boosted penetrability and the holding Polymeric micelles are synthesized by two approaches: efect stimuli; complexing of a defnite aiming ligand (1) convenient solvent-based direct dissolution of poly- molecule to the surface of the micelle; or by combina- mer followed by dialysis process or (2) precipitation tion of the monoclonal antibodies to the micelle corona of one block by adding a solvent [142, 143]. Te factors [146]. Polymeric micelles are reported to be applicable like, hydrophobic chain size in the amphiphilic molecule, for both drug delivery against cancer [143] and also for amphiphiles concentration, solvent system and tem- ocular drug delivery [147] as shown in Fig. 3 in which a perature, afects the micelle formation [144]. Te micelle polymeric micelle is used for reaching the posterior ocu- assembly creation starts when minimum concentration lar tissues [147]. In the work by Li et al. [148], dasatinib

Fig. 3 Polymeric micelles used for reaching the posterior ocular tissues via the transcleral pathway after topical application (the fgure is reproduced from Mandal et al. [147] with required copyright permission) Patra et al. J Nanobiotechnol (2018) 16:71 Page 12 of 33

was encapsulated within nanoparticles prepared from polypropylene imine dendrimers (FA-PPI) as a metho- micellation of PEG-b-PC, to treat proliferative vitreo- trexate (MTX) nanocarrier, for pH-sensitive drug release, retinopathy (PVR), their size was 55 nm with a narrow selective targeting to cancer cells, and anticancer treat- distribution and they turned out to be noncytotoxic to ment. Te in vitro studies on them showed sustained ARPE-19 cells. Tis micellar formulation ominously release, increased cell uptake and low cytotoxicity on repressed the cell proliferation, attachment and reloca- MCF-7 cell lines [157]. Further, it has to be pointed out tion in comparison to the free drugs [148]. Te polymeric that the developed formulations, methotrexate (MTX)- micelles is habitually get into the rear eye tissues through loaded and folic acid-conjugated 5.0G PPI (MTX-FA- the transcleral pathway after relevant applications (Fig. 3; PPI), were selectively taken up by the tumor cells in [147]). comparison with the free drug, methotrexate (MTX).

Dendrimers Dendrimers are highly bifurcated, mono- Inorganic nanoparticles Inorganic nanoparticles disperse, well-defned and three-dimensional structures. include silver, gold, iron oxide and silica nanoparticles Tey are globular-shaped and their surface is function- are included. Studies focused on them are not as many alized easily in a controlled way, which makes these as there are on other nanoparticle types discussed in structures excellent candidates as drug delivery agents this section although they show some potential applica- [149–151]. Dendrimers can be synthesized by means of tions. However, only few of the nanoparticles have been two approaches: Te frst one is the diferent route in accepted for its clinical use, whereas the majority of them which the dendrimer starts formation from its core and are still in the clinical trial stage. Metal nanoparticles, sil- then it is extended outwards and the second is the conver- ver and gold, have particular properties like SPR (surface gent one, starts from the outside of the dendrimer [152]. plasmon resonance), that liposomes, dendrimers, micelles Dendrimers are grouped into several kinds according to do not possess. Tey showed several advantages such as their functionalization moieties: PAMAM, PPI, liquid good biocompatibility and versatility when it comes to crystalline, core–shell, chiral, peptide, glycodendrimers surface functionalization. and PAMAMOS, being PAMAM, the most studied for Studies on their drug delivery-related activity have not oral drug delivery because it is water soluble and it can been able to clear out whether the particulate or ionized pass through the epithelial tissue boosting their transfer form is actually related to their toxicity, and even though via the paracellular pathway [153]. Dendrimers are lim- two mechanisms have been proposed, namely paracel- ited in their clinical applications because of the presence lular transport and transcytosis, there is not enough of amine groups. Tese groups are positively charged or information about their in vivo transport and uptake cationic which makes them toxic, hence dendrimers are mechanism [158]. Drugs can be conjugated to gold nan- usually modifed in order to reduce this toxicity issue or to oparticles (AuNPs) surfaces via ionic or covalent bond- eliminate it. Drug loading in dendrimers is performed via ing and physical absorption and they can deliver them the following mechanisms: Simple encapsulation, electro- and control their release through biological stimuli or static interaction and covalent conjugation [154]. light activation [159]. Silver nanoparticles exhibited Drug is basically delivered by the dendrimers follow- antimicrobial activity, but as for drug delivery, very few ing two diferent paths, a) by the in vivo degradation of studies have been carried out, for example, Prusty and drug dendrimer’s covalent bonding on the basis of avail- Swain [160] synthesized an inter-linked and spongy poly- ability of suitable enzymes or favorable environment that acrylamide/dextran nano-hydrogels hybrid system with could cleave the bonds and b) by discharge of the drug covalently attached silver nanoparticles for the release of due to changes in the physical environment like pH, tem- ornidazole which turned out to have an in vitro release perature etc., [154]. Dendrimers have been developed of 98.5% [160]. Similarly in another study, the iron oxide for transdermal, oral, ocular, pulmonary and in targeted nanoparticles were synthesized using laser pyrolysis drug delivery [155]. method and were covered with Violamycine B1, and Jain et al. [156] have described the folate attached antracyclinic antibiotics and tested against the MCF-7 poly-l-lysine dendrimers (doxorubicin hydrochloride) cells for its cytotoxicity and the anti-proliferation prop- as a capable cancer prevention drug carrier model for erties along with its comparison with the commercially pH dependent drug discharge, target specifcity, antian- available iron oxide nanoparticles [161]. giogenic and anticancer prospective, it was shown that doxorubicin-folate conjugated poly-l-lysine dendrimers Nanocrystals Nanocrystals are pure solid drug particles increased the concentration of doxorubicin in the tumor within 1000 nm range. Tese are 100% drug without any by 121.5-fold after 24 h compared with free doxorubicin. carriers molecule attached to it and are usually stabilized Similarly, (Kaur et al. [157] developed folate-conjugated by using a polymeric steric stabilizers or surfactants. A Patra et al. J Nanobiotechnol (2018) 16:71 Page 13 of 33

nanocrystals suspension in a marginal liquid medium since, unlike conventional organic dyes, the QDs presents is normally alleviated by addition of a surfactant agent emission in the near-infrared region (< 650 nm), a very known as nano-suspension. In this case, the dispersing desirable characteristic in the feld of biomedical images, medium are mostly water or any aqueous or non-aqueous due to the low absorption by the tissues and reduction media including liquid polyethylene glycol and oils [162, in the light scattering [167, 168]. In addition, QDs with 163]. Nanocrystals possesses specifc characters that per- diferent sizes and/or compositions can be excited by the mit them to overcome difculties like increase saturation same light source resulting in separate emission colors solubility, increased dissolution velocity and increased over a wide spectral range [169, 170]. In this sense, QDs glueyness to surface/cell membranes. Te process by are very appealing for multiplex imaging. In the medicine which nanocrystals are synthesized are divided into top- feld QDs has been extensively studied as targeted drug down and bottom-up approaches. Te top-down approach delivery, sensors and bioimaging. A large number of stud- includes, sono-crystallization, precipitation, high gravity ies regarding the applications of QDs as contrast agents controlled precipitation technology, multi-inlet vortex for in vivo imaging is currently available in literature mixing techniques and limited impinging liquid jet precip- [168, 171–173]. Han et al. [172] developed a novel fuo- itation technique [162]. However, use of an organic solvent rophore for intravital cytometric imaging based on QDs- and its removal at the end makes this process quite expen- antibodies conjugates coated with norbornene-displaying sive. Te bottom-up approach involves, grinding proce- polyimidazole ligands. Tis fuorophore was used to label dures along with homogenization at higher pressure [162]. bone marrow cells in vivo. Te authors found that the Among all of the methods, milling, high pressure homog- fuorophore was able to difuse in the entire bone marrow enization, and precipitation are the most used methods and label rare populations of cells, such as hematopoietic for the production of nanocrystals. Te mechanisms by stem and progenitor cells [172]. Shi et al. [171] developed which nanocrystals support the absorption of a drug to the a multifunctional biocompatible graphene oxide quantum system includes, enhancement of solubility, suspension dot covered with luminescent magnetic nanoplatform for rate and capacity to hold intestinal wall frmly [162]. Ni recognize/diagnostic of a specifc liver cancer tumor cells et al. [164] embedded cinaciguat nanocrystals in chitosan (glypican-3-expressing Hep G2). According to the authors microparticles for pulmonary drug delivery of the hydro- the attachment of an anti-GPC3-antibody to the nano- phobic drug. Te nanoparticles were contrived for contin- plataform results in selective separation of Hep G2 hepa- uous release of the drug taking advantage of the swelling tocellular carcinoma cells from infected blood samples and muco-adhesive potential of the polymer. Tey found [171]. QDs could also bring benefts in the sustained and/ that inhalation efcacy might be conceded under the dis- or controlled release of therapeutic molecules. Regard- ease conditions, so more studies are needed to prove that ing the controlled release, this behavior can be achieved this system has more potential [164]. via external stimulation by light, heat, radio frequency or magnetic felds [170, 174, 175]. Olerile et al. [176] have Metallic nanoparticles In recent years, the interest of developed a theranostic system based on co-loaded of using metallic nanoparticles has been growing in diferent QDs and anti-cancer drug in nanostructured lipid carri- medical applications, such as bioimaging, biosensors, tar- ers as a parenteral multifunctional system. Te nanoparti- get/sustained drug delivery, hyperthermia and photoabla- cles were spherical with higher encapsulation efciency of tion therapy [35, 165]. In addition, the modifcation and paclitaxel (80.7 ± 2.11%) and tumor growth inhibition rate functionalization of these nanoparticles with specifc func- of 77.85%. Te authors also found that the system was able tional groups allow them to bind to antibodies, drugs and to specifcally target and detect H22 tumor cells [176]. Cai other ligands, become these making these systems more et al. [177] have synthesized pH responsive quantum dots promising in biomedical applications [166]. Although the based on ZnO quantum dots decorated with PEG and most extensively studied, metallic nanoparticles are gold, hyaluronic acid for become stable in physiological con- silver, iron and copper, a crescent interest has been exploited ditions and for targeting specifc cells with HA-receptor regarding other kinds of metallic nanoparticles, such as, CD44, respectively. Tis nanocarrier was also evaluated zinc oxide, titanium oxide, platinum, selenium, gadolinium, for doxorubicin (DOX) sustained release. Te nanocarrier palladium, cerium dioxide among others [35, 165, 166]. was stable in physiological pH and DOX was loaded in the carrier by forming complex with Zn­ 2+ ions or conju- Quantum dots Quantum dots (QDs) are known as sem- gated to PEG. Te DOX was released only in acidic intra- iconductor nanocrystals with diameter range from 2 to cellular conditions of tumor cells due to the disruption of 10 nm and their optical properties, such as absorbance and ZnO QDs. Te authors found that the anticancer activity photoluminescence are size-dependent [167]. Te QDs was enhanced by the combination of DOX and ZnO QDs has gained great attention in the feld of nanomedicine, [177]. Patra et al. J Nanobiotechnol (2018) 16:71 Page 14 of 33

Protein and polysaccharides nanoparticles Polysaccha- guarantee stability of the polysaccharide chains, guaran- rides and proteins are collectively called as natural biopol- teeing them stability in aqueous environments [182, 183]. ymers and are extracted from biological sources such In Fig. 4, examples of some polysaccharides used in nano- as plants, animals, microorganisms and marine sources medicine obtained from diferent sources are summa- [178, 179]. Protein-based nanoparticles are generally rized. Te success of these biopolymers in nanomedicine decomposable, metabolizable, and are easy to functional- and drug delivery is due to their versatility and specifed ize for its attachment to specifc drugs and other targeting properties such as since they can originate from soft gels, ligands. Tey are normally produced by using two difer- fexible fbers and hard shapes, so they can be porous or ent systems, (a) from water-soluble proteins like bovine non-porous; they have great similarity with components and human serum albumin and (b) from insoluble ones of the extracellular matrix, which may be able to avoid like zein and gliadin [180]. Te usual methods to synthe- immunological reactions [179, 184]. size them are coacervation/desolvation, emulsion/solvent Tere is not much literature related to these kind of extraction, complex coacervation and electrospraying. nanoparticles, however, since they are generated from Te protein based nanoparticles are chemically altered biocompatible compounds they are excellent can- in order to combine targeting ligands that identify exact didates for their further development as drug deliv- cells and tissues to promote and augment their targeting ery systems. Yu et al. [185] synthesized Bovine serum mechanism [180]. Similarly, the polysaccharides are com- albumin and tested its attachment and/or infltration posed of sugar units (monosaccharides) linked through property through the opening of the cochlea and mid- O-glycosidic bonds. Te composition of these monomers dle ear of guinea pigs. Te nanoparticles considered as well as their biological source are able to confer to these as the drug transporters were tested for their loading polysaccharides, a series of specifc physical–chemical capacity and release behaviors that could provide better properties [126, 179, 181]. One of the main drawback of bio-suitability, drug loading capacity, and well-ordered the use of polysaccharides in the nanomedicine feld is its discharge mechanism [185]. degradation (oxidation) characteristics at high tempera- tures (above their melting point) which are often required Natural product‑based nanotechnology and drug in industrial processes. Besides, most of the polysaccha- delivery rides are soluble in water, which limits their application As per the World Health Organization (WHO) report, in in some felds of nanomedicine, such as tissue engineer- developing countries, the basic health needs of approxi- ing [182, 183]. However, techniques such as crosslinking mately 80% of the population are met and/or comple- of the polymer chains have been employed in order to mented by traditional medicine [186]. Currently, the

Fig. 4 Diferent sources of natural biopolymers to be used in nanomedicine applications. Natural biopolymers could be obtained from higher plants, animals, microorganisms and algae Patra et al. J Nanobiotechnol (2018) 16:71 Page 15 of 33

scientifc community is focusing on the studies related to techniques in the medical feld has been extensively the bioactive compounds, its chemical composition and studied in the last few years [193, 194]. Hence these pharmacological potential of various plant species, to can overcome these barriers and allow diferent com- produce innovative active ingredients that present rela- pounds and mixtures to be used in the preparation of tively minor side efects than existing molecules [5, 187]. the same formulation. In addition, they can change the Plants are documented as a huge sources of natural com- properties and behavior of a compound within the bio- pounds of medicinal importance since long time and still logical system [7, 189]. Besides, bringing benefts to it holds ample of resources for the discovery of new and the compound relative to the solubility and stability of highly efective drugs. However, the discovery of active the compounds, release systems direct the compound compounds through natural sources is associated with to the specifc site, increase bioavailability and extend several issues because they originate from living beings compound action, and combine molecules with varying whose metabolite composition changes in the presence degrees of hydrophilicity/lipophilicity [7]. Also, there of stress. In this sense, the pharmaceutical industries is evidence that the association of release systems with have chosen to combine their eforts in the development natural compounds may help to delay the development of synthetic compounds [187–189]. Nevertheless, the of drug resistance and therefore plays an important role number of synthetic molecules that are actually marketed in order to fnd new possibilities for the treatment of are going on decreasing day by day and thus research on several diseases that have low response to treatment the natural product based active compounds are again conventional approaches to modern medicine [7, 189]. coming to the limelight in spite of its hurdles [189, 190]. Te natural product based materials are of two cat- Most of the natural compounds of economic importance egories, (1) which are targeted to specifc location and with medicinal potential that are already being marketed released in the specifc sites to treat a number of dis- have been discovered in higher plants [187, 191]. Sev- eases [43, 195] and (2) which are mostly utilized in eral drugs that also possess natural therapeutic agents the synthesis process [196]. Most of the research is in their composition are already available commercially; intended for treatment against the cancer disease, since their applications and names are as follows: malaria treat- it is the foremost reason of death worldwide nowa- ment ­(Artemotil® derived from Artemisia annua L., a days [197, 198]. In case of the cancer disease, difer- traditional Chinese medicine plant), Alzheimer’s disease ent organs of the body are afected, and therefore the treatment ­(Reminyl®, an acetylcholinesterase inhibi- need for the development of an alternative medicine to tor isolated from the Galanthus woronowii Losinsk), target the cancerous cells is the utmost priority among cancer treatment (Paclitaxel­ ® and its analogues derived the modern researchers, however, a number of applica- from the Taxus brevifolia plant; vinblastine and vincris- tions of nanomedicine to other ailments is also being tine extracted from Catharanthus roseus; camptothecin worked on [199, 200]. Tese delivery systems are cat- and its analogs derived from Camptotheca acuminata egorized in terms of their surface charge, particle size, Decne), liver disease treatment (silymarin from Silybum size dispersion, shape, stability, encapsulation potential marianum) [187]. and biological action which are further utilized as per Te composition and activity of many natural com- their requirements [33]. Some examples of biological pounds have already been studied and established. Te compounds obtained from higher plants and their uses alkaloids, favonoids, tannins, terpenes, saponins, ster- in the nanomedicine feld are described in Fig. 5. Phar- oids, phenolic compounds, among others, are the bio- maceutical industries have continuously sought the active molecules found in plants. However in most of development and application of new technologies for the cases, these compounds have low absorption capac- the advancement and design of modern drugs, as well ity due to the absence of the ability to cross the lipid as the enhancement of existing ones [71, 201]. In this membranes because of its high molecular sizes, and sense, the accelerated development of nanotechnology thus resulting in reduced bioavailability and efcacy has driven the design of new formulations through dif- [192]. Tese molecules also exhibit high systemic clear- ferent approaches, such as, driving the drug to the site ance, necessitating repeated applications and/or high of action (nanopharmaceutics); image and diagnosis doses, making the drug less efective for therapeutic (nanodiagnostic), medical implants (nanobiomaterials) use [189]. Te scientifc development of nanotechnol- and the combination diagnosis and treatment of dis- ogy can revolutionize the development of formulations eases (nanotheranostics) [71, 202, 203]. based on natural products, bringing tools capable of Currently, many of the nanomedicines under devel- solving the problems mentioned above that limits the opment, are modifed release systems for active ingre- application of these compounds in large scale in the dients (AI) that are already employed in the treatment nanomedicine [7, 189]. Utilization of nanotechnology of patients [203, 204]. For this type of approach, it is Patra et al. J Nanobiotechnol (2018) 16:71 Page 16 of 33

Fig. 5 Examples of natural compounds extracted from higher plants used in nanomedicine aiming diferent approaches. Some of these extracts are already being marketed, others are in clinical trials and others are being extensively studied by the scientifc community

evaluated whether the sustained release of these AIs processing of new nano-formulations because they have modifes the pharmacokinetic profle and biodistribution. interesting characteristics, such as being biodegrad- In this context, it can be ascertained that the nano-for- able, biocompatible, availability, being renewable and mulation ofers advantages over the existing formulation presenting low toxicity [178, 179, 213]. In addition to if the AI is directed towards the target tissue shows the aforementioned properties, biomaterials are, for the increased uptake/absorption by the cells and lower tox- most part, capable of undergoing chemical modifcations, icity profle for the organism [205, 206]. Tis section is guaranteeing them unique and desirable properties for focused on berberine, curcumin, ellagic acid, resveratrol, is potential uses in the feld of nanomedicine [45, 214]. curcumin and quercetin [8]. Some other compounds Gold, silver, cadmium sulfde and titanium dioxide of mentioned are doxorubicin, paclitaxel and vancomycin diferent morphological characteristics have been syn- that also come from natural products. thesized using a number of bacteria namely Escherichia Nanoparticles have been synthesized using natural coli, Pseudomonas aeruginosa, Bacillus subtilis and Kleb- products. For example, metallic, metal oxide and sulfdes siella pneumoniae [211]. Tese nanoparticles, especially nanoparticles have been reported to be synthesized using the silver nanoparticles have been abundantly studied various microorganisms including bacteria, fungi, algae, in vitro for their antibacterial, antifungal, and cytotoxic- yeast and so on [207] or plant extracts [208]. For the frst ity potential due to their higher potential among all metal approach, the microorganism that aids the synthesis pro- nanoparticles [215, 216]. In the event of microorganism cedure is prepared in the adequate growth medium and mediated nanoparticle synthesis, maximum research is then mixed with a metal precursor in solution and left focused on the way that microorganisms reduce metal for incubation to form the nanoparticles either intracel- precursors and generate the nanoparticles. For instance, lularly or extracellularly [209–211]. As for the second Rahimi et al. [217] synthesized silver nanoparticles using approach, the plant extract is prepared and mixed after- Candida albicans and studied their antibacterial activity wards with the metal precursor in solution and incubated against two pathogenic bacteria namely Staphylococcus further at room temperature or boiling temperature for a aureus and E. coli. Similarly, Ali et al. [218] synthesized defnite time or exposed to light as an external stimulus silver nanoparticles with the Artemisia absinthium aque- to initiate the synthesis of nanoparticles [212]. ous extract and their antimicrobial activity was assessed Presently, these natural product based materials are versus Phytophthora parasitica and Phytophthora cap- considered as the key ingredients in the preparation and sici [218]. Further, Malapermal et al. [219] used Ocimum Patra et al. J Nanobiotechnol (2018) 16:71 Page 17 of 33

basilicum and Ocimum sanctum extracts to synthesize doxorubicin (DOX) is a hydrolated version of it used in nanoparticles and studied its antimicrobial potential chemotherapy [213]. Spillmann et al. [235] developed a against E. coli, Salmonella spp., S. aureus, and P. aer- multifunctional liquid crystal nanoparticle system for uginosa along with the antidiabetic potential. Likewise, intracellular fuorescent imaging and for the delivery of Sankar et al. [220] also tested the efect of silver nano- doxorubicin in which the nanoparticles were function- particles for both antibacterial and anticancer potential alized with transferrin. Cellular uptake and sustained against human lung cancer cell line. Besides the use of released were attained within endocytic vesicles in HEK microorganism, our group has synthesized silver, gold 293T/17 cells. Perylene was used as a chromophore to and iron oxide nanoparticles using various food waste track the particles and to encapsulate agents aimed for materials such as extracts of Zea mays leaves [221, 222], intracellular delivery [235]. Purama et al. [236] extracted onion peel extract [223], silky hairs of Zea mays [224], dextran from two sucrose based lactic acid bacteria outer peel of fruit of Cucumis melo and Prunus persica namely Streptococcus mutans and Leuconostoc mesen- [225], outer peel of Prunus persica [226] and the rind teroides. Agarwal et al. [237] formulated a dextran-based extract of watermelon [227], etc. and have tested their dendrimer formulation and evaluated its drug discharge potential antibacterial efects against various foodborne capacity and haemolytic activity under in vitro condi- pathogenic bacteria, anticandidal activity against a num- tion. Tey concluded that the dendritic structure selec- ber of pathogenic Candida spp., for their potential anti- tively enters the highly permeable portion of the afected oxidant activity and proteasome inhibitory efects. cells without disturbing the healthy tissues thereby mak- For drug delivery purposes, the most commonly stud- ing more convenient for its application in the biomedi- ied nanocarriers are crystal nanoparticles, liposomes, cal feld [237]. Folate- functionalized superparamagnetic micelles, polymeric nanoparticles, solid lipid nano- iron oxide nanoparticles developed previously for liver particles, superparamagnetic iron oxide nanoparticles cancer cure are also been used for the delivery of Doxil and dendrimers [228–230]. All of these nanocarriers (a form of doxorubicin which was the frst FDA-approved are formulated for natural product based drug delivery. nano-drug in 1995) [238]. Te in vivo studies in rabbits For applications in cancer treatment, Gupta et al. [231] and rats showed a two- and fourfold decrease compared synthesized chitosan based nanoparticles loaded with with Doxil alone while folate aided and enhanced specifc Paclitaxel (Taxol) derived from Taxus brevifolia, and targeting [239]. Liposomes are the nanostructures that utilized them for treatment of diferent kinds of cancer. have been studied the most, and they have been used in Te authors concluded that the nanoparticle loaded drug several formulations for the delivery of natural products exhibited better activity with sustained release, high cell like resveratrol [240]. Curcumin, a polyphenolic com- uptake and reduced hemolytic toxicity compared with pound obtained from turmeric, have been reported to pure Paclitaxel [231]. Berberine is an alkaloid from the be utilized in the cure of cancers including the breast, barberry plant. Chang et al. [232] created a heparin/ber- bone, cervices, liver, lung, and prostate [241]. Liposo- berine conjugate to increase the suppressive Helicobacter mal curcumin formulations have been developed for the pylori growth and at the same time to reduce cytotoxic treatment of cancer [242, 243]. Cheng et al. [244] encap- efects in infected cells [232] which is depicted in Fig. 6. sulated curcumin in liposomes by diferent methods and Aldawsari and Hosny [233] synthesized ellagic acid- compared the outcomes resulting that the one dependent SLNs to encapsulate Vancomycin (a glycopeptide on pH yielded stable products with good encapsulation antibiotic produced in the cultures of Amycolatopsis efciency and bio-accessibility with potential applica- orientalis). Further, its in vivo tests were performed on tions in cancer treatment [244]. rabbits and the results indicated that the ellagic acid pre- Over all, it can be said that the sustained release systems vented the formation of free oxygen radicals and their of naturally occurring therapeutic compounds present clearance radicals, thus preventing damages and promot- themselves as a key tools for improving the biological activ- ing repair [233]. Quercetin is a polyphenol that belongs ity of these compounds as well as minimizing their limita- to the favonoid group, it can be found in citrus fruits and tions by providing new alternatives for the cure of chronic vegetables and it has antioxidant properties. In a study by and terminal diseases [8, 245]. According to BBC Research, Dian et al. [234], polymeric micelles was used to deliver the global market for plant-derived pharmaceuticals will quercetin and the results showed that such micelles could increase from $29.4 billion in 2017 to about $39.6 billion provide continuous release for up to 10 days in vitro, with in 2022 with a compound annual growth rate (CAGR) of continuous plasma level and boosted complete accessibil- 6.15% in this period (BCC-RESEARCH). Some of nano- ity of the drug under in vivo condition [234]. structure-based materials covered in this section have Daunorubicin is a natural product derived from a already been approved by the FDA. Bobo et al. [255] has number of diferent wild type strains of Streptomyces, Patra et al. J Nanobiotechnol (2018) 16:71 Page 18 of 33

Fig. 6 a Structure of berberine/heparin based nanoparticles and berberine/heparin/chitosan nanoparticles. b TEM images of the berberine/ heparin nanoparticles and berberine/heparin/chitosan nanoparticles (the fgure is reproduced from Chang et al. [232] with required copyright permission) provided the information on nanotechnology-based prod- According to a recent review by Caster et al. [249], ucts already approved by the FDA (Table 1). although few nanomedicines have been regulated by the FDA there are many initiatives that are currently Regulation and reality: products now in progress in terms of clinical trials suggesting many on the market nanotechnology-based new drugs will soon be able to In the current medical nanotechnology scenario, there reach the market. Among these nanomaterials that are in are 51 products based on this technology [204, 246–248] phase of study, 18 are directed to chemotherapeutics; 15 which are currently being applied in clinical practice are intended for antimicrobial agents; 28 are for diferent (Table 2). Notably, such nanomedicines are primarily medical applications and psychological diseases, auto- developed for drugs, which have low aqueous solubility immune conditions and many others and 30 are aimed and high toxicity, and these nanoformulations are often at nucleic acid based therapies [249]. Te list of nano- capable of reducing the toxicity while increasing the medicine approved by FDA classifed by type of carrier/ pharmacokinetic properties of the drug in question. Patra et al. J Nanobiotechnol (2018) 16:71 Page 19 of 33 Year approved Year 2007 2001 2008; 2009; 2013; 2013 1990 2004 2017 2017 2015 2002 2014 2003 2000 2002 2010 1996 1994 2002 - related kidney disease ciency disease (SCID) age episodes and prevention of bleed ‑ episodes and prevention setting for ing in the perioperative haemophilia B patients induced Indication(s) Anemia associated with chronic with chronic Anemia associated Hepatitis C Crohn’s disease; Crohn’s Rheumatoid arthritis; Arthritis;Psoriatic Ankylosing Spondylitis Severe combined immunodef ‑ Severe Macular degeneration, neovascular Control and prevention of bleeding and prevention Control Osteoarthritis of the knee (OA) Hemophilia Hepatitis B; C Multiple Sclerosis Acromegaly Chronic kidneyChronic disease Neutropenia, chemotherapy chemotherapy Neutropenia, Chronic gout Chronic Multiple sclerosis (MS) Multiple sclerosis Acute lymphoblastic leukemia Acute Prostate cancer Prostate ‑ acid based polymer with controlled - acid based polymer with controlled PEGylation in vivo genicity PEGylation of bleeds were treated with 1–2 infusions treated of bleeds were introduction of unique mammalian protein molecular weight and clearance characteristicsmolecular weight tion time Nanoparticle advantage Improved stability of aptamer as a result of stabilityImproved of aptamer as a result Improved stability of protein through PEGylation through stabilityImproved of protein Improved circulation time and greater stability time and greater circulation Improved Improve circulation time and decreased immuno time and decreased circulation Improve Improved stability of aptamer as a result of stabilityImproved of aptamer as a result Efective control in 95% of bleeding episodes; 98% control Efective Extended pain relief over 12 weeks over Extended pain relief Improved stability of protein through PEGylation through stabilityImproved of protein Improved stability of protein through PEGylation through stabilityImproved of protein Improved stability of protein through PEGylation through stabilityImproved of protein Improved stability of protein through PEGylation through stabilityImproved of protein Increase circulation and therapeutic deliveryIncrease circulation Improved stability of protein through PEGylation through stabilityImproved of protein Improved stability of protein through PEGylation; through stabilityImproved of protein Large amino Large Improved stability of protein through PEGylation through stabilityImproved of protein Controlled delivery‑ with longer circula Controlled of payload ‑

l glutamate, glutamate, - - tyrosine l l coglycolide)) - VEGF aptamer (vascular - based products and Bobo from et table is reproduced The clinical trials. copyright [ 255 ] with required al. glycolic acid (PLGA) matrix acid (PLGA) glycolic - lysine and - l - lactide - like uricase) dl - asparaginase) stimulating agent) (poly ( zumab) endothelial growth factor) aptamer endothelial growth PEGylated microspheres lactic - co factor VIII) beta - 1a) porcine l alanine, alanine, Material description Material Chemically synthesized ESA (erythropoiesisChemically synthesized - PEGylated IFN alpha - 2a protein PEGylated Leuprolide acetate and polymer (PLGH and polymer (PLGH acetate Leuprolide PEGylated antibody fragment (Certoli antibody fragment ‑ PEGylated PEGylated adenosine deaminase enzymePEGylated PEGylated anti - PEGylated Random copolymer of Coagulation fator IX (Recombinant) Glyco fator Coagulation Triamcinolone acetonide with a poly acetonide Triamcinolone Polymer–protein conjugate (PEGylated (PEGylated conjugate Polymer–protein PEGylated IFN alpha - 2a protein PEGylated Polymer–protein conjugate (PEGylated (PEGylated conjugate Polymer–protein Polymer–protein conjugate (PEGylated IFN (PEGylated conjugate Polymer–protein PEGylated HGH receptor antagonist HGH receptor PEGylated Poly(allylamine hydrochloride) Poly(allylamine PEGylated GCSF protein PEGylated Polymer–protein conjugate (PEGylated (PEGylated conjugate Polymer–protein Tau Tau approved nanotechnology - approved /Glatopa (Teva) /Glatopa [sevelamer carbonate] (Sanof) [sevelamer (Merck) /pegvisomant (Pfzer) /Pegaptanib (Bausch & Lomb) /Pegaptanib /pegaspargase (Enzon pharma ‑ (Enzon /pegaspargase /pegloticase (Horizon) ® ® /pegflgrastim (Amgen) /pegflgrastim ® ® ® ® [sevelamer hydrochloride]/ [sevelamer (Biogen) ® (Genentech) - (Sigma /pegademase bovine List of FDA - glycol /Methoxy polyethylene ® (Tolmar) ® ® /certolizumab pegol (UCB) ® ® ® ® ® 1 epoetin beta (Hofman - La Roche) Pharmaceuticals) ceuticals) Renagel Adagen Neulasta Renagel Copaxone Cimzia Mircera Rebinyn Zilretta PegIntron ADYNOVATE (Baxalta) ADYNOVATE Oncaspar Somavert Pegasys Plegridy Eligard Krystexxa Macugen permission Table nanoparticles-synthetic polymer particlesPolymer with drugs or biologics combined Name Patra et al. J Nanobiotechnol (2018) 16:71 Page 20 of 33 Year approved Year 2004 2012 2002 (2015) 2017 1999 2015 1999 2003 2000 1996 1995 1995 2005; 2012; 2013 2004 2000 2001 2003 1997 1995; 2005; 2008 - operative) - MRC) - cell - related - related with myelodysplasia AMLA changes (AML distress syndrome distress ‑ ocular histoplas myopia; related; mosis Indication(s) Hyperlipidemia Acute lymphoblastic leukemia Acute Psychostimulant Acute myeloid leukemia (AML) or leukemia (AML) myeloid Acute Pulmonary surfactant respiratory for Pancreatic cancer Pancreatic Cutaneous T Cutaneous lymphoma Antiemetic Macular age degeneration, wet Lymphomatous meningitis Lymphomatous Fungal infections Fungal Karposi’s sarcoma Karposi’s Breast cancer;Breast NSCLC; cancer Pancreatic Analgesia (post Immunosuppressant Anti - anorexic Menopausal therapy Fungal/protozoal infections Fungal/protozoal Karposi’s sarcoma; Karposi’s Ovarian cancer; multiple myeloma - loaded efects efects efects efects - - - - extended release toxicity arising from side arisingtoxicity from two molecules with synergistic anti - tumor two molecules with synergistic activity toxicity toxicity arising from side arisingtoxicity from increases bioavailability increases photosensitive release photosensitive toxicity arising from side arisingtoxicity from toxicity arising from side arisingtoxicity from systemic toxicity of free drug of free toxicity systemic Nanoparticle advantage Increases bioavailability simplifes administration Increased drug loading and bioavailability; Increased delivery to tumour site; lower systemic Increased systemic delivery lower tumour site; to Sustained release of the molecules and co Sustained release Increased delivery for smaller volume; reduced Increased delivery reduced smaller volume; for Increased delivery to tumour site; lower systemic Increased systemic delivery lower tumour site; to Targeted T cell specifcity; lysosomal escape Targeted Surface absorption faster and allows area Increased delivery of diseased vessels; site to Increased delivery to tumour site; lower systemic Increased systemic delivery lower tumour site; to Reduced toxicity Increased delivery to tumour site; lower systemic Increased systemic delivery lower tumour site; to Improved solubility;Improved delivery tumor to improved Extended release Increased bioavailability Reduced dosing Controlled deliveryControlled of therapeutic Reduced nephrotoxicity Improved delivery to site of disease; decrease in deliveryImproved of disease; decrease site to - 2 and C - - B and SP and cytarabine diphtheria toxin Material description Material Fenofbrate Morphine sulphate Liposomal vincristine Lipossomal combination of daunorubicin Liposome–proteins SP Liposomal irinotecan Engineered protein combining IL protein Engineered Aprepitant Liposomal verteporfn Liposomal cytarabine Liposomal amphotericin B lipid complex Liposomal daunorubicin bound paclitaxel nanoparticlesAlbumin - bound paclitaxel Liposomal morphine sulphate Sirolimus Megestrol acetate Megestrol Micellar estradiol Liposomal amphotericin B Liposomal doxorubicin Tau) (Janssen) (Galen) ™ ® (Wyeth Pharmaceuticals) (Par Pharmaceuticals) (Par (Gilead Sciences) (Gilead ® ® (Novavax) ® /ABI - 007 (Celgene) (Pacira Pharmaceuticals) (Pacira (Bausch and Lomb) /Poractant alpha (Chiesei alpha (Chiesei /Poractant TCS) (Onco (Merrimack) ® ® ™ - tau) (Sigma ® (continued) ES ® (Merck) ® ® (Pfzer) ® (Eisai Inc) ® (Lupin Atlantis) (Lupin ® /Caelyx ® ® ® farmaceutic Vyxeos (JazzVyxeos Pharma) DaunoXome Rapamune Onivyde Estrasorb

AmBisome Emend Tricor Doxil Marqibo Curosurf - (Sigma DepoCyt© Ontak Visudyne Megace ­ Avinza Abraxane DepoDur Abelcet 1 Table Liposome formulations combined with drugs or biologics Liposome formulations Polymer nanoparticles-synthetic polymer particlesPolymer with drugs or biologics combined Name Micellar nanoparticles combined with drugs or biologics Nanocrystals Protein nanoparticles combined with drugs or biologics Protein Patra et al. J Nanobiotechnol (2018) 16:71 Page 21 of 33 Year approved Year 2003 2000 1957 2004 2005 2005 2002 2002 2009 1999 2009 2003 2010 2014 2009; 2014 2001 (2009) 1996 (2008) 1957 disease (CKD) disease (CKD) disease (CKD) chronic kidneychronic disease (CKD) disease (CKD) Indication(s) Bone substitute Iron defciency kidney in chronic Iron defciency kidney in chronic Bone substitute Bone substitute Psychostimulant Psychostimulant Muscle relaxant Bone substitute Iron defciency kidney in chronic Defciency defciency anemia iron in Bone substitute Glioblastoma Malignant hypothermia Schizophrenia; disorder Schizoafective Imaging agent Imaging agent Iron defciency kidney in chronic growth growth growth release, decreasing number of doses decreasing release, growth netism drug Nanoparticle advantage Mimics cell adhesion and allowing bone structure Allows increased dose increased Allows Allows increased dose increased Allows Mimics cell adhesion and allowing bone structure Mimics cell adhesion and allowing bone structure Increased drug loading and bioavailability Increased drug loading and bioavailability Increased drug loading and bioavailability Mimics bone structure Allows increased dose increased Allows Magnetite suspension allows for prolonged steady steady prolonged for suspension allows Magnetite Mimics cell adhesion and allowing bone structure Allows cell uptake and introduces superparamag cell uptakeAllows ‑ and introduces Faster administration at higher doses Faster Allows slow release of injectable solubility low release slow Allows Superparamagnetic characterSuperparamagnetic Superparamagnetic characterSuperparamagnetic Allows increased dose increased Allows tol carboxymethylether tol Material description Material Calcium phosphate Calcium Iron sucrose Iron dextran MW) (low Hydroxyapatite Hydroxyapatite Dexmethylphenidate HCl Dexmethylphenidate Methylphenidate HCl Methylphenidate Tizanidine HCl Tizanidine Hydroxyapatite Sodium gluconate ferric Ferumoxytol SPION with polyglucose sorbi SPION with polyglucose ‑ Ferumoxytol Hydroxyapatite Iron oxide Dantrolene sodium Dantrolene Paliperidone palmitate Paliperidone SPION coated with silicone SPION coated SPION coated with dextranSPION coated Iron dextran MW) (low (AMAG pharma‑ (AMAG ® (Sanof Avertis) ® (AMAG pharmaceu‑ (AMAG (Janssen Pharms) ® ® ­ umirem (MagForce) ; ® (Zimmer Biomet) ™ ® /ferumoxytol (AMAG pharma‑ (AMAG /ferumoxytol (Novartis) (Eagle Pharmaceuticals) (Novartis) ® (IsoTis Orthobiologics) (IsoTis ™ ® (Acorda) (Sanof Avertis) ® /Dexferrum (Rti surgical) (Luitpold pharmaceuticals) (Luitpold ® (continued) ­ Sustenna /Endorem ®

® ® ® XR ® (Sanof Avertis) (Heraseus Kulzer) ® (Stryker) ® LA ® ® ® ceuticals) ­ Nanotherm ceuticals) ticals) Focalin ­ Focalin Ostim Ferrlecit DexIron OsSatura EquivaBone Ritalin ­ Zanafex Vitoss Invega INFeD Venofer NanOss Feraheme Inorganic and metallic nanoparticles Ryanodex GastroMARK Feridex 1 Table nanoparticles-synthetic polymer particlesPolymer with drugs or biologics combined Name [ 204 , 256 – 261 ] literature various 2016–2018 has been collected from from Data Patra et al. J Nanobiotechnol (2018) 16:71 Page 22 of 33 1999 1994 2002 Year approved Year 2001 2012 1990 2002 2015 1995 2000 1996 2004 2002 2000 1997 1995; 2005; 2008 1996 1996 operative) - - specifc delivery - specifc delivery - specifc delivery - specifc delivery - specifc delivery - specifc delivery - specifc delivery delivery smaller volume; for PEGylation circulation time in body circulation PEGylation (tumor) and decrease toxicity (tumor) and decrease and decrease immunogenicity and decrease PEGylation (tumor) and decrease toxicity (tumor) and decrease (lesion vessels) photosensitive photosensitive (lesion vessels) release (tumor) and decrease toxicity (tumor) and decrease PEGylation and increase in circulation time in circulation and increase in body (tumor) and decrease systemic systemic (tumor) and decrease toxicity polymer with controlled polymer with controlled molecular weight (tumor) and decrease toxicity (tumor) and decrease Decrease toxicity and increased and increased toxicity Decrease Improved protein stability due protein Improved Prolonged drug delivery and Prolonged Advantage Improved protein stability due protein Improved Increase site Improve circulation time in body circulation Improve Improved protein stability due protein Improved Increase site Decrease toxicity Decrease Increase site Increase site Loss of pain (post Loss Improved protein stability due protein Improved Increase site Reduced nephrotoxicity Increase site Regulation of clearance and Increase site ‑ pulmonary surfactant‑ res for piratory syndrome distress decreased vision decreased therapy tions cer; multiple myeloma Lung activator for stress disorder; stress activator for Lung Acute lymphoblastic leukemia Acute Prostate cancer Prostate Application Hepatitis C Acute lymphoblastic leukemia Acute Immunodefciency disease Hepatitis B and C Pancreatic cancer Pancreatic Fungal infection Fungal Ocular histoplasmosis, myopia, myopia, Ocular histoplasmosis, Karposi’s sarcoma Karposi’s Prolonged release Prolonged Neutropenia induced by chemo induced by Neutropenia Chronic renal diseases renal Chronic ‑ infec and/or protozoal Fungal Karposi’s sarcoma; Ovarian sarcoma; can ‑ Karposi’s Multiple sclerosis Lymphomatous meningitis Lymphomatous - - lysine - lactide l dl alanine, - alanine, l - asparaginase l - tyrosine random copoly ‑ l glycolide) co enzyme (GCSF) stimulating factor (GCSF) protein and mer Glutamate, Glutamate, - Liposomes PEGylated PEGylated l Carrier PEGylated IFN - α2b protein PEGylated Liposomes Polymer (PLGH (poly( (PLGH Polymer PEGylated adenosine deaminase PEGylated PEGylated IFN - α2a protein PEGylated Liposomes Liposomes Liposomes Liposomes Liposomes - granulocytePEGylated colony Poly(allylamine hydrochloride) Poly(allylamine Liposomes Liposomes Liposomes C - - B and SP sevelamer carbonate sevelamer - Asparaginase Ingredient active Ingredient Interferon - alpha ( IFN α2b) Vincristine Proteins SP Proteins Leuprolide acetate Leuprolide Pegademase bovine Pegademase Glatopa Interferon - alpha ( IFN α2a) Irinotecan Amphotericin B lipid complex Verteporfn Daunorubicin Morphine sulfate PEG - flgrastim Sevelamer hydrochloride or Sevelamer hydrochloride Amphotericin B Doxorubicin l Cytarabine ‑ Tau) ‑ Pharma Tau (Janssen) (Galen) ™ ® (Gilead Sciences) (Gilead (Teva) (Merck) ® ‑ Pharmaceu (Enzon ‑ Pharmaceu (Pacira (Bausch and Lomb) Nanomedicine approved by FDA classifed by type of carrier/material used in preparation of the formulation used in preparation of carrier/material classifed by type by FDA Nanomedicine approved ® (Amgen) /Poractant alpha (Chie /Poractant ® TCS) (Onco (Merrimack) ® (Sanof) ® (Genentech) - (Sigma ® - tau) (Sigma ® ® ® ® (Tolmar) ® ® ® ® ® /Caelyx ® sei farmaceutici) ceuticals) ticals) ticals) Commercial name (company) Commercial 2 Table Visudyne Copaxone Neulasta Doxil Pegasys Onivyde Oncaspar Eligard Adagen DaunoXome DepoDur - (Sigma DepoCyt© Marqibo PegIntron Curosurf Abelcet Renagel AmBisome Patra et al. J Nanobiotechnol (2018) 16:71 Page 23 of 33 2003 Year approved Year 2004 2007 2002/2015 2008; 2009; 2013; 2013 2003 2004 2004 2003 2005 2002 2002 2005 2015 2009 2003 2001 2000 2009/2014 2010 2015 - ‑ ‑ PEGylation tion bioavailability time in body adhesion and growth tion adhesion and growth availability decreased posology decreased availability adhesion and growth PEGylation adhesion and growth soluble drugs PEGylation PEGylation Improved protein stability due protein Improved Advantage Increased bioavailability Improved stabilityImproved due PEGyla ‑ Prolonged release and increased and increased release Prolonged Increase stability and circulation Mimics cell by bone structure Improved stabilityImproved due PEGyla ‑ Mimics cell by bone structure Increased absorption and bio Increased bioavailability Increased bioavailability and Increased drug loading and bio Mimics cell by bone structure Improved protein stability due to protein Improved Mimics bone structure Mimics cell by bone structure Reduced posology Increased bioavailability Decreased release of poor water release Decreased Improved protein stability due to protein Improved Improved protein stability due to protein Improved related (decreased (decreased - related failure due to diseases due to failure arthritis; psoriatic arthritis and ankylosing spondylitis cular age vision) disorder Acromegaly Application Hyperlipidemia Anemia associated with renal with renal Anemia associated Mental stimulant Crohn’s disease; rheumatoid Crohn’s Bone substitute Macular‑ degeneration; neovas Bone substitute Antiemetic drug Mental stimulant Muscle relaxant Mental stimulant Bone substitute Multiple sclerosis Bone substitute Bone substitute Anti - anorexic Immunosuppressant Schizophrenia schizoafective schizoafective Schizophrenia Chronic gout Chronic Hemophilia ‑ ‑ - like uricase antagonist poiesis - stimulating agent (Certolizumab) lial growth factor aptamer lial growth PEGylated HGH receptor HGH receptor PEGylated Carrier Nanocrystals Chemically synthesized erythroChemically synthesized Nanocrystals PEGylated antibody fragment antibody fragment PEGylated Nanocrystals PEGylated anti vascular endothe PEGylated Nanocrystals Nanocrystals Nanocrystals Nanocrystals Nanocrystals Nanocrystals PEGylated IFN - β1a protein PEGylated Nanocrystals Nanocrystals Nanocrystals Nanocrystals Nanocrystals PEGylated porcine PEGylated PEGylated PEGylated factor VIII visomant epoetin beta Ingredient active Ingredient Fenofbrate - glycol Methoxy polyethylene Morphine sulfate Certolizumab pegol Calcium phosphate Calcium PEG - aptanib Hydroxyapatite Aprepitant Dexmethylphenidate HCl Dexmethylphenidate Tizanidine HCl Tizanidine Methylphenidate HCl Methylphenidate Hydroxypatite Interferon - beta ( IFN β1a) Hydroxypatite Hydroxyapatite Megestrol acetate Megestrol PEG - Sirolimus Paliperidone palmitate Paliperidone PEG - loticase F actor VIII (Janssen ® (Zimmer Biomet) (Wyeth‑ Pharmaceu ‑ Pharmaceu (Par ® (Novartis) (Pfzer) ® ® (Bausch & Lomb) (Horizon) (Novartis) (continued) ® (IsoTis Orthobiologics) (IsoTis (Acorda) ® ® (Biogen) ® ® (Rti Surgical) ® (Hofman - La Roche) ­ Sustenna ­ ES (Merck) ® ®

(UCB) (Pfzer) ® ­ XR ® (Heraseus Kulzer) ® (Stryker) (Lupin Atlantis) (Lupin ® ® ­ LA ® ® ® ® ticals) ticals) Pharms) 2 Table name (company) Commercial Macugen Somavert Focalin Focalin Cimzia Ritalin Krystexxa OsSatura Mircera Tricor Vitoss NanOss Emend Zanafex EquivaBone ADYNOVATE (Baxalta) ADYNOVATE Invega Ostim Avinza Megace Plegridy Rapamune Patra et al. J Nanobiotechnol (2018) 16:71 Page 24 of 33 Year approved Year 2000 1957 2005;2012;2013 2003 2009 1999 2014 2010 2001/2009 1996/2008 1957 - specifc delivery (tumor) and solubility decreased number of doses decreased higher doses tumor cells or sensitized for for tumor cells or sensitized additional therapies Advantage Increased dose capacity Increased dose capacity Increase site Sustained release Prolonged steady release and release steady Prolonged Increased dose capacity Allows higher administration at Allows Thermotherapy for destroy destroy for Thermotherapy Superparamagnetic characterSuperparamagnetic Superparamagnetic characterSuperparamagnetic Increased dose capacity defciency defciency lung cancer and pancreatic lung cancer and pancreatic cancer defciency defciency defciency Application Chronic kidney Chronic with iron failure Chronic kidney Chronic with iron failure Breast cancer;Breast non - small cell Menopause hormone therapy Chronic kidney Chronic with iron failure Chronic kidney Chronic with iron failure Malignant hypothermia Brain tumor Imaging material Imaging material Chronic kidney Chronic with iron failure ‑ coated Iron nano coated - nanoparticles glucose sorbitol carboxym ‑ ethylether particles Carrier Iron sucrose Iron dextran MW) (low bound paclitaxel Albumin - bound paclitaxel Micelles Ferumoxytol SPION with poly ‑ Ferumoxytol Aminosilane Sodium gluconate ferric Nanocrystals SPION coated with silicone SPION coated SPION coated with dextranSPION coated Iron dextran (high MW) ‑ ‑ nano oxide iron paramagnetic partilces (SPION) nanoparticles (SPION) nanoparticles (SPION) Ingredient active Ingredient Iron oxide Iron - 007) (ABI Paclitaxel Estradiol - ultrasmall super Ferumoxytol Iron oxide Sodium ferric Dantrolene sodium Dantrolene Superparamagnetic iron oxide oxide iron Superparamagnetic Superparamagnetic iron oxide oxide iron Superparamagnetic Iron ‑ (AMAG (AMAG ® (Sanof ® (AMAG phar (AMAG ® ­ umirem ; (MagForce) ™ (AMAG pharmaceu‑ (AMAG ® ‑ (Eagle Pharmaceu (Novavax) (Celgene) (continued) ™ ® ® (Sanof Avertis) /Dexferrum ™ ‑ Pharmaceu (Luitpold /Endorem ® ® ® (Sanof Avertis) ® ® ticals) ticals) ticals) pharmaceuticals) maceuticals) Avertis) Commercial name (company) Commercial 2 Table Ryanodex GastroMARK DexIron INFeD Abraxane Nanotherm Venofer Estrasorb Feraheme Ferrlecit Feridex Patra et al. J Nanobiotechnol (2018) 16:71 Page 25 of 33

material used in preparation of the formulation is shown to develop new protocols that must be specifc and suf- in Table 2. fciently rigorous to address any safety concerns, thus Nanotechnology has dynamically developed in recent ensuring the release of safe and benefcial nanomedicine years, and all countries, whether developed or not, are for patients [204, 252, 253]. increasing their investments in research and develop- ment in this feld. However, researchers who work with practical applications of the nano-drugs deal with high Future of nanomedicine and drug delivery system levels of uncertainties, such as a framing a clear defni- Te science of nanomedicine is currently among the tion of these products; characterization of these nanoma- most fascinating areas of research. A lot of research in terials in relation to safety and toxicity; and the lack of this feld in the last two decades has already led to the efective regulation. Although the list of approved nano- flling of 1500 patents and completion of several dozens medicine is quite extensive, the insufciency of specifc of clinical trials [254]. As outlined in the various sections regulatory guidelines for the development and charac- above, cancer appears to be the best example of diseases terization of these nanomaterials end up hampering its where both its diagnosis and therapy have benefted clinical potential [250]. Te structure/function relation- from nonmedical technologies. By using various types of ships of various nanomaterials, as well as their character- nanoparticles for the delivery of the accurate amount of istics, composition and surface coating, interacts with the drug to the afected cells such as the cancer/tumour cells, biological systems. In addition, it is important to evaluate without disturbing the physiology of the normal cells, the the possibility of aggregate and agglomerate formation application of nanomedicine and nano-drug delivery sys- when these nanomedicines are introduced into biologi- tem is certainly the trend that will remain to be the future cal systems, since they do not refect the properties of arena of research and development for decades to come. the individual particle; this may generate diferent results Te examples of nanoparticles showed in this com- and/or unexpected toxic efects depending on the nano- munications are not uniform in their size, with some formulation [250]. truly measuring in nanometers while others are meas- Te lack of standard protocols for nanomedicines ured in sub-micrometers (over 100 nm). More research characterization at physico-chemical and physiological/ on materials with more consistent uniformity and drug biological levels has often limited the eforts of many loading and release capacity would be the further area researchers to determine the toxic potential of nano- of research. Considerable amount of progress in the use drugs in the early stages of testing, and that resulted in of metals-based nanoparticles for diagnostic purposes the failures in late-phase clinical trials. To simplify and/ has also been addressed in this review. Te application or shorten the approval process for nano based medi- of these metals including gold and silver both in diagno- cines/drugs, drug delivery system etc., a closer coopera- sis and therapy is an area of research that could poten- tion among regulatory agencies is warranted [204, 251]. tially lead to wider application of nanomedicines in the As a strategy for the lack of regulation of nanomedi- future. One major enthusiasm in this direction includes cines and nano drug delivery system; the safety assess- the gold-nanoparticles that appear to be well absorbed in ment and the toxicity and compatibility of these are soft tumour tissues and making the tumour susceptible performed based on the regulations used by the FDA to radiation (e.g., in the near infrared region) based heat for conventional drugs. After gaining the status of a new therapy for selective elimination. research drug (Investigational New Drug, IND) by the Despite the overwhelming understanding of the FDA, nanomedicines, nano-drug delivery systems begin future prospect of nanomedicine and nano-drug deliv- the clinical trials phase to investigate their safety and ef- ery system, its real impact in healthcare system, even cacy in humans. Tese clinical trials are divided into three in cancer therapy/diagnosis, remains to be very lim- phases: phase 1 (mainly assesses safety); phase 2 (mainly ited. Tis attributes to the feld being a new area of evaluates efcacy) and phase 3 (safety, efcacy and dos- science with only two decades of real research on the age are evaluated). After approval in these three phases subject and many key fundamental attributes still the IND can be fled by the FDA to request endorsement being unknown. Te fundamental markers of diseased of the new nanomedicine or nano drug delivery systems. tissues including key biological markers that allow However, this approach to nanomedicine regulation has absolute targeting without altering the normal cellu- been extensively questioned [204, 246, 252]. lar process is one main future area of research. Ulti- Due to the rapid development of nanotechnology as mately, the application of nanomedicine will advance well as its potential use of nanomedicine, a reformed and with our increasing knowledge of diseases at molecu- more integrated regulatory approach is urgently required. lar level or that mirrors a nanomaterial-subcellular size In this regard, country governments must come together comparable marker identifcation to open up avenues Patra et al. J Nanobiotechnol (2018) 16:71 Page 26 of 33

for new diagnosis/therapy. Hence, understanding the the discovery of pharmacologically active compounds molecular signatures of disease in the future will lead from natural sources is not a favored option today, as to advances in nanomedicine applications. Beyond compared to some 50 years ago; hence enhancing the what we have outlined in this review using the known efcacy of known natural bioactive compounds through nanoprobes and nanotheragnostics products, further nanotechnology has become a common feature. Good research would be key for the wider application of examples are the therapeutic application of nanotech- nanomedicine. nology for berberine, curcumin, ellagic acid, resveratrol, Te concept of controlled release of specifc drugs at curcumin and quercetin. Te efcacy of these natural the beleaguered sites, technology for the assessment of products has greatly improved through the use of nano- these events, drug’s efect in tissues/cellular level, as well carriers formulated with gold, silver, cadmium sulphide, as theoretical mathematical models of predication have and titanium dioxide polymeric nanoparticles together not yet been perfected. Numerous studies in nanomedi- with solid lipid nanoparticles, crystal nanoparticles, cine areas are centered in biomaterials and formulation liposomes, micelles, superparamagnetic iron oxide nano- studies that appear to be the initial stages of the bio- particles and dendrimers. medicine applications. Valuable data in potential applica- Tere has been a continued demand for novel natu- tion as drug therapeutic and diagnosis studies will come ral biomaterials for their quality of being biodegradable, from animal studies and multidisciplinary researches biocompatible, readily availability, renewable and low that requires signifcant amount of time and research toxicity. Beyond identifying such polysaccharides and resources. With the growing global trend to look for more proteins natural biopolymers, research on making them precise medicines and diagnosis, the future for a more more stable under industrial processing environment and intelligent and multi-centered approach of nanomedicine biological matrix through techniques such as crosslink- and nano-drug delivery technology looks bright. ing is among the most advanced research area nowadays. Tere has been lots of enthusiasm with the simplistic Polymeric nanoparticles (nanocapsules and nanospheres) view of development of nanorobots (and nanodevices) synthesized through solvent evaporation, emulsion that function in tissue diagnosis and repair mecha- polymerization and surfactant-free emulsion polymeriza- nism with full external control mechanism. Tis has not tion have also been widely introduced. One of the great yet been a reality and remains a futuristic research that interest in the development of nanomedicine in recent perhaps could be attained by mankind in the very near years relates to the integration of therapy and diagnosis future. As with their benefts, however, the potential (theranostic) as exemplifed by cancer as a disease model. risk of nanomedicines both to humans and the environ- Good examples have been encapsulated such as, oleic ment at large require long term study too. Hence, proper acid-coated iron oxide nanoparticles for diagnostic appli- impact analysis of the possible acute or chronic toxicity cations through near-infrared; photodynamic detection efects of new nanomaterials on humans and environ- of colorectal cancer using alginate and folic acid based ment must be analyzed. As nanomedicines gain popular- chitosan nanoparticles; utilization of cathepsin B as met- ity, their afordability would be another area of research astatic processes fuorogenic peptide probes conjugated that needs more research input. Finally, the regulation of to glycol chitosan nanoparticles; iron oxide coated hya- nanomedicines, as elaborated in the previous section will luronic acid as a biopolymeric material in cancer therapy; continue to evolve alongside the advances in nanomedi- and dextran among others. cine applications. Since the 1990s, the list of FDA-approved nanotech- nology-based products and clinical trials has stagger- Conclusion ingly increased and include synthetic polymer particles; Te present review discusses the recent advances in liposome formulations; micellar nanoparticles; protein nanomedicines, including technological progresses in the nanoparticles; nanocrystals and many others often delivery of old and new drugs as well as novel diagnos- in combination with drugs or biologics. Even though tic methodologies. A range of nano-dimensional mate- regulatory mechanisms for nanomedicines along with rials, including nanorobots and nanosensors that are safety/toxicity assessments will be the subject of fur- applicable to diagnose, precisely deliver to targets, sense ther development in the future, nanomedicine has or activate materials in live system have been outlined. already revolutionized the way we discover and admin- Initially, the use of nanotechnology was largely based on ister drugs in biological systems. Tanks to advances enhancing the solubility, absorption, bioavailability, and in nanomedicine, our ability to diagnose diseases and controlled-release of drugs. Even though the discovery even combining diagnosis with therapy has also became of nanodrugs deal with high levels of uncertainties, and a reality. Patra et al. J Nanobiotechnol (2018) 16:71 Page 27 of 33

Abbreviations Funding AR: Amaranth red; CBF: ciliary beat frequency; CBZ: carbamazepine; CC: This work was supported by the Korea Environmental Industry & Technology colorectal cancer; CMC: carboxymethylcellulose; Cys-MNA: ((2-amino-2-car‑ Institute (A117-00197-0703-0) and Korea Institute of Planning and Evaluation boxyethyl) disulfanyl) nicotinic acid (Cys-MNA); EPR: penetrability and holding; for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through FA: folic acid-conjugated dextran; FDA: Food and Drug Administration; FeO: Agricultural-BioTechnology Development Program funded by Ministry of ferrous oxide; HA: hyaluronic acid; HDLs: high density lipoproteins; HPMC: Agriculture, Food and Rural Afairs (MAFRA)(710 003-07-7- SB120, 116075-3). hydroxypropylmethylcellulose; LDLs: low density lipoproteins; MR: magnetic resonance; NIR: near infrared; NP: nanoparticle; PFH: perfuorohexane; PTX: paclitaxel; RPG: repaglidine; VEGF: antivascular endothelial growth factor; VLF: Publisher’s Note venlafaxine; XG: xanthan gum. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional afliations. Authors’ contributions JKP, GD, LFF, EVRC, MDPRT, LSAT, LADT, RG, MKS, SS and SH wrote diferent Received: 19 July 2018 Accepted: 25 August 2018 sections of the manuscript. JKP, LFF, MDPRT, RG, SS, SH and HSS edited the manuscript. All authors read and approved the fnal manuscript.

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