Polymeric micelles as nanocarriers for drug delivery

Polymeric micelles are built from amphiphilic polymers through self-assembly effects. Due to their unique core shell structure, small size and modifiable surface, polymeric micelles have been widely investigated as nanoscale drug delivery carriers. Such systems may increase drug solubility and have possible applications in tumour targeting and gene therapy. These biomedical applications require that polymeric micelles are biocompatible, have prolonged blood circulation and possess high drug-loading efficiency. In addition, tumour targeting and smart drug release behaviour need special modification towards micelles with multiplicate functional substances. This review focuses on the present progress of polymeric micelles and highlights some critical issues for their application in drug delivery systems. Composition and micellisation procedures are also briefly discussed.     

Block copolymer micelles for drug delivery: Design,characterization and biological significance

Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core–shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article.     

Block copolymer micelles for drug delivery: design, characterization and biological significance

Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core-shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article.     

Micelles based on HPMA copolymers

Polymeric micelles have been under extensive investigation during the past years as drug delivery systems, particularly for anticancer drugs. They are formed by the self-assembly of amphiphilic block copolymers in aqueous solutions and have a spherical shape and a size in the nano-range (< 200 nm). Tumor accumulation of polymeric micelles upon intravenous administration can occur as a result of the leaky vasculature of tumor tissue (called the enhanced permeation and retention (EPR) effect).To benefit from the EPR effect, polymeric micelles need to have prolonged circulation times as well as high and stable drug loadings. Poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) is a hydrophilic polymer currently under investigation for its use in polymer-drug conjugates. Its biocompatibility, non-immunogenicity and the possibility for functionalization are properties that resulted in broad pharmaceutical and biomedical applications, also in the micelle technology research. Being hydrophilic, it can serve as a micellar stealth corona, while it can also be modified with hydrophobic moieties to serve as a micellar core in which hydrophobic drugs can be solubilized and retained. HPMA-based polymeric micelles have been showing very promising in vitro and in vivo results. This review summarizes the applications of pHPMA in the field of polymeric micelles, either serving as a micellar stealth corona, or, if hydrophobically rendered by derivatization, as a micellar core.     

Disposition of Drugs in Block Copolymer Micelle Delivery Systems

Since their discovery in the early 1980s, polymeric micelles have been the subject of several studies as delivery systems that can potentially improve the therapeutic performance and modify the toxicity profile of encapsulated drugs by changing their pharmacokinetic characteristics. The efforts in this area have led in recent years to the advancement of several polymeric micellar formulations to clinical trials, some of which have shown promise in changing the biodistribution of the incorporated drug after intravenous administration as a means of tumour-targeted drug delivery. Recently, the possible benefit of polymeric micellar delivery in enhancing the absorption and bioavailability of incorporated drugs from alternative routes of drug administration has attracted interest. This article provides an overview of the effect of polymeric micellar delivery on absorption, distribution, metabolism and excretion of incorporated therapeutic agents. It also aims to assess the current information on the performance of polymeric micellar delivery systems in modifying the pharmacokinetics/pharmacodynamics of the incorporated drugs in clinical trials, and to re-examine the important structural factors required for successful design of polymeric micellar delivery systems capable of inducing favourable changes in the pharmacokinetics of the encapsulated drug.     

聚合物胶束作为药物载体及其在肿瘤靶向方面的研究进展

聚合物胶束具有粒径小、稳定性高、滞留时间长、良好的生物相容性等特点,这些优良性质使得聚合物胶束作为药物载体具有许多独特的优势。近年来,涌现了许多围绕聚合物胶束设计肿瘤靶向给药系统的报道,包括利用肿瘤的病理学性质,设计被动靶向给药系统和对聚合物胶束进行表面修饰,设计主动靶向给药系统。本文主要综述了聚合物胶束作为肿瘤靶向药物载体的研究进展。     

多功能聚合物胶束的最新研究进展

由两亲性聚合物形成的胶束是一种很有发展前景的纳米级药物载体。聚合物胶束作为药物载体具有许多优势,如载药能力强、粒径小、体内循环时间长、具有主动和被动靶向性等特点。聚合物胶束的最新研究主要集中在使其功能更加完善方面,即多功能聚合物胶束的研究。现按照多功能聚合物胶束到达目标部位后发挥效用的方式对其进行分类,并对其最新研究进展和应用进行综述。     

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system

The anticancer drug, adriamycin (ADR), was incorporated by physical entrapment into polymeric micelles for selective delivery to a murine solid tumor colon adenocarcinoma 26 (C 26). In vivo antitumor activity of ADR was greatly enhanced by this incorporation into polymeric micelles. Using one polymeric micelle delivery system, the tumor completely disappeared at two doses, while free ADR exhibited a fair inhibition effect on tumor growth only at the maximum tolerated dose. Biodistribution analysis revealed that the physically entrapped micellar ADR accumulated at tumor sites in a highly selective manner. These results indicate that these polymeric micelles are a promising system for delivering hydrophobic anticancer drugs selectively to solid tumor sites using a passive targeting mechanism.     

聚合物胶束在肿瘤靶向给药系统中的研究进展

摘 要 聚合物胶束作为一种有效的药物运送载体已经受到广泛关注,其在肿瘤治疗方面具有高效,长效和高载药量等优势。本文综述了聚合物胶束的类型,制备材料,载药方法,主要讨论了肿瘤靶向载药系统中的靶向策略和应用实例。     

Biodegradable amphiphilic polymer–drug conjugate micelles

The coupling of drugs to macromolecular carriers received an important impetus from Ringsdorf's notion of polymer–drug conjugates. Several water-soluble polymers, poly(ethylene glycol), poly[N-(2-hydroxypropyl) methacrylamide], poly(l-glutamic acid) and dextran, are studied intensively and have been utilized successfully in clinical research. The promising results arising from clinical trials with polymer–drug conjugates (e.g., paclitaxel, doxorubicin, camptothecins) have provided a firm foundation for other synthetic polymers, especially biodegradable polymers, used as drug delivery vehicles. This review discusses biodegradable polymeric micelles as an alternative drug–conjugate system. Particular focus is on A-B or B-A-B type biodegradable amphiphilic block copolymer such as polylactide, morpholine-2,5-dione derivatives and cyclic carbonates, which can form a core–shell micellar structure, with the hydrophobic drug-binding segment forming the hydrophobic core and the hydrophilic segment as a hydrated outer shell. Polymeric micelles can be designed to avoid uptake by cells of reticuloendothelial system and thus enhance their blood lifetime via the enhanced permeability and retention effect. Active tumor-targeting may be achieved by modifying the micelle surface with specific ligands. The potential application areas are discussed and future challenges are highlighted.     

Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor

Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood–brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra-arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid–lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers.     

PEG–lipid micelles as drug carriers: physiochemical attributes,formulation principles and biological implication

PEG–lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG–DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG–DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG–lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG–lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG–lipid micelles and their relevance to the inherent advantages and applications of PEG–lipid micelles for drug delivery.     

Nanocarriers for cancer-targeted drug delivery

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.     

Amphiphilic block copolymers for drug delivery

Amphiphilic block copolymers (ABCs) have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery. The utility of ABCs for delivery of therapeutic agents results from their unique chemical composition, which is characterized by a hydrophilic block that is chemically tethered to a hydrophobic block. In aqueous solution, polymeric micelles are formed via the association of ABCs into nanoscopic core/shell structures at or above the critical micelle concentration. Upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate. Although the Pluronics, composed of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), are the most widely studied ABC system, copolymers containing poly(L-amino acid) and poly(ester) hydrophobic blocks have also shown great promise in delivery applications. Because each ABC has unique advantages with respect to drug delivery, it may be possible to choose appropriate block copolymers for specific purposes, such as prolonging circulation time, introduction of targeting moieties, and modification of the drug-release profile. ABCs have been used for numerous pharmaceutical applications including drug solubilization/stabilization, alteration of the pharmacokinetic profile of encapsulated substances, and suppression of multidrug resistance. The purpose of this minireview is to provide a concise, yet detailed, introduction to the use of ABCs and polymeric micelles as delivery agents as well as to highlight current and past work in this area.     

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs

Introduction: Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo.

Areas covered: In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed.

Expert opinion: During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.     

Polymeric micelles - a new generation of colloidal drug carriers.

Polymeric micelles have recently emerged as a novel promising colloidal carrier for the targeting of poorly water soluble and amphiphilic drugs. Polymeric micelles are considerably more stable than surfactant micelles and can solubilize substantial amounts of hydrophobic compounds in their inner core. Due to their hydrophilic shell and small size they sometimes exhibit prolonged circulation times in vivo and can accumulate in tumoral tissues. This review examines the chemical nature of polymeric micelles as well as the methods used to characterize them with regard to drug delivery. Special emphasis is put on the determination of critical micelle concentration and on drug loading procedures. Potential medical applications, especially in cancer chemotherapy, are described and discussed.