Temperature-responsive biodegradable star-shaped block copolymers for vaginal gels

Abstract

A novel biodegradable temperature-responsive copolymer, 4-arm star-shaped poly(D,L-lactic-coglycolic acid)-b-methoxy poly(ethylene glycol) (4sPLGA-mPEG), was synthesized via the arm-first method. The copolymer solution of various concentrations was prepared to form vaginal gels at body temperature, in order to encapsulate different anti-HIV drugs, anti-inflammatory drugs or contraceptive drugs. The 4sPLGA-mPEG block copolymer solutions were liquid at room temperature and only the 4sPLGA-mPEG block copolymer solutions with a copolymer concentration from 20 to 40 wt% show a sol-gel transition as the temperature was increased. The viscosity change associated with the sol-gel phase transition depended on the copolymer concentration and DL-lactide/glycolide (LA/GA) mol ratio. The in vitro and in vivo biodegradation and biocompatibility of a thermogelling polymeric material were examined in this study. The degradation of the copolymer gel, proceeded by hydrolysis of ester bonds, was followed by the erosion of the gel in a simulated vaginal fluid solution at body temperature for nearly one month. Mass loss and reduction of the molecular weight were detected. The LA/GA mol ratio was found to significantly influence the degradation profiles. The rapid in vivo gel formation was confirmed after subcutaneous injection of the copolymer solution into Sprague-Dawley (SD) rats. The in vivo degradation was slightly accelerated compared to in vitro hydrolysis, and the persistence time of the injected hydrogels in vivo was found to be tuned by the LA/ GA mol ratio. MTT assay and histological observations were used to examine the copolymer solution. Both in vitro and in vivo results illustrate acceptable biocompatibility of our materials. Collectively, our results show that the 4sPLGA-mPEG block copolymer is a promising candidate as a novel vaginal gel.

Synthesis, micellization and gelation of temperature‐responsive star‐shaped block copolymers

“…In our previous reported paper, sol–gel–sol transition of four‐arm star‐shaped PLGA‐mPEG block copolymer in aqueous solution was found. The in vitro and in vivo biodegradability of 4sPLGA‐mPEG copolymer gel at body temperature were investigated.…”

“…A series of star‐shaped PLGA‐mPEG block copolymers were synthesized from the following three‐step synthesis using arm‐first method: (i) Synthesis of linear hydroxyl‐terminated PLGA‐mPEG diblock copolymer(LPLGA‐mPEG) by bulk ring‐opening polymerization, (ii) Carboxylation of EG, TMP or PTOL to produce CEG, CTMP or CPTOL with two, three or four carboxyl acid terminal groups, (iii) Esterification reaction of two reactive precursors, LPLGA‐mPEG and CEG, CTMP or CPTOL, to obtain two‐arm (actually linear), three‐arm or four‐arm star‐shaped PLGA‐mPEG block copolymer (2LPLGA‐mPEG, 3sPLGA‐mPEG or 4sPLGA‐mPEG). The reaction scheme and detailed synthesis process were shown in our reported papers …”

“…The reaction scheme and detailed synthesis process were shown in our reported papers. [4,20] Characterization of the star-shaped PLGA-mPEG block copolymers A proton nuclear magnetic resonance ( 1 H NMR) spectrometer (Bruker DMX500) was used to characterize the chemical compositions of the star-shaped copolymers using CDCl3 as the solvent and TMS as standard. The molecular weight (MW) and composition of the mPEG and PLGA segments in the 4sPLGA-mPEG block copolymers were determined from 1 H NMR spectra by comparing the intensity of the terminal methoxy proton signal of mPEG at d = 3.38 ppm and the methylene proton signal at d = 3.65 ppm, the methyl proton signal of LA units in PLGA segments at d = 1.55 ppm and the methylene proton signals of GA units in PLGA segments at d = 4.82 ppm.…”

Stimuli-Responsive InjectableIn situ-Forming Hydrogels for Regenerative Medicines

“…227,236 PEG-PLGA-PEG triblock copolymers have been developed using PLGA in PPO segments to create biodegradable, injectable in situ-forming hydrogels. 200,201,213,[228][229][230][231][232][233][234][235] PEG-PLGA-PEG triblock copolymers exhibit sol-to-gel phase transition from low-viscosity and water-soluble solutions at low temperatures to viscous, waterinsoluble, biodegradable hydrogels at 37 • C. The temperature or temperature range of the sol-to-gel phase transition is influenced by PLGA/PEO ratios-specifically, by the molecular weight of PEG and the LA/GA ratios of the PLGA segments. The more hydrophobic the PEG-PLGA-PEG, the lower the temperature and PEG-PLGA-PEG concentration required to obtain the desired in situ-forming hydrogel.…”

Thermogelling Copolymers for Medical Applications

“…The degradation of the copolymer gel proceeded nearly up to 1 month and the LA/GA mol ratio within the copolymer was found as an important factor in determining the degradation pro¯les. 39 However, several inherent weaknesses were present in this system. The thermogelling copolymers were di±cult to handle due to its paste form and the dissolution of the copolymers took a very long time.…”