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Pharmaceutical Commentary

Nanotechnology in : innovation to market

Nanotechnology based medicine is an advanced biomedical field. After producing a plethora Bajwa SZ*, Munawar A & of laboratory based research, nanotechnology is facing a transition into the Khan WS tangible advancement of human therapeutics. If nanoproducts are to be translated into National Institute for Biotechnology meaningful benefits for patients, innovation in the laboratory must be supported by the and , Faisalabad, standard research protocols and regulatory pathways. Both for therapeutics and for medical Pakistan *Author for correspondence: devices now researchers and pharma-entrepreneurs have gathered at one platform to transfer [email protected] innovation to market for the benefit of mankind.

Keywords: nanotechnology ▪ nanomedicine ▪ therapeutics ▪ nanoimgaging

Nanomedicine size materials can be included due to their active components in the size range from one possess exceptional unique nanometre to hundreds of nanometres [3]. nanoscale size dependent physical, optical, catalytic, electrical, and chemical properties that Nanomaterials based systems can can be controlled (scalable). These properties are interact with biomolecules positioned on both entirely different than their bulk counterpart. cell surface and within the cell. Thus nano One of the exciting feature of nanotechnology based drug delivery systems not only transfer is its utility in the field of nanomedicine, encapsulated or grafted chemotherapeutics, therapeutics, and medical devices [1]. When but can also deliver them within the cellular these small size materials are introduced into system once they have penetrated. Such biological systems, their extremely small size and systems can also be modified and decorated with different functionalizing agents such their unique nanoscale properties make it possible as antibodies to develop target specific drug to use them as delivery vectors and probes for delivery system [4]. At present only two families biological diagnostics, imaging and therapeutics of therapeutic nanomedicine-albumin and [2]. Infact, when size decreases, the surface area are clinically established to volume ratio of materials becomes very large, worldwide. so that a vast suitable surface is available for chemical interactions with biomolecules. This Nano Drug Delivery Systems (DDS) generally critically implied that nanotechnology is facing possess three vector generation; First generation a transition into the tangible advancement of vectors comprising nano spheres and nano human therapeutics. Recently, we have seen capsules. Second generation vectors of the beginning of multiple clinical trials of nanoparticles that are coated with hydrophilic nanomaterials; both for therapeutics and for polymers such as Polyethylene Glycol (PEG). medical devices. Third generation vectors which combines a biodegradable core and a Polymer Envelope When we talk about nanomedicine, its aim (PEG) with a functionalization agent. Such can be broadly defined as the comprehensive systems offer inherent merits of protecting drug production of materials to control, either from being degraded in the body before it is repair, defence or , and improvement actually delivered to its target, enhance drug of different human biological systems. For this absorption, better control over drug distribution purpose different nano-engineered structures to tissue and avoiding by preventing are applied at molecular level. Here, nanoscale interaction with normal cells. Many FDA

11 Pharm. Bioprocess. (2017) 5(2), 011–015 ISSN 2048-9145 Commentary Bajwa, Munawar, Khan

approved are available for clinical or active targeting. Passive targeting depends use (TABLE 1). upon enhanced permeability and retention. Due to small size and different surface properties of Nanotechnology offers a different means to nanomaterials they can drip through vessel selectively deliver at diseased cells walls into tissues [5]. On the other hand on or tissues, for instance, with application in active target approach, functional molecules on inflammation or cancer. The behaviour of nanomaterials can bind specific cellular receptors nanomaterials is based on two approaches, passive to functionalize them for targeted delivery. Active

Table 1. List of drugs approved by FDA. Source: Adapted from US-FDA and EMA. Year Active pharmaceutical Trade name Indication Nanotechnology approved ingredient Photodynamlic therapy Visudyne 2000 Verteporfin for age-related muscular degeneration Doxil/Caelyx 1995 Antineoplastic PEGylated liposome AmBisome 1990 Amphotericin B Fungal Liposome Abelcet 1995 Amphotericin B Fungal infections Liposome Definity 2001 Octofluoro-propane - Liposome Myocet 2001 Doxorubicin - Liposome Lymphomatous DepoCyte 1999 Cytarabine Liposome meningitis DepoDur 2004 Morphine - Liposome Daunoxome 1996 Daunirubicin Antineoplastic Liposome Octocog alfa 2009 Factor VIII - Liposome Albumin bound Abraxane 2005 paclitaxel Metastatic nanoparticles Rapamune 2000 Rapamycin Immunosuppresant Nanocrystal Elan Emend 2003 Aprepitant Anti-emetic Nanocrystal Elan Tricor 2004 Fenofibrate Hypercholesterolemia Nanocrystal Elan Megace ES 2005 Megestrol Anti-anoretic Nanocrystal Elan IDP-P Skyepharma Triglide 2005 Fenofibrate Hypercholesterolemia nanocrystal Mepact - Mifamurtide - Liposome Amphotec 1996 - Fungal infections Micelle Vasomotor symptoms Estrasorb 2003 - associated with Micelle menopause Taxotere 1996 - Antineoplastic Micelle Somatuline depot 2007 - Acromegaly Nanotube Treatment of iron deficiency in SPIO Feraheme injection 2009 - patient with Chronic Polymer- Kidney Disease Improved stability of through Polymer-protein conjugate Krystexxa®/ 2010 PEGylation; introduction Chronic gout (PEGylated porcine-like Pegloticase (Horizon) of unique mammalian uricase) protein Increased delivery to tumour site; lower Acute Lymphoblastic Marqibo® (Onco TCS) 2012 Liposomal Vincristine systemic toxicity arising Leukemia from side-effects Improved solubility; Abraxane®/ABI-007 Breast cancer NSCLC Albumin-bound paclitaxel 2013 improved delivery to (Celgene) nanoparticles tumor Allows slow release of Invega® Sustenna® Schizophrenia 2014 injectable low solubility Paliperidone Palmitate (Janssen Pharms) Schizoaffective Disorder drug Improved stability protein conjugate Adynovate (Baxalta) 2015 of protein through Hemophilia (PEGylated factor VIII) PEGylation

Pharm. Bioprocess. (2017) 5(2) 12 Nanotechnology in medicine: innovation Commentary and passive targeting can be combined to boast devices require small sample and will provide chemotherapeutic, achieving more significant more accurate and complete biological data disease control at lower drug doses [6]. Nano- from a single test/measurement/reading. based materials are also being investigated as Nanotechnology refines the diagnostic regenerative . techniques/devices, resulted in high throughput is the procedure of generating functional and screening and resulted to the development living tissues, to replace or repair damaged organ of Point-of-Care (POC) diagnostics [13]. or tissue due to congenital defects, age, damage Nanoimaging includes numerous approaches for or disease. The main aim behind for nano- the study of in vivo molecular proceedings and based regenerative medicine is the availability molecules management. Main purpose of in vivo of cost-efficient, user friendly disease treating diagnostics research is to create highly sensitive, techniques that will permit for in-situ tissue specificity and reliable detecting agents that [7]. Nanomaterial assisted gene can be used to deliver and monitor therapeutic delivery for employing stem cells has an energetic agents. This is the ‘Find, Fight and Follow’ (FFF) role in recognizing the potential of regenerative concept of early diagnosis and therapy [14]. Now medicine. The major goal of continuing and molecular imaging is a basic tool for future efforts in this field will be to effectively and diagnosis of disease and in developing in exploit the enormous newly discovered self- vivo nano medical application [15]. For wide repair capability that has been observed in adult range of diagnosis, targeted molecular imaging stem cells [3,8]. Here, two main objectives are is important for different purposes such as perused; firstly recognising signalling systems (assessing drug distributions, controlled drug in order to power the self-healing potential of release and early diagnosis of unexpected and endogenous stem cells. Secondly, emerging potentially dangerous drug accumulations) [16]. efficient targeting systems for adult Nano medical Implants therapies. Whereas, another possible application of regenerative medicine strategies is to evade Nanotechnology also has different implications pre-seed a nanostructured biomaterial scaffold/ for in vivo diagnostic tools such as the new matrix of a patient’s own cells. endoscopic instruments and swallow able imaging ‘pill’. Monitoring and observing of circulating Nanotechnology is an excellent mean to develop molecules is of important for some chronic different structures and materials that mimic diseases such as AIDS or diabetes. Different the biological but also promises to provide nano sensors (for example catheters), will efficient delivery systems. The application of provide immediate data to surgeons. Nanoscale nanotechnology in this field is a wide topic. entities could identify defects/; and It includes the fabrication of different unique the subsequent removal or correction could materials, such as nanoparticles, nano patterning also set a future vision [17]. Implanted drug and scaffolds for [9-11]. Future delivery devices–DDD–can be benefited by biomaterials must instantaneously improve tissue nanotechnology. Nanotechnology enable to regeneration while reducing immune responses fabricate and design the ultra-small devices and preventing . (pumps, reservoirs and actuators) for accurately Medical diagnostics and targeted release of drug. Due to their small size viscosity, and low invasiveness, these Drug In vitro diagnosis for medical problems has Delivery Devices (DDD) can be introduced conventionally been a laborious task; different within the body, even in the brain [18]. Smaller tissue samples or body fluids are directed to devices offer less damage and invasiveness a laboratory for an examination, which could so these can even be implanted for different take hours, days, weeks or months. Different purposes. Ultra-miniaturisation: Sensing part disadvantages include cost, sample deterioration, lies in the ultra-small size of the biological lengthy waiting times (not suitable for urgent sample like some biopsies. Low concentrations: cases), imprecise results for minute sample On the contrary, measuring of biological quantities, and poor standardisation and molecules (blood, urine) like some biomarkers management of sample collection. Different in large samples like blood drops requires some properties on a single device, nano industry, initial steps for concentrating these molecules. have led to the expansion of a new generation There are different types of implant-nano of sensing devices that are smaller, cheaper, materials in the market e.g. orthopaedic, wound user friendly, laborious free, provide accurate management, dental/dental care products, reading system, and faster [12]. These nano cardiac implants, bone replacement scaffold,

13 Commentary Bajwa, Munawar, Khan

nano-hydroxyapatite, silver NP solution, nano- and computer tools or softwares. Equally hydroxyapatite, nanoporous hydroxyapatite, important is the establishment of reference ultraporous beta-tricalcium phosphate NPs, materials and testing methods that can provide boneSource (Lebinger), Silvagard (AcryMed, standard yardsticks for the development of 2005), UltraDEX Recalcifying (Periproducts), novel classes of medicines. Many scientists Vestasync (MIV Therapeutics), Vitosswho specialize in nanomedicine have no prior (Orthovita, 2000), these amount to about 10 experience with the regulatory procedures. It is billion USD market. valuable to educate about the approval process of medicines. For drugs often 10 years are required offers important inputs to with expenditure of hundreds of millions the development of detection/sensing devices of dollars. Published materials, conferences, and of the tagging/following of disease related training workshops can produce a meaningful indicators, that results to the advancement in pool for faster drug approval system. imaging. The combination of in vitro diagnosis and in vivo imaging (by nanoparticles) could Conclusion results in targeted diseased cells disruption or removal. Tagging diseased cells with The early on medicine functionalised nanoparticles, that can respond is beginning to get realized, with novel nanoscale to external stimuli, consents for in situ, local therapeutic and diagnostic modalities under ‘’ (breaking/heating of nanoparticles by development or in clinical practice today. In magnetic fields, laser, microwaves, etc.) without this commentary the field of “nanomedicine” inappropriateness within the is briefly reviewed form the perspective of [19]. Theranostic, used for the combination of where are today in wake of nanomedicine, diagnosis and therapy. Imaging can be used to therapeutics, and devices. All these strenuous trace the drug delivery system within the body. In and laborious efforts doesn’t reach to the end other hand imaging can also be used to activate benefit owing to different sort of technical the drug release, by some external stimulus. Such issues. A full understanding of the basic science external stimuli such as temperature, laser light, of transport, biological barriers, or ultrasounds [20]. understanding of basic biology, control over possible adverse effects, and as well as training Limitations about the scientific and official procedures of drug approval can yield advanced generation of The global nanomedicine market was valued at therapeutics in market. $53 billion in 2009, and is forecast to increase at a Compound Annual Growth Rate (CAGR) of References 13.5% to reach more than $100 billion in 2014. 1. Webster TJ, Waid MC, McKenzie JL et al. Nano- The vision of producing a more efficient system biotechnology: carbon nanofibres as improved neural to the development of nano-product, following and orthopaedic implants. Nanotechnology. 15, 48 limitations are encountered. Understanding (2003). of the bio-distribution of nanomaterials in the 2. Umemura K. Hybrids of nucleic acids and carbon body is very crucial step. This is connected to nanotubes for nanobiotechnology. Nanomaterials. 5, a second constraint, which requires imaging 321–350 (2015). modalities for investigating the bio-distribution 3. Nikalje A. Nanotechnology and its applications in of nanomedicine over time. Another important medicine. Med. Chem. 5, 081–089 (2015). issue is the determination of mass transport of 4. Roco MC. The long view of nanotechnology medicine across biological barriers in the body. development: the National Nanotechnology Initiative at The bio-distribution of medicine is a function 10 years. Springer (2011). of their biological affinity, however, in case of 5. Weissig V, Guzman-Villanueva D. nanoparticles, it is primarily managed by their Nanopharmaceuticals (part 2): products in the pipeline. Int. J. Nanomed. 10, 1245 (2015). ability to negotiate compartmental barriers. This issue is further compounded by further 6. Li J, Wang Y, Liang R et al. Recent advances in targeted hurdles as degradation of enzyme, uptake by nanoparticles drug delivery to melanoma. Nanomed. Nanotechnol. Bio. Med. 11(3), 769–794 (2015). phagocytic agents, hydrostatic pressure at target cell, abnormal flow of blood, and molecular 7. Weissig V, Pettinger TK, Murdock N. Nanopharmaceuticals (part 1): products on the market. and ionic efflux pumps that tend to eject drugs Intl. J. Nanomed. 9, 4357 (2014). from target site. There is a dire need to establish 8. Tomalia DA. Interview: An architectural journey: bioinformatics models. Very less research efforts from trees, dendrons/ to nanomedicine. are being directed to develop new mathematical Nanomedicine. 7(7), 953–956 (2012).

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