ATRP of Methacrylic Derivative of Camptothecin Initiated with PLA toward Three-Arm Star Block Copolymer Conjugates with Favorable Drug Release (original) (raw)
Related papers
Journal of Biomaterials Science, Polymer Edition, 2011
Amphiphilic block copolymers consisting of hydrophilic poly(ethylene glycol) and hydrophobic polyester bearing pendent cyclic ketals were synthesized by ring-opening copolymerization of εcaprolactone (CL) and 1,4,8-trioxaspiro-[4,6]-9-undecanone (TSU) using α-hydroxyl, ω-methoxy, polyethylene glycol as the initiator and stannous octoate as the catalyst. Compositional analyses indicate that TSU was randomly distributed in the hydrophobic blocks. When the TSU content in the copolymers increased, the polymer crystallinity decreased progressively and the glass transition temperature increased accordingly. Hydrophobic, anticancer drug, camptothecin (CPT), was successfully encapsulated in the block copolymer nanoparticles. The CPT encapsulation efficiency and release kinetics were strongly dependent on the copolymer composition and crystallinity. CPT release from nanoparticles constructed from copolymers containing 0, 39 and 100 mol% TSU in the hydrophobic block followed the same trend, with an initial burst of ~40% within one day followed by a moderate and slow release lasting up to 7 days. At a TSU content of 14 mol%, CPT was released in a continuous and controlled fashion with a reduced initial burst and a 73% cumulative release by day 7. In vitro cytoxicity assay showed that the blank nanoparticles were not toxic to the cultured bone metastatic prostate cancer cells (C4-2B). Compared to the free drug, the encapsulated CPT was more effective in inducing apoptotic responses in C4-2B cells. Modulating the physical characteristics of the amphiphilic copolymers via copolymerization offers a facile method for controlling the bioavailability of anticancer drugs ultimately increasing effectiveness and minimizing toxicity.
Bioconjugate Chemistry, 2011
Poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH 2 ). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20À125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005À0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.
Journal of Controlled Release, 1999
Camptothecin (CPT) and its water-insoluble derivatives are known as topoisomerase-I inhibitors exhibiting high antitumoral activity against a wide spectrum of human malignancies. Until now clinical application of CPT is restricted by insolubility and instability of the drug in its active lactone form resulting in less antitumor potency and poor bioavailability. For these reasons CPT-loaded-microspheres were prepared by the solvent evaporation method using the H-series of poly(D,L-lactide-co-glycolide) (H-PLGA), which contain more carboxylic acid end chains and hydrate faster than the non-H-series. At 1.2% CPT-payload the drug was molecular dispersed throughout the matrix whereas at higher CPT-payload the amount of crystalline CPT-islets increased with the CPT content. The release pattern of CPT was biphasic comprising a first burst effect delivering 20-35% of the payload and increasing with drug-loading. This phase was followed by sustained delivery of CPT releasing 40-75% of the payload within 160 h. In comparison to PLGA-microspheres, the CPT-release rate from H-PLGA was twofold higher and accelerated. The active CPT-lactone was maintained during preparation, storage and release due to hindered diffusion of acidic oligomers among other mechanisms. Thus stabilization and sustained release of CPT from PLGA-microspheres might reduce local toxicity combined with prolonged efficacy offering new perspectives in CPT chemotherapy.
BioMed Research International, 2013
Slowly degradable copolymers of L-lactide and -caprolactone can provide long-term delivery and may be interesting as alternative release systems of cyclosporine A (CyA) and rapamycin (sirolimus), in which available dosage forms cause a lot of side effects. The aim of this study was to obtain slowly degradable matrices containing immunosuppressive drug from PLACL initiated by nontoxic Zr[Acac] 4 . Three kinds of poly(L-lactide-co--caprolactone) (PLACL) matrices with different copolymer chain microstructure were used to compare the release process of cyclosporine A and rapamycine. The influence of copolymer chain microstructure on drug release rate and profile was also analyzed. The determined parameters could be used to tailor drug release by synthesis of demanded polymeric drug carrier. The studied copolymers were characterized at the beginning and during the degradation process of the polymeric matrices by NMR spectroscopy, GPC (gel permeation chromatography), and DSC (differential scanning calorimetry). Different drug release profiles have been observed from each kind of copolymer. The correlation between drug release process and changes of copolymer microstructure during degradation process was noticed. It was determined that different copolymer composition (e.g., lower amount of caprolactone units) does not have to influence the drug release, but even small changes in copolymer randomness affect this process.
e-Polymers, 2012
Present research is a preliminary report on the amphiphilic diblock copolymer (mPLA-b-PGMA) comprising hydrophobic methoxy poly(L-lactide) (mPLA) and hydrophilic poly(glycidyl methacrylate) (PGMA) segments was used as a promising drug carrier. Diblock copolymer was synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) methods. Methanol first initiated ROP of L-lactide in the presence of tin(II)bis(2-ethylhexanoate) (Sn(oct)2) as a catalyst. The resulting monohydroxyl-terminated polylactic acid (mPLA) was subsequently converted to a bromine-ended macroinitiator (mPLA-Br) by esterification with 2-bromisobutyryl bromide. The copolymer mPLA-b-PGMA was synthesized in a subsequent ATRP of GMA. The obtained polymers were characterized by means of 1H NMR, FTIR, DSC and TGA. The copolymer mPLA-b- PGMA self-assembled into nanoscale micelles in aqueous solutions, as investigated by transmission electron microscopy (TEM) and dynamic light scattering (...
Investigation of The Stabilization of Camptothecin Anticancer Drug via PSA-PEG Polymeric Particles
Anadolu University Journal of Science and Technology-A Applied Sciences and Engineering, 2016
Syntheses of biodegradable PSA:PEG copolymers for the formation of nano and micro carriers were performed. Camptothecin (CPT) was selected as an anti-cancer drug. CPT can easily hydrolyze at physiological conditions (pH=7.4). This causes the loss of its activity, and it turns into inactive toxic carboxylate form from active lactone state. To keep anti cancer drug in the lactone form, it was efficiently loaded into PSA:PEG nanoparticles and microparticles, and the stability of CPT in the carriers was fully examined with HPLC. It was found that the drug was highly stable in active form in the prepared nano and microcarriers (>95 %). Particles were imaged with confocal, SEM, and optic microscopes.
Journal of Controlled Release, 2004
The capability of a family of copolymers comprising PluronicR (PEO-PPO-PEO) surfactants covalently conjugated with poly(acrylic acid) (Pluronic-PAA) to enhance the aqueous solubility and stability of the lactone form of camptothecin (CPT) was studied. The unprotected lactone form of CPT, which possesses cytotoxic activity, is rapidly converted to the ring-opened carboxylate form under physiological conditions. Firstly, surfactant properties such as critical micellization concentration (CMC) of Pluronic-PAA copolymers were characterized. Then, the equilibrium solubility partitioning and hydrolysis of the lactone form of CPT in the presence of Pluronic-PAA in water and in human serum were analyzed. CPT solubility in polymer micellar solutions was ca. 3-to 4-fold higher than that in water at pH 5. The amount of CPT solubilized per PPO was considerably greater in the Pluronic-PAA solutions than in the parent PluronicR solution, which suggests that the drug is not only solubilized by the hydrophobic cores and also by the hydrophilic POE-PAA shells of the micelles. The equilibrium partition coefficient of the CPT lactone between Pluronic-PAA solutions and water exceeded (2-3) Â 10 3. The complete solubilization of CPT and the absence of chemical interactions between CPT and Pluronic-PAA were confirmed by modulated temperature differential scanning calorimetry (MTDSC), infrared spectroscopy, and X-ray diffraction of films. The loading of CPT into the Pluronic-PAA micelles was able to prevent the hydrolysis of the lactone group of the drug for 2 h at pH 8 in water. When compared to the unprotected CPT, the kinetics of the CPT hydrolysis in human serum was about 10-fold slower in the Pluronic-PAA formulations.
Macromolecular Bioscience, 2013
A series of amphiphilic linear AB, BAB and star shaped (AB) 3 block copolymers of PCL/P(M)AA have been used for preparation of nanoparticles and drug entrapment. Both the topology of the copolymer and the type of hydrophilic segment are much influencing the critical aggregation concentration (CAC). Two different model drugs, i.e. indomethacin and quercetin, have been employed to investigate drug-copolymer interactions. The size of nanoparticles determined by DLS is less than 160 nm and increases with the amount of drug entrapped in their hydrophobic interior. Drug loading experiments with the nanoparticles based on PAA block copolymers demonstrate a higher efficiency for the star structure, whereas the PMAA star copolymer presents the lowest entrapment ability. The release properties of polymeric self-assemblies being potential candidates for new nanocarriers in drug delivery systems have been studied at room temperature and 37 C in phosphate buffer solutions with pH equal to 5 and 7.4. The kinetic profiles show a strong relation to the copolymer's topology, indicating the lowest release rates from the star based superstructures, while the PMAA particles are less stable than those containing PAA segment(s). The drug release could be controlled by changing the pH value, whereas the influence of temperature is minor.