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.     

Polymeric Micelles in Anticancer Therapy: Targeting,Imaging and Triggered Release

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward.     

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.     

Micellar Nanocarriers: Pharmaceutical Perspectives

Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol–phosphatidyl ethanolamine conjugate, PEG–PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers.     

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.     

Advances in polymeric micelles for drug delivery and tumor targeting

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α₂-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.From the Clinical EditorThis review summarizes recent developments related to targeted anticancer drug delivery to tumor sites using polymeric micelles via active and passive mechanisms. Polymeric micelles can be conjugated with diverse ligands such as antibodies fragments, epidermal growth factors, α2-glycoprotein, transferrin, folate to target micelles to cancer cells.     

Block copolymer micelles as a solution for drug delivery problems

Micelles, nanosized colloidal particles with a hydrophobic core and hydrophilic shell, can be successfully used for the solubilisation of various poorly soluble pharmaceuticals, and demonstrate a series of attractive properties as drug carriers. Polymeric micelles, such as micelles formed by amphiphilic block copolymers, are of a special interest as they possess high stability both invitro and invivo, and good biocompatibility. Drug-loaded micelles can spontaneously accumulate in body areas with compromised vasculature (tumours, infarcts) via the enhanced permeability and retention (EPR) effect. Micelles made of stimuli-responsive (pH- or temperature-sensitive) amphiphilic block copolymers can release their contents in pathological areas demonstrating hyperthermia or acidosis. Various specific targeting ligand molecules, such as antibodies, can be attached to the micelle surface and bring drug-loaded micelles to, and into, target cells (cancer cells being a primary target). Micelles carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. This review will consider some recent trends in using micelles as pharmaceutical carriers.     

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.     

Polymeric micelles as a new drug carrier system and their required considerations for clinical trials

Importance of the field: A polymeric micelle is a macromolecular assembly composed of an inner core and an outer shell, and most typically is formed from block copolymers. In the last two decades, polymeric micelles have been actively studied as a new type of drug carrier system, in particular for drug targeting of anticancer drugs to solid tumors.

Areas covered in this review: In this review, polymeric micelle drug carrier systems are discussed with a focus on toxicities of the polymeric micelle carrier systems and on pharmacological activities of the block copolymers. In the first section, the importance of the above-mentioned evaluation of these properties is explained, as this importance does not seem to be well recognized compared with the importance of targeting and enhanced pharmacological activity of drugs, particularly in the basic studies. Then, designs, types and classifications of the polymeric micelle system are briefly summarized and explained, followed by a detailed discussion regarding several examples of polymeric micelle carrier systems.

What the reader will gain: Readers will gain a strategy of drug delivery with polymeric carriers as well as recent progress of the polymeric micelle carrier systems in their basic studies and clinical trials.

Take home message: The purpose of this review is to achieve tight connections between the basic studies and clinical trials.     

PEG-b-PPS diblock copolymer aggregates for hydrophobic drug solubilization and release: cyclosporin A as an example

Micelles formed from amphiphilic block copolymers have been explored in recent years as carriers for hydrophobic drugs. In an aqueous environment, the hydrophobic blocks form the core of the micelle, which can host lipophilic drugs, while the hydrophilic blocks form the corona or outer shell and stabilize the interface between the hydrophobic core and the external medium. In the present work, mesophase behavior and drug encapsulation were explored in the AB block copolymeric amphiphile composed of poly(ethylene glycol) (PEG) as a hydrophile and poly(propylene sulfide) PPS as a hydrophobe, using the immunosuppressive drug cyclosporin A (CsA) as an example of a highly hydrophobic drug. Block copolymers with a degree of polymerization of 44 on the PEG and of 10, 20 and 40 on the PPS respectively (abbreviated as PEG44-b-PPS10, PEG44-b-PPS20, PEG44-b-PPS40) were synthesized and characterized. Drug-loaded polymeric micelles were obtained by the cosolvent displacement method as well as the remarkably simple method of dispersing the warm polymer melt, with drug dissolved therein, in warm water. Effective drug solubility up to 2 mg/mL in aqueous media was facilitated by the PEG- b-PPS micelles, with loading levels up to 19% w/w being achieved. Release was burst-free and sustained over periods of 9-12 days. These micelles demonstrate interesting solubilization characteristics, due to the low glass transition temperature, highly hydrophobic nature, and good solvent properties of the PPS block.     

Pharmacokinetics and disposition of nanomedicine using biodegradable PEG/PCL polymers as drug carriers

Micelles assembled from amphiphilic poly(ethylene glycol)/poly(-caprolactone) (PEG/PCL) copolymers are promised as safe and effective drug delivery systems. They offer the potential to achieve high solubility of hydrophobic drugs, long blood circulation time and effective delivery to target organs. These advantages contribute to their application as vehicles of a broad variation of therapeutic compounds. In this review, we discussed the safety of the copolymers, release behavior of PEG/PCL micelles in vitro, and pharmacokinetic profiles referring to the optimized fate in vascular system and targeting biodistribution.     

pH响应性聚合物胶束及其在抗癌药物给药系统中的研究进展

 聚合物纳米粒作为一种有效的药物运送载体已经受到广泛的关注,具有环境响应性的聚合物胶束的制备及应用是目前引人瞩目的研究方向。最近,pH响应性聚合物胶束已被用作抗癌药物的运送载体,其显著的优势就是能够靶向给药于病灶部位,从而降低不良反应,提高抗癌药物的化疗指数。文中综述了pH值响应性的聚合物胶束的两种主要制备策略,即依赖于共聚物骨架中的“可滴定”基团;引入可被酸降解的连接臂,还介绍了pH值响应性聚合物胶束在抗癌药物给药系统中的应用。     

Lipid-core micelles for targeted drug delivery

Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used for the solubilization of various poorly soluble pharmaceuticals and demonstrate a series of attractive properties as drug carriers. Polymeric micelles, i.e. micelles formed by amphiphilic block co-polymers possess high stability both in vitro and in vivo and good biocompatibility. Among those micelles, lipid-core micelles, i.e. micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol-phosphatidyl ethanolamine conjugate, PEG-PE) are of special interest. These micelles can effectively solubilize a broad variety of poorly soluble drugs (anticancer drugs in particular) and diagnostic agents. Drug-loaded lipid-core micelles can spontaneously target body areas with compromised vasculature (tumors, infarcts) via the enhanced permeability and retention (EPR) effect. Lipid-core mixed micelles containing certain specific components (such as positively charged lipids) are capable of escaping endosomes delivering incorporated drugs directly into the cell cytoplasm. Various specific targeting ligand molecules (such as antibodies) can be attached to the surface of the lipid-core micelles and bring drug-loaded micelles to and into target cells. Lipid-core micelles carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities.     

Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles

A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t _1/2β and AUC of the micelle formulation were 4.9 and 5.3-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs.

The objective of this study is to investigate the solubilization of poorly water-soluble anticancer drugs, octaethylporphine (OEP), meso-tetraphenyl porphine (mTPP) and camptothecin (CPT), in Pluronic and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) polymeric micelles. Three different Pluronic and PEG-DSPE polymers with various chain lengths were chosen and micelle formulations were prepared by using various drug:polymer ratios. Formulations were characterized by critical micellization concentration (CMC) values of copolymers, micelle particle size and distribution, zeta potential, loading efficiency and stability. Polymers formed very stable, low CMC micelles with smaller sizes than 100 nm. It was shown that drug loading efficiency highly depends on the polymer type, drug type and their ratios. The most efficient drug loading was obtained by loading mTPP in PEG2000-DSPE and Pluronic F127 micelles. This result is attributed to phenyl groups in mTPP might lead to attraction between alkyl groups in the polymer and increase drug incorporation. PEG-DSPE formulations had higher zeta potential values indicating that they would be more stable against aggregation than Pluronic micelles. From the drug assay aspect Pluronic micelles remained more stable in 3-month long stability test. These results showed that besides their solubilizing effects, polymeric micelles could be useful as novel drug carriers for hydrophobic drugs.     

Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids

Paclitaxel-loaded mixed polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-PE), solid triglycerides (ST), and cationic Lipofectin lipids (LL) have been prepared. Micelles with the optimized composition (PEG-PE/ST/LL/paclitaxel = 12/12/2/1 by weight) had an average micelle size of about 100 nm, and zeta-potential of about -6 mV. Micelles were stable and did not release paclitaxel when stored at 4 degree C in the darkness (just 2.9% of paclitaxel have been lost after 4 months with the particle size remaining unchanged). The release of paclitaxel from such micelles at room temperature was also insignificant. However, at 37 degree C, approx. 16% of paclitaxel was released from PEG-PE/ST/LL/paclitaxel micelles in 72 h, probably, because of phase transition in the ST-containing micelle core. In vitro anticancer effects of PEG-PE/ST/LL/paclitaxel and control micelles were evaluated using human mammary adenocarcinoma (BT-20) and human ovarian carcinoma (A2780) cell lines. Paclitaxel in PEG-PE/ST/LL micelles demonstrated the maximum anti-cancer activity. Cellular uptake of fluorescently-labeled paclitaxel-containing micelles by BT-20 cells was investigated using a fluorescence microscopy. It seems that PEG-PE/ST/LL micelles, unlike micelles without the LL component, could escape from endosomes and enter the cytoplasm of BT-20 cancer cells thus increasing the anticancer efficiency of the micellar paclitaxel.     

Ketal containing amphiphilic block copolymer micelles as pH-sensitive drug carriers

pH-Responsive linkages have been widely exploited in the development of polymeric drug delivery systems, which trigger drug release selectively at tumor tissues or endosomes and lysosomes of cells. Herein we report new pH-sensitive amphiphilic poly(ketal adipate)-co-poly(ethylene glycol) block copolymers (PKA-PEG), which have acid-cleavable ketal linkages in their hydrophobic backbone. PKA-PEG copolymers self-assemble to form stable micelles with a mean diameter of ~175 nm, which can encapsulate a payload of anticancer drugs and rapidly dissociate to release drug payload at the acid environment. The micelles are biocompatible and exhibit abilities to disrupt endosomes to enhance the cytosol drug delivery. Taken together, we anticipate that the pH-sensitive PKA-PEG micelles have great potential as anticancer drug carriers.