Biodegradable Block Copolymers Research Articles

Preparation of novel curcumin-loaded multifunctional nanodroplets for combining ultrasonic development and targeted chemotherapy

Recently, a new class of multifunctional nanodroplets that combine the properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated drug delivery has been developed. We studied the formation mechanism of nanodroplets of a drug and its application in chemotherapy. Curcumin was loaded in polymeric micelles as a anti-cancer drug using polyethylene glycol block-poly(caprolactone) with encapsulation efficiency of 95.60%. At room temperature, the developed systems comprised perfluorocarbon nanodroplets stabilized by walls comprising biodegradable block copolymers. Upon heating to 37°C, the nanodroplets were converted to nano/microbubbles. Under ultrasound, nanobubbles cavitated and collapsed, resulting in release of the encapsulated drug. The percentage release of curcumin-loaded nanodroplets by insonation was 90.95%, showing enhancement compared with the non-ultrasound group. Nanodroplets strongly retained the loaded drugs in vivo yet, under ultrasound-mediated vaporization, they released the drugs, thereby implementing effective targeting into the tumor. The tumor inhibition of the group in which curcumin-loaded nanodroplets were combined with ultrasound was 71.30%, more than that of the group of curcumin-loaded nanodroplets (53.00%). Nanodroplets showed high enhancement of anti-cancer effects under ultrasound. Upon intravenous injection, a long-lasting, strong and selective ultrasound contrast was observed, suggesting their coalescence into larger, highly echogenic microbubbles. These multifunctional nanodroplets, which manifest excellent therapeutic and ultrasound properties, could be promising anti-cancer drug delivery systems.

The heat–chill method for preparation of self-assembled amphiphilic poly(ε-caprolactone)–poly(ethylene glycol) block copolymer based micellar nanoparticles for drug delivery

A new method is developed for preparation of amphiphilic block copolymer micellar nanoparticles and investigated as a delivery system for celecoxib, a hydrophobic model drug. Biodegradable block copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) were synthesized by ring opening copolymerization and characterized thoroughly using FTIR, (1)H NMR and GPC. The block copolymer was dispersed in distilled water at 60 °C and then it was chilled in an ice bath for the preparation of the micellar nanoparticles. Polymers self-assembled to form micellar nanoparticles (<50 nm) owing to their amphiphilic nature. The prepared micellar nanoparticles were analyzed using HR-TEM, DLS and DSC. The cytotoxicity of the polymer micellar nanoparticles was investigated against HaCaT cell lines. The study of celecoxib release from the micellar nanoparticles was carried out to assess their suitability as a drug delivery vehicle. Addition of the drug to the system at low temperature is an added advantage of this method compared to the other temperature assisted nanoparticle preparation techniques. In a nutshell, polymer micellar nanoparticles prepared using the heat-chill method are believed to be promising for the controlled drug release system of labile drugs, which degrade in toxic organic solvents and at higher temperatures.

Structures and morphologies of biocompatible and biodegradable block copolymers

Biocompatible and biodegradable block copolymers (BBCPs) have become increasingly important in polymer science, and have many potential applications in polymer materials.

Nanofibrillar Micelles and Entrapped Vesicles from Biodegradable Block Copolymer/Polyelectrolyte Complexes in Aqueous Media

Here we report a viable route to fibrillar micelles and entrapped vesicles in aqueous solutions. Nanofibrillar micelles and entrapped vesicles were prepared from complexes of a biodegradable block copolymer poly(ethylene oxide)-block-poly(lactide) (PEO-b-PLA) and a polyelectrolyte poly(acrylic acid) (PAA) in aqueous media and directly visualized using cryogenic transmission electron microscopy (cryo-TEM). The self-assembly and the morphological changes in the complexes were induced by the addition of PAA/water solution into the PEO-b-PLA in tetrahydrofuran followed by dialysis against water. A variety of morphologies including spherical wormlike and fibrillar micelles, and both unilamellar and entrapped vesicles, were observed, depending on the composition, complementary binding sites of PAA and PEO, and the change in the interfacial energy. Increasing the water content in each [AA]/[EO] ratio led to a morphological transition from spheres to vesicles, displaying both the composition- and dilution-dependent micellar-to-vesicular morphological transitions.

SU-E-U-01: Development of Docetaxel Encapsulated, Ultrasound-Responsive Nanodroplets for Treatment of Prostate Cancer

Purpose: To formulate ultrasound‐responsive nanodroplets loaded with Docetaxel (DTX) drug molecules for efficient delivery into the prostate tumor while minimizing drug related toxicities. Methods: Five mg of DTX and 20 mg of biodegradable amphiphilic block copolymer {poly (ethylene oxide)‐co‐poly (D, L‐lactide)} (PEG‐PDLA) with a molecular weight of either block of 2000 Da, were co‐dissolved in 1ml of tetrahydrofuran (THF). The THF was then evaporated under gentle nitrogen stream at 60°C or pumped out at room temperature. The residual gel matrix obtained was dissolved in 1ml of phosphate buffered saline (pH 7.4) to form polymeric micelles. Subsequently, 20 microlitre of Perfluorocarbon (PFCE) was introduced into this micellar solution and the mixture was emulsified on ice using the ultrasonic processor (Fig.1) (VCX500, Sonics and Materials Inc., CT, USA) to obtain docetaxel‐loaded droplets of the composition− 2% PEG‐PDLA− 0.1% DTX− 2% PFCE (Fig.2). Size distribution of nanodroplets was measured by dynamic light scattering using DynaPro Plate Reader (Fig.3) (Wyatt technology, Santa Barbara, CA). Results: Our results showed that the mean diameter of the drug‐loaded nanodroplets was 220 ± 30nm. Based on published data, the size of the drug‐loaded nanodroplet allows effective accumulation in most tumor types via Enhanced Permeability and Retention (EPR) effect. The core of the nanodroplets containing PFCE is expected to be converted into micro bubbles by pulsed focused ultrasound resulting in localized drug release. Conclusion: We have successfully developed techniques for formulation of docetaxel‐encapsulated nanodroplets which responds to ultrasound. Studies were carried out to characterize the effect of docetaxel‐loaded nanodroplets on the treatment of prostate cancer (LNCaP cell line) in vitro. The treatment effects on tumor growth control were also evaluated using an orthotopic animal prostate tumor model. The results of these studies are reported elsewhere in this meeting.

Linear–dendritic biodegradable block copolymers: from synthesis to application in bionanotechnology

Besides biodegradability and biocompatibility, linear–dendritic biodegradable block copolymers present unique hierarchical self-assembly and multivalent characteristics, making them appealing in stimuli-responsive nanomedicine and hydrogel applications. This minireview highlights the recent progress on linear–dendritic biodegradable block copolymers synthesized via click chemistry, the DNA–/protein–dendritic biohybrids, and their prospects in bionanotechnology.

Nanoparticle Fabrication with Biodegradable Block Copolymer Composed of Hydrophilic Poly(trimethylene carbonate) Derivative and Hydrophobic Polylactide

Abstract A poly(trimethylene carbonate) derivative with a methoxyethoxyl group, poly[5-(2-methoxyethyoxymethyl)-5-methyl-1,3-dioxan-2-one] (poly(TMCM-MOE1OM)), was used as a block copolymer component with polylactide. The hydrophilic properties of the poly(TMCM-MOE1OM) segment resulted in nanoparticles with acetonitrile/water through a self-organized precipitation process. Wide applications of the obtained nanoparticles are expected owing to the biodegradability of both the interior and exterior parts, which are composed of different polymer backbones.

The use of polymeric platinum(IV) prodrugs to deliver multinuclear platinum(II) drugs with reduced systemic toxicity and enhanced antitumor efficacy

Two dinuclear platinum(IV) prodrugs were prepared from cisplatin and oxaliplatin, and tethered to amphiphilic biodegradable block copolymers. The polymeric dinuclear platinum(IV) prodrugs were allowed to self-assemble into nanomicelles, which showed reduced systemic toxicity, relatively long blood circulation, and enhanced antitumor efficacy. In this way, the bottleneck of present multinuclear platinum drugs, especially their severe systemic toxicity, might be overcome.

Block copolymer of poly(ester amide) and polyesters: Synthesis, characterization, and in vitro cellular response

In order to expand the properties and applications of aliphatic absorbable polyesters, a new biodegradable block copolymer family, poly(ester amide)-b-poly(ε-caprolactone) (PEA-b-PCL), was synthesized and characterized. These copolymers were synthesized by first preparing l-phenylalanine-based poly(ester amide) macroinitiators (Phe-PEAs) with free amine end groups via a solution polycondensation. The amine-terminated Phe-PEA macroinitiators were then used to initiate the ring-opening polymerization of ε-caprolactone monomer to prepare the PEA-b-PCL copolymers. The molecular weight (MW) of PEA-b-PCLs can be well controlled by adjusting the Phe-PEA MW and weight ratio of ε-caprolactone to Phe-PEA, and ranged from 7 to 50kgmol−1. The copolymers’ structure and properties were characterized by various physicochemical methods, such as nuclear magnetic resonance, gel permeation chromatography and solubility testing. The in vitro enzymatic biodegradation tests were performed to evaluate the biodegradation rate of the copolymers. The results showed that the introduction of Phe-PEA to PCL did not significantly change the degradation rate of PCL. Biological studies were conducted to assess the polymer’s biological properties, like supporting the cell attachment and proliferation, and inflammation response. The results showed that the bovine aortic endothelial cells had very good attachment and proliferation performance on PEA-b-PCL coating surface. TNF-α release profiles showed that PEA-b-PCL exhibited a muted J774 macrophage inflammatory response.

Encapsulation of cell‐adhesive RGD peptides into a polymeric physical hydrogel to prevent postoperative tissue adhesion

Peptides containing the sequence of arginine-glycine-aspartate (RGD), a famous adhesion moiety, can specifically conjugate integrins in cell membranes, and are usually applied to enhance cell adhesion after linking to solid substrates in tissue engineering or to nanoparticles in targeting delivery. This paper reveals, however, that free RGD peptides can assist in preventing tissue adhesion by blocking focal adhesion between cells and surfaces of barrier devices. In order to avoid a rapid peptide loss after straightforward injection of a peptide solution, we employed a thermosensitive injectable hydrogel composed of a biodegradable block copolymer poly(ε-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA) to encapsulate peptides cyclo(-RGDfK-). A sustainable release for one week was achieved in vitro. The rabbit model of sidewall defect and bowel abrasion was selected to examine the in vivo anti-adhesion efficacy. It reveals a significant reduction of postoperative peritoneal adhesion in the group of RGD-loaded PCLA-PEG-PCLA hydrogels. We interpret this excellent efficacy by the combination of two effects: first, our hydrogel affords a physical barrier to prevent adhesion between injured abdominal wall and cecum; second, the RGD molecules as integrin blockers released from the hydrogel assist the anti-adhesion.

The use of cholesterol-containing biodegradable block copolymers to exploit hydrophobic interactions for the delivery of anticancer drugs

A series of biodegradable amphiphilic block copolymers with controlled composition and relatively low polydispersity index were synthesized from monomethoxy polyethylene glycol (mPEG-OH, 5 kDa) via organocatalytic ring opening polymerization of aliphatic cyclic carbonate monomers - trimethylene carbonate (TMC) or cholesteryl 2-(5-methyl-2-oxo-1,3-dioxane-5-carboxyloyloxy)ethyl carbamate (MTC-Chol) or a copolymer of both the monomers (TMC and MTC-Chol): mPEG 113- b-PTMC 67, mPEG 113- b-P(MTC-Chol 11) and mPEG 113- b-P(MTC-Chol x- co-TMC y) x+y. These well-defined polymers were employed to study the role of molecular weight and composition of the hydrophobic block of the polymers in loading paclitaxel (PTX), an extremely hydrophobic anticancer drug with rigid structure and strong tendency of self-association to form long fibers. The PTX-loaded micelles were fabricated by simple self-assembly without sonication or homogenization procedures. The results demonstrated that the presence of both MTC-Chol and TMC in the hydrophobic block significantly increased PTX loading levels, and the micelles formed from the polymer with the optimized composition (i.e. mPEG 113- b-P(MTC-Chol 11- co-TMC 30)) were in nanosize (36 nm) with narrow size distribution (PDI: 0.07) and high PTX loading capacity (15 wt.%). In vitro treatment of human liver hepatocellular carcinoma HepG2 cells with blank micelles showed that these polymeric carriers were non-cytotoxic with cell viability greater than 90% at ∼2400 mg/L. Importantly, PTX-loaded micelles were able to kill cancer cells much more effectively compared to free PTX. In addition, these nanocarriers also possessed exceptional kinetic stability. The results from non-invasive near-infrared fluorescence (NIRF) imaging studies showed that these micelles allowed effective passive targeting, and were preferably accumulated in tumor tissue with limited distribution to healthy organs.

Synthesis and characterization of a novel biodegradable amphiphilic MPEG-dendritic block copolymer containing (glycolic acid)-alt-(lactic acid) oligomer and glycerol

Synthesis and characterization of a novel biodegradable amphiphilic MPEG-dendritic block copolymer containing (glycolic acid)-alt-(lactic acid) oligomer and glycerol

Block copolymers containing poly (3-hydroxybutyrate-co-3-hydroxyvalerate) and poly (ɛ-caprolactone) units: Synthesis, characterization and thermal degradation

Biodegradable block copolymers containing poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and poly (ɛ-caprolactone) (PCL) units (PHCLs) with different contents of PCL block were synthesized successfully by using telechelic hydroxylated PHBV (PHBV-diol) with low molecular weight as a macroinitiator to initiate ring-opening bulk polymerization of ɛ-caprolactone (ɛ-CL). The chemical structure and molecular weight were characterized by 1H NMR, FTIR and GPC. The PHBV and PCL blocks in PHCLs were miscible in amorphous state, and formed separate crystalline phases with lower crystallinity than corresponding homopolymers, which was characterized by DSC and WAXD. The results of TGA showed that PHCLs underwent a two-step thermal degradation process. The thermal degradation process of PCL blocks was significantly different from PCL homopolymers. The activation energies of thermal degradation of PCL blocks calculated by Horowitz and Metzger method were much higher than that of each step of thermal degradation of PCL homopolymers.

Novel Biodegradable Block Copolymers of Poly(ethylene glycol) (PEG) and Cationic Polycarbonate: Effects of PEG Configuration on Gene Delivery

A novel amine-functionalized polycarbonate was synthesized and its excellent gene transfection ability in vitro is demonstrated. In the framework of adapting the cationic polycarbonate for in vivo gene delivery applications, here the design and synthesis of biodegradable block copolymers of poly(ethylene glycol) (PEG) and amine-functionalized polycarbonate with a well-defined molecular architecture and molecular weight is achieved by metal-free organocatalytic ring-opening polymerization. Copolymers in triblock cationic polycarbonate-block-PEG-block-cationic polycarbonate and diblock PEG-block-cationic polycarbonate configurations, in comparison with a non-PEGylated cationic polycarbonate control, are investigated for their influence on key aspects of gene delivery. Among the polymers with similar molecular weights and N content, the triblock copolymer exhibit more favorable physicochemical (i.e., DNA binding, size, zeta-potential, and in vitro stability) and biological (i.e., cellular uptake and luciferase reporter gene expression) properties. Importantly, the various cationic polycarbonate/DNA complexes are biocompatible, inducing minimal cytotoxicities and hemolysis. These results suggest that the triblock copolymer is a more useful architecture in future cationic polymer designs for successful systemic therapeutic applications.

Biodegradable Block Copolymer Micelles with Thiol-Responsive Sheddable Coronas

Novel sheddable micelles having hydrophilic coronas capable of being shed from biodegradable polylactide (PLA) cores by the cleavage of disulfide linkages in response to thiols were prepared by aqueous micellization of PLA-based amphiphilic block copolymers functionalized with disulfides at block junctions. These well-defined copolymers were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization in the presence of a new disulfide-functionalized double-head initiator having both terminal OH and Br groups. (1)H NMR and GPC results indicate that both polymerizations were well-controlled with molecular weight distribution as low as M(w)/M(n) < 1.2. Aqueous micellization to form core/shell micelles with disulfides at the interface of PLA cores and hydrophilic coronas and their thiol-responsive degradation were investigated. In the presence of water-soluble thiols, disulfide linkages in the micelles were cleaved and hydrophilic coronas were lost, causing PLA cores to precipitate due to the loss of colloidal stability. In a biomedical perspective, the new sheddable micelles were not cytotoxic and hence biocompatible.

Novel docetaxel-loaded nanoparticles based on poly(lactide-co-caprolactone) and poly(lactide-co-glycolide-co-caprolactone) for prostate cancer treatment: formulation, characterization, and cytotoxicity studies.

Docetaxel (Dtx) chemotherapy is the optional treatment in patients with hormone-refractory metastatic prostate cancer, and Dtx-loaded polymeric nanoparticles (NPs) have the potential to induce durable clinical responses. However, alternative formulations are needed to overcome the serious side effects, also due to the adjuvant used, and to improve the clinical efficacy of the drug.In the present study, two novel biodegradable block-copolymers, poly(lactide-co-caprolactone) (PLA-PCL) and poly(lactide-co-caprolactone-co-glycolide) (PLGA-PCL), were explored for the formulation of Dtx-loaded NPs and compared with PLA- and PLGA-NPs. The nanosystems were prepared by an original nanoprecipitation method, using Pluronic F-127 as surfactant agent, and were characterized in terms of morphology, size distribution, encapsulation efficiency, crystalline structure, and in vitro release. To evaluate the potential anticancer efficacy of a nanoparticulate system, in vitro cytotoxicity studies on human prostate cancer cell line (PC3) were carried out. NPs were found to be of spherical shape with an average diameter in the range of 100 to 200 nm and a unimodal particle size distribution. Dtx was incorporated into the PLGA-PCL NPs with higher (p < 0.05) encapsulation efficiency than that of other polymers. Differential scanning calorimetry suggested that Dtx was molecularly dispersed in the polymeric matrices. In vitro drug release study showed that release profiles of Dtx varied on the bases of characteristics of polymers used for formulation. PLA-PCL and PLGA-PCL drug loaded NPs shared an overlapping release profiles, and are able to release about 90% of drug within 6 h, when compared with PLA- and PLGA-NPs. Moreover, cytotoxicity studies demonstrated advantages of the Dtx-loaded PLGA-PCL NPs over pure Dtx in both time- and concentration-dependent manner. In particular, an increase of 20% of PC3 growth inhibition was determined by PLGA-PCL NPs with respect to free drug after 72 h incubation and at all tested Dtx concentration. In summary, PLGA-PCL copolymer may be considered as an attractive and promising polymeric material for the formulation of Dtx NPs as delivery system for prostate cancer treatment, and can also be pursued as a validated system in a more large context.

Reaction of Diphenylpicrylhydrazyl (DPPH) with Antioxidants in Presence of Poly(ε-caprolactone)/Poly(N-vinyl-2-pyrrolidone) Block Copolymer Nanoaggregates

The reaction of antioxidants with 2,2-diphenyl-l-picrylhydrazyl (DPPH) has been studied employing both, ethanol and nano aggregates biodegradable block copolymers (BBC) in aqueous solution, as reaction media. Gallate derivatives with different chain lengths (gallic acid, methyl, propyl and octyl gallate) were used as antioxidants model, and BBC containing a central section of poly-epsilon-caprolactone (PCL) and three arms of poly-vinylpirrolidone (PVP) were used to originate nano aggregates in aqueous solution. The course of the reaction was followed by the changes of the DPPH absorption band at 517 nm. In ethanol, using an excess of antioxidants, DPPH was consumed completely by all gallate derivatives. Nevertheless, when the same reaction was carried out in aqueous nano aggregates of BBC, only a partial consumption of DPPH was observed, suggesting the occurrence of a complex reaction mechanism.

Synthesis of Biodegradable Amphiphilic Y-shaped Block Co-polymers via Ring-Opening Polymerization for Drug Delivery

A series of novel Y-shaped biodegradable block co-polymers of poly(ε-caprolactone) (PCL) and poly(ethyl ethylene phosphate) (PEEP) (PCL–(PEEP)2) were synthesized via ring-opening polymerization (ROP) of EEP with bis-hydroxy-functional ROP initiator (init–PCL–(OH)2). The init–PCL–(OH)2 was synthesized by ROP of CL using 4-hydroxybutyl acrylate (HBA) as initiator and L-tartaric acid as catalyst in bulk, and subsequently the resulting vinyl-terminated PCL was end-capped by acetyl chloride, followed by Michael addition using excess diethanolamine. The Y-shaped co-polymers and their intermediates were characterized by 1H-, 13C-, 31P-NMR, FT-IR and gel-permeation chromatography. The results indicated that the molecular weight of the Y-shaped co-polymers increased with the increasing of the molar ratios of EEP to init–PCL–(OH)2 in the feed, while the PCL chain length was kept constant. The amphiphilic block co-polymers could self-assemble into micelles in aqueous solution, which was demonstrated by dynamic light scattering, 1H-NMR and atomic force microscopy. A study of controlled release of indomethacin indicated that the amphiphilic block co-polymers could potentially provide novel vehicles for drug delivery.

Bioreducible micelles and hydrogels with tunable properties from multi-armed biodegradable copolymers

Multi-armed biodegradable block copolymers with a bioreducible core mPCL-b-PEO were for the first time synthesized by thiol-yne click chemistry. They self-assembled into bioreducible micelles and hydrogels in aqueous solution, which demonstrated tunable size, mechanical and drug-release properties.

Syntheses and characterization of block copolymers of poly(aliphatic ester) with clickable polyphosphoester

AbstractWe report a series of biocompatible and biodegradable block copolymers of poly(ε‐caprolactone) with “clickable” polyphosphoester (PPE). The block copolymers are synthesized through controlled ring‐opening polymerization of five‐membered cyclic phosphoester monomer, propargyl ethylene phosphate (PAEP), initiated with poly(ε‐caprolactone) macroinitiator. The polymerization followed first‐order kinetics with living polymerization characteristics, thus the molecular weight and composition of copolymers are tunable by adjusting the feed ratio of PAEP monomer to macroinitiator. Azide‐functionalized poly(ethylene glycol) has been grafted to the copolymer to demonstrate the reactive feasibility by Cu(I)‐catalyzed “click” chemistry of azides and alkynes, generating “brush‐coil” polymers. The mild conditions associated with the click reaction are shown to be compatible with poly(ε‐caprolactone) and PPE backbones, rendering the click reaction a generally useful method for grafting numerous types of functionality onto the block copolymers. The block copolymers also show good biocompatibility to cells, suggesting their suitability for a range of biomaterial applications. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011