Biodegradable Block Copolymers Research Articles

Preparation of lactic acid- and glucose-responsive poly(ε-caprolactone)-b-poly(ethylene oxide) block copolymer micelles using phenylboronic ester as a sensitive block linkage.

The present study describes the synthesis, self-assembly and responsiveness to glucose and lactic acid of biocompatible and biodegradable block copolymer micelles using phenylboronic ester as the linkage between hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly(ethylene oxide) (PEO). The PCL block with pendant phenylboronic acid (PCLBA) was synthesized by combining ε-caprolactone (ε-CL) ring-opening polymerisation (ROP), using 4-hydroxymethyl(phenylboronic) acid pinacolate as the initiator, and pinacol deprotection. The glucose-terminated PEO (PEOGlc) was prepared by 1,3-dipolar, Cu(i)-catalysed, alkyne-azide cycloaddition of α-methoxy-ω-propargyl poly(ethylene oxide) and 1-azido-1-deoxy-d-glucopyranose. All new compounds were evaluated by 1H NMR spectroscopy and by SEC analysis. PCLBA and PEOGlc blocks were linked in NaOH acetone solution, which was indirectly confirmed by Alizarin Red S fluorescence and directly by 1H NMR spectroscopy. Dialysis against Milli-Q water induced the self-assembly of PCLBA-b-PEOGlc nanoparticles, which were characterised by static (SLS) and dynamic (DLS) light scattering and by cryogenic transmission electron microscopy (cryo-TEM). Furthermore, the microscopic properties of the charged interface between the hydrophobic PCLBA core and the hydrophilic PEOGlc shell were examined by electrophoretic light scattering (zeta potential) and by fluorescence spectroscopy using the fluorescent probe 5-(N-dodecanoyl)aminofluorescein (DAF) as a pH indicator. Subsequently, the nanoparticles were transferred to a phosphate buffer saline (PBS) solution supplemented with different concentrations of glucose to simulate the physiological conditions in blood or lactic acid to simulate acidic cytosolic or endosomal conditions in tumour cells. Adding a surplus of glucose or lactic acid, which competitively binds to PBA, removes the stabilising hydrophilic PEOGlc blocks, thereby triggering marked nanoparticle aggregation. However, the rate of aggregation induced by lactic acid is considerably faster than that induced by glucose, as confirmed by light scattering. Thus, this novel block copolymer may contribute to the field of selective, lactic acid- and/or glucose-responsive drug delivery vehicle design under both pathological and physiological conditions.

Pickering emulsions stabilized by biodegradable block copolymer micelles for controlled topical drug delivery

Surfactant-free biocompatible and biodegradable Pickering emulsions were investigated as vehicles for skin delivery of hydrophobic drugs. O/w emulsions of medium-chain triglyceride (MCT) oil droplets loaded with all-trans retinol as a model hydrophobic drug were stabilized by block copolymer nanoparticles: either poly(lactide)-block-poly(ethylene glycol) (PLA-b-PEG) or poly(caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG). Those innovative emulsions were prepared using two different processes allowing drug loading either inside oil droplets or inside both oil droplets and non-adsorbed block copolymer nanoparticles. Skin absorption of retinol was investigated in vitro on pig skin biopsies using the Franz cell method. Supplementary experiments by confocal fluorescence microscopy allowed the visualization of skin absorption of the Nile Red dye on histological sections. Retinol and Nile Red absorption experiments showed the large accumulation of hydrophobic drugs in the stratum corneum for the Pickering emulsions compared to the surfactant-based emulsion and an oil solution. Loading drug inside both oil droplets and block copolymer nanoparticles enhanced again skin absorption of drugs, which was ascribed to the supplementary contribution of free block copolymer nanoparticles loaded with drug. Such effect allowed tuning drug delivery to skin over a wide range by means of a suitable selection of either the formulation or the drug loading process.

Micro-structured 3D-electrospun scaffolds of biodegradable block copolymers for soft tissue regeneration

The present article describes the application of a poly(ethylene terephthalate) mesh as template for the preparation of micro-structured fibres mat by electrospinning of biodegradable triblock copolymers based on polylactic acid and poly(butylene succinate/azelate) random copolymer. These copolymers present and excellent controlled biodegradation process in physiological conditions, with interesting applications in targeting and controlled release of different drugs.After the application of the poly(ethylene terephthalate) mesh in the electrospinning process, the detachment of the template provides a specific oriented microfibres mat, that affect to the adhesion and proliferation of cell seeded on the networks. In addition, the microfibres mats were loaded with dexamethasone as anti-inflammatory drug. The release of the drug takes place in a controlled relative short period due to the formation of drug crystals on the surface of the fibres during the electrospinning process. This issue can be restrained by acting on the triblock copolymer composition, improving the drug-polymer compatibility. Copolymerization also allows the modulation of the biodegradation rate. The biodegradable scaffolds under investigation can be therefore considered very promising for regenerative medicine and soft tissue engineering.

Redox-responsive molecular gels based on camptothecin prodrug with disulfide linkage for controlled and sustained drug release

A novel camptothecin (CPT) prodrug was successfully synthesized by conjugating CPT to adamantanecarboxylic acid (AD) via a cleavable disulfide linkage. The resulting CPT-ss-AD prodrug could act as a low molecular weight gelator to form molecular gels in water/water-miscible organic solvent mixture. Meanwhile, biodegradable amphiphilic block copolymer mPEG-b-P (MAC-co-DTC) (PPMD) was also employed as an organic framework together with CPT-ss-AD to form gel structure. CPT-ss-AD/PPMD gel exhibited less compact molecular arrangement but much more stability than CPT-ss-AD gel. The two kinds of gels could effectively release the original CPT under reductive condition at a near-constant rate without any initial burst. As compared to CPT-ss-AD single-component gel, the two-component gel, CPT-ss-AD/PPMD, had a significantly higher release rate of CPT, while 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assays also indicated highly potent cytotoxic activity against HeLa cells.

Structural and Rheological Properties of Temperature-Responsive Amphiphilic Triblock Copolymers in Aqueous Media.

Thermoresponsive amphiphilic biodegradable block copolymers of the type poly(ε-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lactide) (PCLA-PEGm-PCLA) have great potential for various biomedical applications. In the present study, we have surveyed the effects of PEG spacer length (m = 1000 and 1500), temperature, and polymer concentration on the self-assembling process to form supramolecular structures in aqueous solutions of the PCLA-PEGm-PCLA copolymer. This copolymer has a lower critical solution temperature, and the cloud point depends on both concentration and PEG length. Thermoreversible hydrogels are formed in the semidilute regime; the gel windows in the phase diagrams can be tuned by the concentration and length of the PEG spacer. The rheological properties of both dilute and semidilute samples were characterized; especially the sol-to-gel transition was examined. Small-angle neutron scattering (SANS) experiments reveal fundamental structural differences between the two copolymers for both dilute and semidilute samples. The intensity profiles for the copolymer with the long PEG spacer could be described by a spherical core-shell model over a broad temperature domain, whereas the copolymer with the short hydrophilic spacer forms rod-like species over an extended temperature range. This finding is supported by cryo-TEM images. At temperatures approaching macroscopic phase separation, both copolymers seem to assume extended rod-like structures.

Synthesis and Characterization of Novel Biodegradable Di‐ and Tri‐Block Copolymers Based on Ethylene Carbonate Polymer as Hydrophobic Segment

ABSTRACTSynthesis of novel amphiphilic biodegradable block copolymers based on ethylene carbonate is reported in this study. Polyethylene glycol monomethyl ether (MeO‐PEO) and polyethylene glycol (PEG) of varying molar masses are used as macro‐initiator for ring‐opening polymerization of ethylene carbonate in the presence of sodium stannate trihydrate as a heterogeneous transesterification catalyst. Earlier elution of block copolymer from macro‐initiator in size exclusion chromatography (SEC) indicated the successful synthesis of the block copolymers. Ratios of both types of blocks are varied systematically. Liquid chromatography at critical conditions is used for the analysis of the non‐critical individual blocks, and if there are any critical segments that are not attached to the non‐critical block. To the best of our knowledge, this is the first report on the synthesis of ethylene carbonate‐based amphiphilic block copolymers. Chromatographic critical conditions of the ethylene carbonate polymer are also reported for the first time. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 1887–1893

Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle

Osteosarcoma is the most common primary malignant bone tumor in the pediatric age group, and chemotherapy directed by targeted nanoparticulate drug delivery system represents a promising approach for osteosarcoma treatment recently. Here, we designed and developed a novel DOX-loaded targeted polymeric micelle self-assembled from RGD-terminated poly(ethylene glycol)-block-poly (trimethylene carbonate) (RGD-PEG-PTMC) amphiphilic biodegradable block copolymer, for high-efficiency targeted chemotherapy of osteosarcoma. Notably, the RGD-installed DOX-loaded biodegradable polymeric micelle (RGD-DOX-PM) with drug loading efficiency of 57%–73% displayed a narrow distribution (PDI=0.05–0.12) with average sizes ranging from 46 to 73nm depending on the DOX loading content. The release amount of DOX from RGD-DOX-PM achieved 63% within 60h under physiological condition. Interestingly, MTT assays in MG-63 and MNNG/HOS osteosarcoma cells exhibited that half-maximal inhibitory concentration (IC50) value of RGD-DOX-PM was much lower than its non-targeted counterpart (DOX-PM), implying RGD decorated nanoparticles had enhanced cell targeting ability and led to more effective anti-tumor effect. Furthermore, the targeting ability of RGD-DOX-PM was confirmed by in vitro flow cytometry and confocal laser scanning microscopy (CLSM) imaging assays, where the results showed more RGD-DOX-PM were taken up by MG-63 cells than that of DOX-PM. Therefore, this RGD decorated DOX-loaded polymeric micelle is promising for targeted chemotherapy of osteosarcoma.

Development of a fast curing tissue adhesive for meniscus tear repair

Isocyanate-terminated adhesive amphiphilic block copolymers are attractive materials to treat meniscus tears due to their tuneable mechanical properties and good adhesive characteristics. However, a drawback of this class of materials is their relatively long curing time. In this study, we evaluate the use of an amine cross-linker and addition of catalysts as two strategies to accelerate the curing rates of a recently developed biodegradable reactive isocyanate-terminated hyper-branched adhesive block copolymer prepared from polyethylene glycol (PEG), trimethylene carbonate, citric acid and hexamethylene diisocyanate. The curing kinetics of the hyper-branched adhesive alone and in combination with different concentrations of spermidine solutions, and after addition of 2,2-dimorpholinodiethylether (DMDEE) or 1,4-diazabicyclo [2.2.2] octane (DABCO) were determined using FTIR. Additionally, lap-shear adhesion tests using all compositions at various time points were performed. The two most promising compositions of the fast curing adhesives were evaluated in a meniscus bucket handle lesion model and their performance was compared with that of fibrin glue. The results showed that addition of both spermidine and catalysts to the adhesive copolymer can accelerate the curing rate and that firm adhesion can already be achieved after 2 h. The adhesive strength to meniscus tissue of 3.2–3.7 N was considerably higher for the newly developed compositions than for fibrin glue (0.3 N). The proposed combination of an adhesive component and a cross-linking component or catalyst is a promising way to accelerate curing rates of isocyanate-terminated tissue adhesives.

Structural Engineering of Biodegradable PCL Block Copolymer Nanoassemblies for Enzyme-Controlled Drug Delivery in Cancer Cells.

Biodegradable block copolymer chemical structures were engineered as drug nanocarriers to precisely program the enzyme-controlled release of anticancer drugs at intracellular compartments in cancer cells. New classes of amide and ester side chain-substituted caprolactone monomers were designed by multistep organic synthesis and polymerized under ring opening processes to make new classes of substituted polycaprolactone-block-polyethylene glycol copolymers. These block copolymers were self-assembled as stable nanoparticles of <200 nm in water. The polymer nanoparticles were found to be excellent scaffolds for loading a wide range of anticancer drugs and stabilized them at extracellular circulating conditions (37 °C in PBS). At the intracellular level, lysosomal-esterase enzyme biodegraded the aliphatic polyester PCL backbone and facilitated the release of drugs in a steady and controlled manner. In vitro drug release studies confirmed that the amide-PCL block copolymers exhibited controlled drug release compared to that of their non-hydrogen-bonded ester-PCL blocks or unsubstituted PCL blocks. The influence of hydrogen bonding interactions on the drug release profiles of PCL nanoparticles were studied by FT-IR and time-resolved fluorescent decay measurements. Cytotoxicity experiments in cervical cancer (HeLa) and breast cancer (MCF-7) cell lines demonstrated that amide diblock copolymer nanoassemblies show slow and prolonged cell killing. The new block copolymers were capable of loading multiple anticancer drugs like doxorubicin (DOX), curcumin (CUR), camptothecin (CPT), and methotrexate (MTX) that largely differ in pharmacokinetics as well as fluorescent regions for cellular imaging. Interestingly, these different drugs could be delivered to the intracellular compartments of the cancer cells by an identical enzyme-controlled delivery pathway from a single biodegradable block copolymer nanoscaffold. Confocal microscopic images exhibited that the engineered block copolymer nanoparticles were capable of transporting all of these drugs across the cell membrane and accumulating them predominantly in the cytoplasm and peri-nuclear region. The present investigation presents a new opportunity in the structural engineering of biodegradable diblock copolymer nanoassemblies for enzyme-controlled multiple-anticancer-drug administration in cancer therapy.

Low-Temperature Processable Block Copolymers That Preserve the Function of Blended Proteins.

Low-temperature processable polymers have attracted increasing interest as ecological materials because of their reduced energy consumption during processing and suitability for making composites with heat-sensitive biomolecules at ambient temperature. In the current study, low-temperature processable biodegradable block copolymers were synthesized by ring-opening polymerization of l-lactide (LLA) using polyphosphoester as a macroinitiator. The polymer films could be processed under a hydraulic pressure of 35 MPa. The block copolymer films swelled in water because the polyphosphoester block was partially hydrated. Interestingly, the swelling ratio of the films changed with temperature. The pressure-induced order-to-disorder transition of the block copolymers was characterized by small-angle X-ray scattering; a crystallinity reduction in the block copolymers was observed after application of pressure. The crystallinity of the block copolymers was recovered after removing the applied pressure. The Young's modulus of the block copolymer films increased as the LLA unit content increased. Moreover, the modulus did not change after multiple processing cycles and the recyclability of the block copolymers was also confirmed. Finally, polymer films with embedded proteinase K as a model protein were prepared. The activity of catalase loaded into the polymer films was evaluated after processing at different temperatures. The activity of catalase was preserved when the polymer films were processed at room temperature but was significantly reduced after high-temperature processing. The suitability of low-temperature processable biodegradable polymers for making biofunctional composites without reducing protein activity was clarified. These materials will be useful for biomedical and therapeutic applications.

Finely Tuned Thermo-Responsive Block Copolymer Micelles for Photothermal Effect-Triggered Efficient Cellular Internalization.

Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low-efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect-promoted cellular internalization of finely tuned thermo-responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near-infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(ε-caprolactone)-block-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PCL-b-P(NIPAM-co-DMA)), are prepared with finely tuned compositions of P(NIPAM-co-DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co-encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect-induced collapse and hydrophilic-to-hydrophobic transition of P(NIPAM-co-DMA) shells significantly enhance the interactions between drug-loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.

Abstract B40: Concomitant delivery of paclitaxel and NuBCP9 peptide, for the enhancement of synergistic effect, in cancer therapy

Abstract Introduction: Paclitaxel (PTX) is a powerful chemotherapeutic agent that binds to microtubules to prevent tumour cell division. However, a traditional high dose of Paclitaxel may also induce apoptosis in normal cells. NuBCP9, an anticancer peptide (ACP), which selectively binds to the Bcl-2 protein overexpressed almost in all the cancers and convert the anti-apoptotic Bcl-2 to pro-apoptotic and initiate apoptosis. The combination of two or more therapeutic drugs is feasible means to overcome the limitations. Present study explores the synergistic potential of this anticancer peptide in combination with traditional cytotoxic chemotherapeutic drug, to minimize the amount of each drug, for cancer therapy. Method: Drug-containing nanoparticles composed of biodegradable amphiphilic block copolymers of Polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol (PLA-PEG-PPG-PEG, MW = 70K-12K) were synthesized and nanoparticle size was examined. At varying ratios of drugs, loading efficiency and release behaviour was determined. In vitro growth inhibition of these nanoparticle formulations were evaluated in MCF-7 and MDA-MB 231 breast cancer cells by XTT cell proliferation assay, after which IC50 analyses and combination index calculations were conducted. To assess the antitumor effects of nanoparticles in vivo, we treated Balb/c mice bearing established (∼200 mm3) subcutaneous BCL-2-positive Ehrlich syngeneic tumors, intraperitoneally once a week for the duration of three weeks. Results: Developed biodegardable polymeric core-shell nanoparticles were spherical, with an average diameter of ∼90 nm. Both paclitaxel and NuBCP9 peptide loaded favourably in different ratios within nanoparticles. The drug-loaded NPs possessed a better polydispersity (PDI), indicating that they are more readily subject to controlled size distribution. Studies on cellular uptake and drug release from the system demonstrated that both drugs were effectively taken up by the cells and also releases simultaneously for up to 30 days. Combination indices demonstrated that 1:1 ratio of PTX: ACP had the most synergy in both MCF7 and MDA-MB 231 breast cancer cells and IC50 was found to be 30 fold less than the drugs alone in vitro. Significant tumor regression was observed in vivo in combination of PTX-ACP nanoparticles as compared upon single drug administration. Conclusion: Polylactic acid based biodegradable polymeric nanoparticles have the great potential of prolonged delivery of synergistic agents against breast cancer. The synergy shown here permits the use of relatively low concentrations of peptides and drugs to achieve significant anticancer effects in vitro and in vivo. This dose reduction minimizes drug effects on normal cells, enabling an effective apoptosis-mediated anticancer effect without inducing harmful adverse events. Nanoparticle delivery of drugs may also yield enhanced understanding of mechanisms of synergy between molecular-targeted drugs and traditional chemotherapeutics in vivo, resulting in novel and more efficacious treatment regimens. Citation Format: Dikshi Gupta, Sumeet Kapoor, Priyanka Tyagi, Manoj Kumar, Amit Kumar Tyagi, Surender Kharbanda, Harpal Singh. Concomitant delivery of paclitaxel and NuBCP9 peptide, for the enhancement of synergistic effect, in cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B40.

Multifunctional biocompatible and biodegradable folic acid conjugated poly(ε-caprolactone)-polypeptide copolymer vesicles with excellent antibacterial activities.

Cancer patients after chemotherapy may also suffer bacterial attack due to badly decreased immunity. Although with high bacterial efficacy, conventional antibiotics are prone to inducement of drug resistance and may be not suitable for some cancer patients. In contrast, antibacterial peptides are highly effective in inhibiting bacteria without inducing resistance in pathogens. Presented in this article is a novel kind of highly effective antibacterial peptide-based biocompatible and biodegradable block copolymer vesicle. The copolymer is poly(ε-caprolactone)-block-poly[phenylalanine-stat-lysine-stat-(lysine-folic acid)] [PCL19-b-poly[Phe12-stat-Lys9-stat-(Lys-FA)6]], which can self-assemble into vesicles in aqueous solution. The biocompatible and biodegradable PCL forms the vesicle membrane, whereas the poly[Phe12-stat-Lys9-stat-(Lys-FA)6] block constitutes the vesicle coronas. Compared to the individual polymer chains, the vesicles showed enhanced antibacterial activities against both Gram-positive and Gram-negative bacteria (16 μg mL(-1)) due to the locally concentrated antibacterial poly[Phe12-stat-Lys9-stat-(Lys-FA)6] coronas, which may avoid the inducement of antibiotic-resistant bacteria and side effects of multidrug interactions. Furthermore, folic acid is introduced into the vesicle coronas for potential further applications such as cancer-targeted drug delivery. Moreover, the amino groups can be further functionalized when necessary. This low cytotoxic, biocompatible, biodegradable, and antibacterial vesicle (without antibiotic resistance) may benefit patients after tumor surgery because it is highly anti-inflammatory, and it is possible to deliver the anticancer drug to tumor cells simultaneously.

Synthesis and characterization of valproic acid ester pro-drug micelles via an amphiphilic polycaprolactone block copolymer design

The attachment of Histone deacetylase (HDAC) inhibitors via covalent bonds to biocompatible and biodegradable block copolymers provides a new research direction for cancer treatment.

ChemInform Abstract: Structures and Morphologies of Biocompatible and Biodegradable Block Copolymers

AbstractReview: 146 refs.

18. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs: reflections and commentary a decade later: Original research article: Biodegradable block copolymers for delivery and proteins water-insoluble drugs, 2001.

18. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs: reflections and commentary a decade later: Original research article: Biodegradable block copolymers for delivery and proteins water-insoluble drugs, 2001.

Crystallization Behaviors and Structure Transitions of Biocompatible and Biodegradable Diblock Copolymers

Biocompatible and biodegradable block copolymers (BBCPs) containing crystalline blocks become increasingly important in polymer science, and have great potential applications in polymer materials. Crystallization in polymers is accompanied by the adoption of an extended conformation, or often by chain folding. It is important to distinguish between crystallization in homopolymers and in block copolymers. In homopolymers, chain folding leads to metastable structures introduced by the crystallization kinetics. In contrast, equilibrium chain folding in diblocks can be achieved as the equilibrium number of the folds is controlled by the size of the second block. The structures of BBCPs, which are determined by the competition between crystallization, microphase separation, kinetics and processing, have a tremendous influence on the final properties and applications. In this review, we present the recent advances on crystalline–crystalline diblock copolymer in our group.

Development of high drug loaded and customizing novel nanoparticles for modulated and controlled release of Paclitaxel.

The objective of this study was to develop a custom-tailored polymeric drug delivery system for paclitaxel, employing a novel biodegradable block co-polymer (P), intended to be intravenously administered, capable of improving therapeutic index of the drug and devoid of the adverse effect of an uncontrolled release. Paclitaxel loaded nanoparticles (PTX-NPs) were prepared by a modified nanoprecipitation method and emulsification-solvent evaporation method. Our approach involves a focusing on the formulation parameters that can be modified in order to obtain completely customized NPs in terms of size, zeta-potential, drug content and release profile. The biocompatibility and anti-proliferative efficiency of PTX-NPs against glioblastoma cell line were evaluated in vitro by MTS. All formulations showed spherical nanometric (<200nm), monodisperse (~0.1), Poly (Ethylene Glycol) (PEG)-coated and negatively charged particles. Selected NPs revealed higher PTX content (up to 24%) in comparison with polyester-based NPs. The release behaviour of PTX from the developed NPs exhibited an approximately first-order profile, without initial burst and characterized by a slow and constant release. Hydrophobic character of the NPs can be set in order to achieve a slower and more controlled release for a prolonged period of time. PTX-NPs were hemocompatible and had significant in vitro anti-tumoral activity against human primary glioblastoma cell line (U-87 MG); cytotoxicity was in time- and drug concentration- dependent manner. The developed drug delivery system proved to be suitable for intravenous administration. NPs characteristics can be customized to obtain high PTX loaded NPs that can improve therapeutic index and avoid an uncontrolled release.

Polymeric micelles for GSH-triggered delivery of arsenic species to cancer cells

Arsenic trioxide (ATO), dissolved in water as arsenous acid or inorganic arsenite (AsIII), is an effective chemotherapeutic agent against acute promyelocytic leukemia (APL). It has been under investigation as a potential treatment for a variety of solid tumors although with much poorer efficacy than for APL. The toxicity of AsIII and its derivatives is a common concern that has limited its use. The objective of the current study was to develop a polymeric micelle drug delivery system for efficient and controlled delivery of trivalent arsenicals to solid tumor cells. A polymeric micelle-based drug delivery system can potentially extend the duration of drug circulation in blood, restrict access of encapsulated drug to normal tissues, achieve tumor targeted drug delivery, enhance drug accumulation in the tumor area, and trigger drug release at tumor sites if designed properly. These, in turn, can lead to an improved therapeutic index for the polymeric micellar formulation of arsenic species compared to their free form. Towards this goal, a biodegradable block copolymer with pendent thiol groups on the hydrophobic block, i.e., methoxy poly(ethylene oxide)-block-poly[α-(6-mecaptohexyl amino)carboxylate-ε-caprolactone] [PEO-b-P(CCLC6-SH)], was synthesized and used for conjugation of a trivalent arsenical, phenylarsine oxide (PAO), to free thiol groups on the polymer backbone. PAO-loaded micelles had refined size distribution with an average diameter of 150 nm as evidenced by dynamic light scattering (DLS) in water. Prepared polymeric micelles were characterized for the level of PAO conjugation using inductively coupled plasma mass spectrometry (ICP-MS). The results showed 65% of total free thiols were conjugated to PAO providing an arsenic/polymer loading content of ∼2.5 wt%. In vitro release study suggests prolonged release of PAO from its polymeric micellar carrier, which was accelerated in the presence of glutathione (GSH). Cytotoxicity studies against MDA-MB-435 cells show that the IC50 of PEO-b-P(CCLC6-S-PAO) is not significantly different from that of free PAO. The results indicate that PEO-b-P(CCLC6-SH) is a promising carrier for successful arsenic delivery for cancer therapy.