Interfacial properties and micellization of triblock poly(ethylene glycol)-poly(ε-caprolactone)-polyethyleneimine copolymers

This study aimed to explore the link between block copolymers’ interfacial properties and nanoscale carrier formation and found out the influence of length ratio on these characters to optimize drug delivery system. A library of diblock copolymers of PEG-PCL and triblock copolymers with additional PEI (PEG-PCL-PEI) were synthesized. Subsequently, a systematic isothermal investigation was performed to explore molecular arrangements of copolymers at air/water interface. Then, structural properties and drug encapsulation in self-assembly were investigated with DLS, SLS and TEM. We found the additional hydrogen bond in the PEG-PCL-PEI contributes to film stability upon the hydrophobic interaction compared with PEG-PCL. PEG-PCL-PEI assemble into smaller micelle-like (such as PEG-PCL4006-PEI) or particle-like structure (such as PEG-PCL8636-PEI) determined by their hydrophilic and hydrophobic block ratio. The distinct structural architectures of copolymer are consistent between interface and self-assembly. Despite the disparity of constituent ratio, we discovered the arrangement of both chains guarantees balanced hydrophilic–hydrophobic ratio in self-assembly to form stable construction. Meanwhile, the structural differences were found to have significant influence on model drugs incorporation including docetaxel and siRNA. Taken together, these findings indicate the correlation between molecular arrangement and self-assembly and inspire us to tune block compositions to achieve desired nanostructure and drug loading.     

Drug stabilization and controlled release from AB3 type tetra block copolymer based polymersome

In order to increase the bioavailability of hydrophilic unstable drugs, polymersomes from AB₃ type tetra block copolymers composing of poly(ethylene glycol)-b-(3) poly(lactic acid) (EO-3LA) as a water-soluble drug delivery carrier have been investigated due to its unique properties such as high stability and high water soluble drug loading efficiency. The sizes of EO-3LA polymersomes determined by dynamic light scattering were ranged in 190?C220?nm with monodispersion. Its polymeric layer with 10?C20?nm at the outershell was observed by field emission scanning electron microscopy. The polymersomes showed low critical aggregation concentrations (9.2?C14.9?ug/ml). Anthocyanin was employed as a model drug for unstable drug in this study. The anthocyanin loading contents of EO-3LA polymersomes are depending on PLLA content in the polymers. The high loading contents (6.6?C7.0?wt%) of the polymersomes are due to their tight and rigid polymeric membranes. The polymeric membrane in EO-3LA polymersomes contributed to improve drug stability on various pHs. Moreover, this property induced sustained anthocyanin release pattern from the polymersome. Therefore, the polymersome has potential as a drug carrier for water-soluble and unstable drugs.     

A review on comb-shaped amphiphilic polymers for hydrophobic drug solubilization

Comb-shaped amphiphilic polymers are rapidly emerging as an alternative approach to amphiphilic block copolymers for hydrophobic drug solubilization. These polymers consist of a homopolymer or copolymer backbone to which hydrophobic and hydrophilic pendant groups can be grafted resulting in a comb-like architecture. The hydrophobic pendants may consist of homopolymers, copolymers and other low-molecular weight hydrophobic structures. In this review, we focus on hydrophobically modified preformed homopolymers. Comb-shaped amphiphilic polymers possess reduced critical aggregation concentration values compared with traditional surfactant micelles indicating increased stability with decreased disruption experienced on dilution. They have been fabricated with diverse architectures and multifunctional properties such as site-specific targeting and external stimuli-responsive nature. The application of comb-shaped amphiphilic polymers is expanding; here we report on the progress achieved so far in hydrophobic drug solubilization for both intravenous and oral delivery.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the 'stealth' properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

Poly(ethylene oxide) based copolymers: solubilisation capacity and gelation

It is thought that almost half of potentially useful drug candidates fail to progress to formulation development because of their low aqueous solubility and associated poor or erratic absorption characteristics. A response to this challenge has been the development of a variety of colloidal delivery systems in which the therapeutic agent is encapsulated in nanosized particles. In this review, attention is focussed on colloidal vectors based on amphiphilic block copolymers, the micelles of which can accommodate a wide range of water-insoluble guest molecules, and particularly on copolymers with poly(oxyethylene) as the hydrophilic block and with poly(oxyalkylene) or polyester hydrophobic blocks, taking advantage of the ‘stealth’ properties of the poly(oxyethylene) corona of their micelles. Although copolymers of this type have been commercially available for several decades in the form of the Pluronic^® (BASF) polyols, which have a poly(oxypropylene) hydrophobic block, they have not found wide application for drug solubilisation, primarily because of their low solubilisation capacity. In attempts to achieve greater drug loading, recent work has concentrated on copolymers in which the core-forming blocks are designed to be more hydrophobic and more compatible with the drug to be encapsulated. Progress in this area has been reviewed and recent developments in the design of block copolymers of this type that combine high drug loading capacity with thermally reversible gelation characteristics in the temperature range suitable for potential application as in situ gelling vehicles following subcutaneous injection have also been discussed.     

High loading of hydrophilic/hydrophobic doxorubicin into polyphosphazene polymersome for breast cancer therapy

Breast cancer remains one of the most common cancers for females. Drug delivery based on cancer nanotechnology could improve the performance of some chemotherapeutic medicines already used in clinic. The emergence of polymersomes provided the potential to encapsulate hydrophobic/hydrophilic drugs. By modifying the weight ratio of methoxy-poly (ethylene glycol) (mPEG) chain to ethyl-p-aminobenzoate (EAB) side group, a series of amphiphilic graft polyphosphazenes (PEPs) was prepared. PEP can be tuned from micelles to polymersomes with the decrease of mPEG content via dialysis. Either hydrophilic doxorubicin hydrochloride (DOX·HCl) or hydrophobic doxorubicin base (DOX) could be encapsulated into PEP polymersomes with high payload and high encapsulation efficiency due to the strong intermolecular interaction with PEP. Compared with free DOX·HCl administration, in vivo investigation in growth inhibition of MCF-7 xenograft tumors in nude mice demonstrated that PEP polymersomes could enhance life safety without compromise of therapeutic efficacy, especially DOX·HCl loaded delivery system.From the Clinical EditorIn this preclinical study, polymerosomes based on PEPs were investigated as doxorubicin delivery systems, demonstrating similar efficacy but less toxicity compared to standard delivery methods.     

ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins.

Hydrogels are very attractive delivery systems for hydrophilic macromolecules such as proteins and DNA because they provide a protective environment and allow control of diffusion by adjusting cross-link densities. Physically cross-linked hydrogels generated by rapid swelling upon exposure to an aqueous environment can be obtained from ABA triblock copolymers containing hydrophobic polyester A-blocks and hydrophilic polyether B-blocks. They provide an attractive alternative to chemically cross-linked systems since they allow incorporation of macromolecular drug substances under mild process conditions. Moreover, they show controlled degradation behavior and excellent biocompatibility. In this review the synthesis and characterization of ABA triblock copolymers from polyester hard segments and poly(ethylene oxide) [PEO] soft segments as well as their biological and degradation properties will be discussed. Their use as biodegradable drug delivery devices in the form of implants, micro- and nanospheres has attracted considerable interest especially for proteins and may provide an alternative to poly(lactide-co-glycolide).     

Block copolymer micelles as long-circulating drug vehicles

The development of block copolymer micelles as long-circulating drug vehicles is described. As well, a recent fundamental study of block copolymer micelles, where much insight into their structures and properties has been realized, is briefly summarized in order to shed light on their properties in vivo. There is emphasis on block copolymer micelles having poly(ethylene oxide) as the hydrophilic block and poly(l-amino acid) as the hydrophobic block, with some discussion on the properties of poly(ethylene oxide). Comparisons are drawn with other drug vehicles and with micelles formed from low molecular weight surfactants. Micelle-forming, block copolymer-drug conjugates are described. Hydrophobic drugs, such as doxorubicin, distribute into block copolymer micelles, and details of several examples are given. Finally, the paper presents studies that evidence the long circulation times of block copolymer micelles. Like long-circulating liposomes, block copolymers that form micelles accumulate passively at solid tumors and thus have great potential for anti-cancer drug delivery.     

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.     

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.     

Hydrophilic polymeric matrices for enhanced transdermal drug delivery

For many drugs with various chemical structures, delivery rates from the hydrophilic polyvinylpyrrolidone (PVP)-polyethylene oxide (PEO) based pressure sensitive adhesive (PSA) matrices of transdermal therapeutic systems (TTS) are higher compared to the hydrophobic TTS matrices. Delivery of propranolol, glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) from the hydrophilic water soluble TTS matrix across human cadaver skin epidermis or skin-imitating polydimethylsiloxane-polycarbonate block copolymer Carbosil membrane in vitro is characterized by high rate values and zero-order drug delivery kinetics up to the point of 75–85% drug release from their initial contents in matrix. Both in vitro and in vivo drug delivery rates from the TTS hydrophilic diffusion matrix are controlled by the skin or membrane permeability and may be described by Fick's law. The contributions of various physicochemical determinants to the control of transdermal drug delivery kinetics are discussed. Pharmacokinetic and pharmacodynamic properties of hydrophilic TTS matrix with propranolol, GTN and ISDN are described.     

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.     

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.     

Design of nanoparticles composed of graft copolymers for oral peptide delivery

The development of a dosage form that improves the absorption of peptide and protein drugs via the gastrointestinal tract is one of the greatest challenges in the pharmaceutical field. Many researchers have taken up the challenge, using approaches including mucoadhesive drug delivery, colon delivery, particulate drug delivery such as nanoparticles, microcapsules, liposomes, emulsions, micelles, and so on. The objective of this article is to provide the reader with outlines of novel nanoparticle technologies for oral peptide delivery based on polymer chemistry. The physicochemical properties of nanoparticles and their behavior on exposure to physiological media are greatly dominated by their chemical structures and surface characteristics. We will especially focus on the design of nanoparticles composed of novel graft copolymers having a hydrophobic backbone and hydrophilic branches as drug carriers.     

Block copolymer micelles for delivery of gene and related compounds

Block copolymers composed of a cationic segment and a hydrophilic segment spontaneously associate with polyanionic DNA to form block copolymer micelles. The distinct feature of the associate is that the core of the polyion complex between DNA and the polycation is coated by a layer of the hydrophilic polymer. The characteristic core-shell structure endows the associate with a high colloidal stability and reduced interaction with blood components. These desirable properties are the major advantages of the micellar DNA delivery system for in vivo application. In this article, the synthesis of block copolymers as well as graft copolymers utilized as DNA delivery systems are described. Particular emphasis is devoted to the association behavior and the physicochemical properties of polyion complex micelles entrapping DNA and related substances in relation to the biological aspects of the associates. Biodistribution and the factors that affect the intracellular fate of the micelles is also addressed based on recent studies in this field.     

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.     

Diffusion Studies of Nanometer Polymersomes Across Tissue Engineered Human Oral Mucosa

Purpose  To measure the diffusion of nanometer polymersomes through tissue engineered human oral mucosa. Methods   In vitro models of full thickness tissue engineered oral mucosa (TEOM) were used to assess the penetration properties of two chemically different polymersomes comprising two of block copolymers, PMPC-PDPA and PEO-PDPA. These copolymers self-assemble into membrane-enclosed vesicular structures. Polymersomes were conjugated with fluorescent rhodamine in order to track polymersome diffusion. Imaging and quantification of the diffusion properties were assessed by confocal laser scanning microscopy (CLSM). Results  TEOM is morphologically similar to natural oral mucosa. Using CLSM, both formulations were detectable in the TEOM within 6 h and after 48 h both penetrated up to 80 μm into the TEOM. Diffusion of PMPC-PDPA polymersomes was widespread across the epithelium with intra-epithelial uptake, while PEO-PDPA polymersomes also diffused into the epithelium. Conclusions  CLSM was found to be an effective and versatile method for analysing the level of diffusion of polymersomes into TEOM. The penetration and retention of PMPC-PDPA and PEO-PDPA polymersomes means they may have potential for intra-epithelial drug delivery and/or trans-epithelial delivery of therapeutic agents.