Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel

In this work, a series of biodegradable triblock poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) copolymers were successfully synthesized by ring-opening copolymerization, and were characterized by (1)H NMR, FT-IR, GPC, and DSC. Aqueous solutions of PECE copolymers underwent thermosensitive sol-gel-sol transition as temperature increases when the concentration was above corresponding critical gel concentration (CGC). Sol-gel-sol phase transition diagrams were recorded using test tube inverting method, which depended on hydrophilic/hydrophobic balance in macromolecular structure, as well as some other factors, including topology of triblock copolymers and solution composition of the hydrogel. As a result, the sol-gel-sol transition temperature range could be varied, which might be very useful for its application as injectable drug delivery systems. The in vivo gel formation and degradation behavior was conducted by injecting aqueous PECE solution into KunMing mice subcutaneously. In vitro degradation behavior, in vitro drug release behavior, and cytotoxicity were also investigated in this paper. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PECE hydrogel is believed to be promising for in situ gel-forming controlled drug delivery system.     

Modified polypeptides containing gamma-benzyl glutamic acid as drug delivery platforms

We previously reported the development of diffusion-controlled biodegradable polypeptides for drug delivery purposes. In this paper, we describe the synthesis of three modified polypeptides that contain gamma-benzyl glutamic acid as the common structural backbone. The properties of these polymers were characterized with regard to their potential application as drug delivery platforms. Procainamide hydrochloride, a hydrophilic drug, and protamine sulfate, a low molecular weight protein, were used as model drugs for examining release rate profiles from these polymers. The homopolymer of poly(gamma-benzyl-L-glutamic acid), PBLG, showed a highly helical configuration and a moderate release rate of procainamide. Modification of structural attributes by random copolymerization of the D- and L- isomers of gamma-benzyl glutamic acid produced poly(gamma-benzyl-D,L-glutamic acid), PBDLG, which displayed a significantly slower release of procainamide when compared to PBLG. The modification of polymer bulk hydrophobicity by copolymerization of PBLG (A) with poly(ethylene glycol) (B) yielded an ABA triblock copolymer exhibiting much faster release rates for both procainamide and protamine than those demonstrated by the other two polymers. Using this triblock copolymer, protamine release rates ranging from 2 weeks to approximately 2 months were obtained by simply varying the polymer processing conditions and protein particle size. A nearly complete release of protein was obtained from the triblock copolymer blends and this occurred without reliance upon degradation of the polymer backbone. Fickian diffusion-controlled release mechanisms were implied for release of procainamide and protamine from these polypeptide formulations based on the linear relationship displayed between cumulative drug release and the square root of time.     

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.     

Biodegradable microspheres for vitreoretinal drug delivery.

Vitreoretinal disorders are one of the major causes of blindness in the developed world. Treatments of these pathologies often include repeated intravitreous injections to achieve intraocular drug levels within the therapeutical range. However, the risks of complications increase with the frequency of intravitreous injections. Controlled drug delivery formulations, offer an excellent alternative to multiple administrations. These systems are capable of delivering drugs over longer time periods than conventional formulations. Currently, several kinds of polymer devices for drug delivery to the posterior segment of the eye are under clinical use, or under investigation. Among these devices, microparticulates, such as microspheres, provide an alternative to multiple injections to obtain sustained release of the drug with a single administration. Among the polymers used to make the injectable microparticles, the most commonly used are poly(lactic acid), poly(glycolic acid) and copolymers of lactic and glycolic acids because they are biocompatible and degrade to metabolic products that are easily eliminated from the body. This article reviews the literature of biodegradable polymeric microspheres loaded with drugs, that have been investigated for delivery by intravitreous injection to treat diverse vitreoretinal diseases.     

Renewable poly(δ-decalactone) based block copolymer micelles as drug delivery vehicle: in vitro and in vivo evaluation

Polymers from natural resources are attracting much attention in various fields including drug delivery as green alternatives to fossil fuel based polymers. In this quest, novel block copolymers based on renewable poly(δ-decalactone) (PDL) were evaluated for their drug delivery capabilities and compared with a fossil fuel based polymer i.e. methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL). Using curcumin as a hydrophobic drug model, micelles of PDL block copolymers with different orientation i.e. AB (mPEG-b-PDL), ABA (PDL-b-PEG-b-PDL), ABC (mPEG-b-PDL-b-poly(pentadecalactone) and (mPEG-b-PCL) were prepared by nanoprecipitation method. The size, drug loading and curcumin stability studies results indicated that mPEG-b-PDL micelles was comparable to its counterpart mPEG-b-PCL micelles towards improved delivery of curcumin. Therefore, mixed micelles using these two copolymers were also evaluated to see any change in size, loading and drug release. Drug release studies proposed that sustained release can be obtained using poly(pentadecalactone) as crystalline core whereas rapid release can be achieved using amorphous PDL core. Further, mPEG-b-PDL micelles were found to be non-haemolytic, up to the concentration of 40?mg/mL. In vivo toxicity studies on rats advised low-toxic behaviour of these micelles up to 400?mg/kg dose, as evident by histopathological and biochemical analysis. In summary, it is anticipated that mPEG-b-PDL block copolymer micelles could serve as a renewable alternative for mPEG-b-PCL copolymers in drug delivery applications.     

PEGylated nanoparticles for biological and pharmaceutical applications

The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core–shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.     

PEGylated nanoparticles for biological and pharmaceutical applications

The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core-shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.     

Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: is the erosion controlled by degradation, swelling or diffusion?

Erosion of biodegradable parenteral delivery systems (PDS) based on ABA copolymers consisting of poly(L-lactide-co-glycolide) (PLGA) A-blocks attached to polyethylene oxide (PEO) B-blocks, or PLGA is important for the release of macromolecular drugs. The degradation behavior of four types of PDS, namely extruded rods, tablets, films and microspheres, was studied with respect to molecular weight, mass, polymer composition and shape and microstructure of the PDS. For each device the onset time of bulk erosion (t(on)) and the apparent rate of mass loss (k(app)) were calculated. In the case of PLGA, the t(on) was 16.2 days for microspheres, 19.2 days for films and 30.1 days for cylindrical implants and tablets. The k(app) was 0.04 days(-1) for microspheres, 0.09 days(-1) for films, 0.11 days(-1) for implants and 0.10 days(-1) for tablets. The degradation rates were in the same range irrespective of the geometry and the micrographs of eroding PDS demonstrated pore formation; therefore, a complex pore diffusion mechanism seems to control the erosion of PLGA devices. In contrast, PDS based on ABA copolymers showed swelling, followed by a parallel process of molecular weight degradation and polymer erosion, independent of the geometry. The contact angles of ABA films increased either with decreasing PEO content or with increasing chain length of the PEO B-blocks. In summary, the insertion of a hydrophilic B-block leads to an erosion controlled by degradation of ABA copolymers, whereas for PLGA a complex pore diffusion of degradation products controls the rate of bulk erosion.     

Nanostructures as promising tools for delivery of antimicrobial peptides

Antimicrobial peptides have been extensively investigated for their potential applications as therapeutics and food biopreservatives. The antimicrobial activity may be impaired by the susceptibility for proteolytic degradation and undesirable interactions of the antimicrobial peptide in the biological environment. Development of nanostructures for entrapment and delivery of antimicrobial peptides may represent an alternative to the direct application of these substances. Lipid nanovesicles have been developed for encapsulation of antimicrobial peptides. Phosphatidylcholine is often employed in liposome manufacture, which is mostly achieved by the thin-film hydration method. Nanofibers may allow different physical modes of drug loading, including direct adsorption on the nanofiber surface or the assembly of drug-loaded nanoparticles. Self-assembled peptides reveal attractive features as nanostructures for applications in drug delivery and promising as antimicrobial agent for treatment of brain infections. Magnetic nanoparticles and nanotubules are also potential structures for entrapment of antimicrobial peptides. Nanoparticles can be also chemically modified with specific cell surface ligands to enhance cell adhesion and site specific delivery. This article reviews the most important nanostructures as promising tools for peptide delivery systems.     

Varying polymer architecture to deliver drugs

Variable architecture polymers are of considerable interest for the delivery of therapeutic biopolymers, such as DNA and proteins, to their site of action. Polymers that can respond with a change in conformation to biologically relevant stimuli, such as temperature and pH, are being carefully designed to take advantage of the change in environmental conditions the polymer-drug conjugate encounters upon progression from larger-scale systems in the body to subcellular compartments. Viruses respond to changes in the cellular environment to gain access to their desired region of cells, and much can be learned from the mechanisms they employ in this effort. However, despite the efficiency of therapeutic biopolymers, undesirable immune and inflammatory responses may result from their repeated administration, so synthetic polymers are an attractive alternative. This mini-review examines a range of recently developed variable architecture polymers, mainly focusing on polymers responsive to temperature and pH, covering both synthetic copolymers and derivatives of naturally occurring polymers for advanced drug delivery applications. The polymers discussed in the article have some of the properties that are most important for polymer drug delivery vehicles to be effective, such as biodegradability, specificity, and biocompatibility.     

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.     

New poly(ester-amide) copolymers modified with polyether (PEAE) for anticancer drug encapsulation

New poly(ester–amide) copolymers modified with polyethers were developed for carboplatin encapsulation. These new copolymers contain hydrophobic blocks made of tyrosine derivative and dimer fatty acid, and poly(ethylene glycol) (PEG) as hydrophilic blocks. Short-term hydrolytic degradation revealed high water absorption, slight increase of pH of simulated body fluid and change of sample shape, which indicated the erosive mechanism of polymers degradation. Poly(ester-amide)-PEG copolymers were used for microspheres preparation and carboplatin encapsulation. A double emulsification process was used to produce microspheres with an average diameter of 20–30?μm. It was found that the amount of drug released was controlled by the molecular mass of PEG used for microspheres preparation. Mathematical models were used to elucidate the release mechanism of the carboplatin from the microspheres. The results demonstrate that poly(ester-amide)-PEG copolymers may be used for targeted carboplatin encapsulation and release.     

Solubilisation in aqueous micellar solutions of block copoly(oxyalkylene)s

The solubilisation capacities of micellar solutions of diblock and triblock copolymers composed of hydrophilic poly(ethylene oxide) and hydrophobic poly(styrene oxide) have been compared using the poorly water-soluble drug griseofulvin as a model solubilisate. Our results showed an increase of solubilisation capacity (expressed as mg griseofulvin per gram of hydrophobic block) with temperature and, for spherical micelles, with core volume before reaching limiting values. A change of micelle shape from spherical to cylindrical (or worm-like) resulting from an increase in micelle aggregation number was accompanied by a further enhancement of solubilisation capacity. Comparison with the solubilisation of the same drug in micellar solutions of block copolymers of poly(ethylene oxide) and poly(1,2-butylene oxide) showed that the solubilisation capacity of a poly(styrene oxide) block was approximately four times that of a poly(1,2-butylene oxide) block for spherical micelles. Solubilisation capacity at 25 degrees C was approximately doubled when griseofulvin was incorporated into a copolymer melt and micelles initially formed from the drug-loaded melt at 65 degrees C rather than by loading the drug into pre-micellised solution at 25 degrees C in the usual manner.     

Thermosensitive PEG–PCL–PEG Hydrogel Controlled Drug Delivery System: Sol–Gel–Sol Transition and In Vitro Drug Release Study

In this article, biodegradable and low molecular weight poly(ethylene glycol)–poly(ε-caprolactone)–poly(ethylene glycol) (PEG–PCL–PEG, PECE) triblock copolymers were successfully synthesized. Aqueous solution of the obtained PECE copolymers underwent sol–gel–sol transition as temperature increased which was flowing sol at room temperature and then turned into nonflowing gel at body temperature. Sol–gel–sol phase transition behaviors of aqueous PECE solutions were studied using rheometry and test tube-inverting method, which were affected by many factors, including the heating/cooling procedure and different additives in copolymers aqueous solution. In vitro drug release behavior was studied using bovine serum albumin (BSA) and Vitamin B₁₂ (VB₁₂) as model drugs, and the PECE hydrogel could protect BSA from acidic degradation for 1 week at least. Therefore, PECE hydrogel is believed to be promising for injectable in situ gel-forming controlled drug delivery system due to their great thermosensitivity and biodegradability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3707–3717, 2009     

Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles

The process of opsonization is one of the most important biological barriers to controlled drug delivery. Injectable polymeric nanoparticle carriers have the ability to revolutionize disease treatment via spatially and temporally controlled drug delivery. However, opsonin proteins present in the blood serum quickly bind to conventional non-stealth nanoparticles, allowing macrophages of the mononuclear phagocytic system (MPS) to easily recognize and remove these drug delivery devices before they can perform their designed therapeutic function. To address these limitations, several methods have been developed to mask or camouflage nanoparticles from the MPS. Of these methods, the most preferred is the adsorption or grafting of poly(ethylene glycol) (PEG) to the surface of nanoparticles. Addition of PEG and PEG-containing copolymers to the surface of nanoparticles results in an increase in the blood circulation half-life of the particles by several orders of magnitude. This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.     

Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor-specific drug delivery

When a nanoparticle is developed for systemic application, its surface is typically protected by poly(ethylene glycol) (PEG) to help prolonged circulation and evasion of immune clearance. On the other hand, PEG can interfere with interactions between nanocarriers and target cells and negatively influence the therapeutic outcomes. To overcome this challenge, we propose low molecular-weight chitosan (LMWC) as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in the weakly acidic pH of tumors. LMWCs with a molecular weight of 2-4 kDa, 4-6.5 kDa, and 11-22 kDa were produced by hydrogen peroxide digestion and covalently conjugated with poly(lactic-co-glycolic acid) (PLGA). Nanoparticles created with PLGA-LMWC conjugates showed pH-sensitive cell interactions, which enabled specific drug delivery to cells in a weakly acidic environment. The hydrophilic LMWC layer reduced opsonization and phagocytic uptake. These properties qualify LMWCs as a promising biomaterial for pH-sensitive stealth coating.     

In situ Hydrogels Prepared by Photo-initiated Crosslinking of Acrylated Polymers for Local Delivery of Antitumor Drugs

A triblock copolymer was synthesized by ring opening polymerization of ε‐caprolactone in the presence of poly(ethylene glycol) (PEG). The resulted PCL-PEG-PCL triblock copolymer, PEG and monomethoxy (MPEG) were functionalized by end group acrylation. NMR and FT-IR analyses evidenced the successful synthesis and functionalization of polymers. A series of photo-crosslinked hydrogels composed of acrylated PEG-PCL-Acr and MPEG-Acr or PEG-Acr were prepared by exposure to visible light using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as initiator. The hydrogels present a porous and interconnected structure as shown by SEM. The swelling performance of hydrogels is closely related to the crosslinking density and hydrophilic content. Addition of MPEG or PEG results in increase in water absorption capacity of hydrogels. In vitro degradation of hydrogels was realized in the presence of a lipase from porcine pancreas. Various degradation rates were obtained which mainly depend on the hydrogel composition. MTT assay confirmed the good biocompatibility of hydrogels. Importantly, in situ gelation was achieved by irradiation of a precursor solution injected in the abdomen of mice. Doxorubicin (DOX) was selected as a model antitumor drug to evaluate the potential of hydrogels in cancer therapy. Drug-loaded hydrogels were prepared by in situ encapsulation. In vitro drug release studies showed a sustained release during 28 days with small burst release. DOX-loaded hydrogels exhibit antitumor activity against A529 lung cancer cells comparable to free drug, suggesting that injectable in situ hydrogel with tunable properties could be most promising for local drug delivery in cancer therapy.     

Thermoresponsive hydrogels in biomedical applications: A seven-year update

Thermally responsive hydrogels modulate their gelation behavior upon temperature change. Aqueous solutions solidify into hydrogels when a critical temperature is reached. In biomedical applications, the change from ambient temperature to physiological temperature can be employed. Their potential as in situ forming biomaterials has rendered these hydrogels very attractive. Advances in drug delivery, tissue engineering and cell sheet engineering have been made in recent years with the use of thermoresponsive hydrogels. The scope of this article is to review the literature on thermosensitive hydrogels published over the past seven years. The article concentrates on natural polymers as well as synthetic polymers, including systems based on N-isopropylacrylamide (NIPAAm), poly(ethylene oxide)–b-poly(propylene oxide)–b-poly(ethylene oxide) (PEO–PPO–PEO), poly(ethylene glycol) (PEG)-biodegradable polyester copolymers, poly(organophosphazenes) and 2-(dimethylamino) ethyl methacrylate (DMAEMA).