Injectable thermosensitive PLGA-PEG-PLGA triblock copolymers-based hydrogels as carriers for interleukin-2.

Thermosensitive PLGA-PEG-PLGA triblock copolymers with the DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized by bulk copolymerization of DL-lactide, glycolide and PEG1500. The resulting copolymers are soluble in water to form a freely flowing fluid at room temperature but become hydrogels at body temperature. The release of IL-2 from the copolymer-based hydrogel in the phosphate buffer (pH 7.2) was studied at 37 degrees C under agitation. IL-2 was released from the copolymer-based hydrogels over 20 days in vitro and the release rate decreased with increasing copolymer concentration. The change of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer had little effect on the IL-2 release. The released IL-2 remained 57-90% of its original activity during the release period. To evaluate the anti-tumor effect of the IL-2 loaded copolymer, solutions were injected subcutaneously to H22 tumor-bearing mice. IL-2 loaded copolymer hydrogel for in vivo use showed good anti-tumor effect. These results indicate that the thermosensitive PLGA-PEG-PLGA triblock copolymers could be a promising platform for sustained delivery of IL-2.

Effect of bee venom peptide-copolymer interactions on thermosensitive hydrogel delivery systems.

The objectives of this study were to investigate the potential interactions between the model protein drug (bee venom peptide, BVP) and thermosensitive poly(dl-lactide-co-glycolide-b-ethyleneglycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and to examine the drug-copolymer interactions on the in vitro drug release and hydrogel degradation. The PLGA-PEG-PLGA copolymers were synthesized by ring-opening copolymerization of dl-lactide and glycolide with PEG as an initiator. Drug-copolymer co-precipitate blends were prepared and analyzed by Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) to characterize the specific interactions between drug and copolymer. For the better understanding the drug-copolymer interactions on drug release, insulin was selected for comparison. The release of the two protein drugs from the copolymer-based hydrogels and hydrogel degradation was studied at 37 degrees C under agitation. The results of FTIR and XRD indicated that the hydrogen bonding interactions existed between the NH group of BVP and CO group of the copolymers. The insulin and BVP released from the copolymer hydrogel over 15 and 40 days, respectively. The BVP-copolymer interactions retarded the BVP release rate and degradation of hydrogel, but did not significantly affect the biological activity of BVP. These results indicate that the drug-copolymer interactions need to be considered when attempting to use PLGA-PEG-PLGA hydrogels as sustained delivery carriers of protein or peptide drugs.

Sustained release of bee venom peptide from biodegradable thermosensitive PLGA-PEG-PLGA triblock copolymer-based hydrogels in vitro.

Biodegradable thermosensitive poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and were evaluated for sustained release of bee venom peptide in vitro. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The gelation temperature of the copolymer solutions can be influenced by the concentration and DL-lactide/glycolide molar ratio of the copolymers. The release of bee venom peptide from the copolymer-based hydrogel and hydrogel degradation in the phosphate buffer (pH 7.4) was studied at 37 degrees C under agitation. Bee venom peptide was released from the copolymer-based hydrogels over 40 days in vitro and the variation of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer did not significantly affect the release rate of bee venom peptide (P > 0.05). The hydrogels undergo slower degradation and then faster degradation rate during the whole release stage. Accordingly, the mechanism of bee venom peptide was Fickian diffusion during initial stage and then may be a combination of diffusion and degradation. The synthesized copolymers have the advantage of gelation temperature over the ReGel system. These results indicate that the PLGA-PEG-PLGA copolymer-based hydrogel could be a promising platform for sustained delivery of bee venom peptide.

Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels.

Injectable biodegradable temperature-responsive poly(DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/l were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and characterized by 1H NMR. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The hydrophobicity of the copolymer increased with the increasing of DL-lactide/glycolide molar ratio. In vitro dissolution studies with two different hydrophobic drugs (5-fluorouracil and indomethacin) were performed to study the effect of DL-lactide/glycolide molar ratio on drug release and to elucidate drug release mechanism. The release mechanism for hydrophilic 5-fluorouracil was diffusion-controlled, while hydrophobic indomethacin showed an biphasic profile comprising of an initial diffusion-controlled stage followed by the hydrogel erosion-dominated stage. The effect of DL-lactide/glycolide molar ratio on drug release seemed to be dependent on the drug release mechanism. It has less effect on the drug release during the diffusion-controlled stage, but significantly affected drug release during the hydrogel erosion-controlled stage. Compared with ReGel system, the synthesized copolymers showed a higher gelation temperature and longer period of drug release. The copolymers can solubilize the hydrophobic indomethacin and the solubility (13.7 mg/ml) was increased 3425-fold compared to that in water (4 microg/ml, 25 degrees C). Two methods of physical mixing method and solvent evaporation method were used for drug solubilization and the latter method showed higher solubilization efficiency.