International Journal of Molecular Sciences Review Nanocarriers for Biomedicine: From Lipid Formulations to Inorganic and Hybrid Nanoparticles Ruslan Kashapov *, Alsu Ibragimova, Rais Pavlov, Dinar Gabdrakhmanov, Nadezda Kashapova, Evgenia Burilova, Lucia Zakharova and Oleg Sinyashin A.E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov Street 8, 420088 Kazan, Russia; [email protected] (A.I.); [email protected] (R.P.); [email protected] (D.G.); [email protected] (N.K.); [email protected] (E.B.); [email protected] (L.Z.); [email protected] (O.S.) * Correspondence: [email protected]; Tel.: +7-(843)-273-22-93; Fax: +7-(843)-273-22-53 Abstract: Encapsulation of cargoes in nanocontainers is widely used in different fields to solve the problems of their solubility, homogeneity, stability, protection from unwanted chemical and biological destructive effects, and functional activity improvement. This approach is of special importance in biomedicine, since this makes it possible to reduce the limitations of drug delivery related to the toxicity and side effects of therapeutics, their low bioavailability and biocompatibility. This review highlights current progress in the use of lipid systems to deliver active substances to the human body. Various lipid compositions modified with amphiphilic open-chain and macrocyclic compounds, peptide molecules and alternative target ligands are discussed. Liposome modification also evolves by creating new hybrid structures consisting of organic and inorganic parts. Such nanohybrid platforms include cerasomes, which are considered as alternative nanocarriers allowing to reduce inherent limitations of lipid nanoparticles. Compositions based on mesoporous silica Citation: Kashapov,R.; Ibragimova, A.; are beginning to acquire no less relevance due to their unique features, such as advanced porous Pavlov, R.; Gabdrakhmanov, D.; Kashapova, N.; Burilova, E.; properties, well-proven drug delivery efficiency and their versatility for creating highly efficient Zakharova, L.; Sinyashin, O. nanomaterials. The types of silica nanoparticles, their efficacy in biomedical applications and hybrid Nanocarriers for Biomedicine: From inorganic-polymer platforms are the subject of discussion in this review, with current challenges Lipid Formulations to Inorganic and emphasized. Hybrid Nanoparticles. Int. J. Mol. Sci. 2021, 22, 7055. https://doi.org/ Keywords: drug delivery; liposome; non-covalent modification; surfactant; peptide; macrocycle; 10.3390/ijms22137055 mesoporous silica; hybrid nanocarriers; cerasome Academic Editor: Christian Celia Received: 3 June 2021 1. Introduction Accepted: 26 June 2021 Published: 30 June 2021 One of the ways to improve the effectiveness of medical therapies is the use of drug delivery systems. This makes it possible to increase bioavailability and biocompatibility of Publisher’s Note: MDPI stays neutral drugs, to optimize their release profile, overcome biological barriers, and control targeting with regard to jurisdictional claims in properties, cellular uptake and intracellular trafficking [1–3]. Of particular interest is the published maps and institutional affil- delivery of anticancer drugs that can, in the future, reduce the severity of disease and iations. mortality rate. The chemotherapy drugs used today for the treatment of tumors, such as 5-fluorouracil, methotrexate and doxorubicin (DOX), do efficiently suppress tumors, but also cause concomitant tissue damage, which leads to the development of adverse reactions comparable in severity to the underlying disease. In this concern, the nanosystems capable of shielding a chemotherapy drug from interacting with healthy tissues and their release Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. after penetrating into tumor cells, are of great interest. Despite numerous publications This article is an open access article on the topic, this problem has not yet been fully resolved, and further progress in this distributed under the terms and area is obviously related to a rational design of nanocarriers with controlled transport conditions of the Creative Commons properties, morphology and size, taking into account the behavior in biological media and Attribution (CC BY) license (https:// mechanisms of penetration into cells. creativecommons.org/licenses/by/ To construct drug carriers, numerous strategies are developed, in which different 4.0/). factors should be taken into account, including size characteristics, composition of formu- Int. J. Mol. Sci. 2021, 22, 7055. https://doi.org/10.3390/ijms22137055 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7055 2 of 50 lations, nature and therapeutic indications of the drug, and a route of administration. A powerful tool for engineering the formulated medicines is their conjugation with functional ligands, thereby producing prodrugs with beneficial characteristics. For this purpose, polyethylene glycol (PEG), peptides and amphiphilic molecules are used [4–8], which allow modifying pharmacokinetics, toxicity, targeting properties, stimuli responsibility and other effects. Alternatively, encapsulation techniques are used, which provide effective facilities for the design of drug delivery systems. Importantly, the combination of these approaches may be successfully applied, resulting in synergic effect. Encapsulation strate- gies address different techniques and involve numerous types of systems composed of a variety of materials, which can be basically divided in organic and inorganic carriers. In turn, the two main families of organic systems are those based on amphiphilic (lipid and surfactant) [9–11] and polymeric [12,13] compounds. Both these groups provide marked advances in efficacy of loaded drugs due to optimizing their circulation and stability in bioenvironment. Essential feature of organic formulations is soft nature of the systems that allow for tailoring of morphology and shape characteristics, thereby providing the diversity of forms and sub-types of nanocarriers, including liposomes, solid lipid nanoparticles, nanostructural lipid particles, nanoemulsions, cubosomes, polymersomes, etc. [14,15]. In- organic nanoparticles, e.g., metal oxides, gold and silica particles, fullerenes, quantum dots, etc., provide effective and versatile platform for the fabrication of drug delivery vehicles and diagnostic imaging agents [16–18]. These materials demonstrate exclusive optical, mag- netic and electric properties in combination with enhanced loading capacity, mechanical stability, easy fabrication, controlled size and/or pore characteristics and other beneficial features, which can be tailored through proper choice of synthetic and functionalization techniques. Meanwhile, the highest biomedicine potential in terms of efficacy of therapy, safety, targeted delivery, triggered release, reduced toxicity and side effect can be offered by hybrid nanocarriers [19–22]. The current trends towards the development of hybrid for- mulations allow for attaining the synergy of beneficial properties of organic/inorganic [18], polymer/inorganic [19], lipid/inorganic [20], lipid/polymer [21] systems, etc. The urgency of this review is motivated by an intensively developed sphere of drug delivery, which is reflected in sharp growth of publications on this theme. High interest of researchers in the design of different types of nanocontainers occurs, with a clear trend towards multifunctional and complicated formulations observed. Meanwhile, there are a number of recent comprehensive reviews in different specific aspects, in which drug delivery systems are classified based on the chemical nature and prescription of a medicine, the type of nanocarriers [9], the target site [3,23,24] and the administration route [25,26]. Alternatively, based on the above analysis, two distinct families of nanocarriers, namely, lipid formulations and silicon-containing nanoparticles (Figure1), as well as intermediary cerasomes, have been chosen herein, with a focus on recent publications covering the drug encapsulation technique and emphasizing the aspects insufficiently highlighted elsewhere, e.g., development of hybrid formulations via non-covalent modification of nanocarriers aimed at the improving of their stability, targeting effects, multicentered drug loading and toxicity profile. First, liposomal formulations are discussed, with main attention paid to those non-covalently modified with surfactants, peptide moieties, macrocycles and other ligands that may offer targeting properties, morphological diversity, additional binding sites for drugs, etc. Further, mesoporous silica nanoparticles are reviewed, with those modified by polymers emphasized. Various liposomal forms containing inorganic frag- ments, namely lipid-modified mesoporous nanoparticles and cerasomes are also considered. Such structure of the review may allow researchers to receive comparative analysis of these nanocarriers and their potential applications for different drugs and administration pathways. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 52 Int. J. Mol. Sci. 2021, 22, 7055 3 of 50 Figure 1. Main types of lipid- and silicon-containing nanoparticles, comprising many kinds of Figure 1. Mainnanocarriers types of lipid that- canand be silicon used-containing to achieve thenanoparticles, best medical comprising performance. many kinds of nanocarriers that can be used to achieve the best medical performance. 2. Lipid Formulations: Modification with Surfactants, Peptides, and Macrocycles