No abstract

Age-related macular degeneration (ARMD) and intraocular neovascular diseases have been treated clinically by anti-VEGF antibody drug bevacizumab. However, the use of bevacizumab in the treatment of retinal neovascular diseases has been limited due to the short half-life and frequent injections. In this research, novel amphiphilic hydrophilichydrophobic block copolymers of methoxy-poly (ethylene glycol)-block-poly (lactic-co-glycolic acid) were synthesized with ring-opening polymerization, and cross-linked with 2,2-bis (2-oxazoline) (BOX). The aqueous solution of the block copolymers can reverse the sol-gel-sol phase transition. After 1 month of intravitreal injection, the histomorphology of a rabbit's retina was preserved, which indicated the mPEG-PLGA-BOX hydrogel had no cytotoxicity in vivo. Released bevacizumab from the mPEG-PLGA-BOX hydrogel inhibited the RF/6A (Maraca mulatta retina epithelial cell) and HUVEC cell growth, and anti-angiogenesis in 3-D cultures, which showed the bioactivity of the anti-VEGF agent, were maintained in the hydrogel within the release process. In conclusion, the mPEG-PLGA-BOX hydrogel had a sol-gel behavior phase transition, and its intraocular biocompatibility and the characteristics of biodegradability and bioactivity appear to be a promising intravitreal injection carrier for bevacizumab delivery.

BackgroundReconstruction of a segmental fracture with massive bone loss is still a challenge for orthopaedic surgeons. The aim of our study was to develop a suitable biodegradable thermosensitive hydrogel system as a carrier for bone morphogenetic protein (BMP)-2 delivery in the treatment of critical-sized femoral defects.MethodsA block copolymer composed of monomethoxypoly(ethylene glycol) (mPEG), poly(lactic-co-glycolic acid) (PLGA) and 2, 2’-Bis (2-oxazolin) (Box) was synthesized by ring opening polymerization. The synthesized block copolymer was characterized by 1H-NMR spectroscopy and gel permeation chromatography (GPC). Different biophysical and biochemical properties of the synthesized copolymer, including temperature-induced structure changes, degradation rate, pH changes during hydrolytic degradation, cell toxicity, and the release profile of BMP-2, were also evaluated and/or were compared with those of a well-characterized mPEG-PLGA copolymer. In animal testing, rabbits (n = 36) that received critically sized (10 mm) femoral defects were divided into 6 groups. These experimental groups included an untreated group, autograft, and groups treated with the synthesized copolymer carrying different concentrations of BMP-2 (0, 5, 10, and 20 μg/ml). Bone repair was evaluated using X-ray radiography, histological staining, micro-computed tomography (μCT), biomarker examination and biomechanical testing in a 12-week treatment period.ResultsA new thermosensitive mPEG-PLGA/Box/mPEG-PLGA block copolymer, or named as BOX copolymer, was successfully prepared. Compared to the reported mPEG-PLGA in vitro, the prepared BOX copolymer at the same weight percent concentrations exhibited wider temperature ranges of gelation, slower degradation rates, higher the pH values, as well as less cytotoxicity. Furthermore, the BMP-2 release from BOX hydrogel exhibited a near-linear release profile in vitro. In animal experiments, treatment of critical-sized bony defects with 25 wt% BOX hydrogel carrying BMP-2 effectively promoted fracture healing during the 12-week trial period and higher concentrations of BMP-2 treatment correlated with better bone quality. Most importantly, clinical outcome and bone healing in the BOX-hydrogel group with 20 μg/ml BMP-2 were nearly equivalent to those in the autograft group in a 12-week treatment course.ConclusionThese data support that the use of BOX hydrogel (25 wt%) as a drug delivery system is a promising method in the treatment of large bone defects.

BACKGROUND: Wet age-related macular degeneration (Wet AMD) has been treated clinically by intravitreal injection of bevacizumab, which is a kind of the anti-VEGF antibody drug. Nevertheless, because of the short half-life and frequent injections, the use of this treatment is limited. OBJECTIVE: To confirm whether mPEG-PLGA-BOX can be considered as a VEGF drug delivery system to inhibit retinal angiogenesis. METHODS: A thermo-responsive hydrogel of methoxy-poly (ethylene glycol)-block-poly (lactic-co-glycolic acid) (mPEG-PLGA-BOX) was synthesized. The thermo-responsive hydrogel mPEG-PLGA-BOX was able to have sol-gel phase transition upon stimulation by the body temperature with improved biocompatibility and biodegradation. The bevacizumab released from mPEG-PLGA-BOX inhibited RF/6A cells according to a JC-1 assay, which indicated that the released bevacizumab was active to be able to suppress the growth of new blood vessels. In an animal study, retinal laser photocoagulation was performed to induce angiogenesis in the eyes of Rex rabbits using an 810-mm laser. RESULTS: The retina was penetrated when the laser power was more than 500 mW and the exposure time was more than 500 ms. New blood vessels were created at the 28th day after retinal laser photocoagulation. At this time, intravitreal 0.05-mL injections of mPEG-PLGA-BOX (bevacizumab) solution were administered. The bevacizumab released from mPEG-PLGA-BOX (bevacizumab) solution suppressed the angiogenesis. In an in vivo study, the histomorphology of the rabbit retina also indicated that mPEG-PLGA-BOX after intravitreal injection is not toxic to the rabbit retina. CONCLUSIONS: Bevacizumab released from mPEG-PLGA-BOX (bevacizumab) solution suppressed angiogenesis, and mPEG-PLGA-BOX can be considered as a novel thermo-responsive hydrogel with potential as a gelling carrier for extended bevacizumab drug release to treat intraocular neovascular diseases.