ABSTRACT
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.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Drug Delivery Systems , Lactates/administration & dosage , Neovascularization, Pathologic/prevention & control , Polyethylene Glycols/administration & dosage , Retina/drug effects , Vascular Endothelial Growth Factor A/administration & dosage , Animals , Bevacizumab/administration & dosage , Hydrogels , RabbitsABSTRACT
A new fabrication process for designing nerve conduits with a porous ionic cross-linked alginate/chitosan composite for nervous regeneration could be prepared. New designed nerve conduits with a porous ionic cross-linked alginate/chitosan composite were developed for nervous regeneration. Nerve conduits (NCs) represent a promising alternative to conventional treatments for peripheral nerve repair. NCs composed of various polysaccharides such as sodium alginate were designed and prepared by lyophilization as potential matrices for tissue engineering. The use of a porous ionic cross-linked alginate/chitosan composite could provide penetration channels that would lead to the products' increasing penetration rate properties. Furthermore, the use of a porous ionic cross-linked alginate/chitosan composite also has a highly cross-linked structure, which would give the products relatively good mechanical properties. Furthermore, the drug could be incorporated into nerve conduits as a new drug-carrying system for nerve regeneration because of its porous and cross-linked structures.
Subject(s)
Absorbable Implants , Alginates/chemistry , Chitosan/chemistry , Guided Tissue Regeneration/instrumentation , Nerve Regeneration/physiology , Peripheral Nerves/growth & development , Animals , Cross-Linking Reagents/chemistry , Equipment Failure Analysis , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Humans , Ions , Materials Testing , Porosity , Prosthesis Design , Tissue ScaffoldsABSTRACT
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 hydrophilic-hydrophobic 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.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Choroidal Neovascularization/drug therapy , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemical synthesis , Hydrogels/chemical synthesis , Neovascularization, Pathologic/drug therapy , Absorption, Physicochemical , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/chemistry , Animals , Bevacizumab , Choroidal Neovascularization/pathology , Diffusion , Hot Temperature , Humans , Neovascularization, Pathologic/pathology , Rabbits , Temperature , Treatment OutcomeABSTRACT
Hydroxypropyl methylcellulose (HPMC) was employed in this study to design controllable drug release systems because of its non-toxic nature, swelling properties. New interpenetrating polymer networks (IPN) of HPMC / tri-isocyanate crosslinked polyurethane (TCPU) could be prepared on the surfaces of IPN materials. To design "Novel Drug-carrying Matrix Systems", incorporation of novel structure is important to the possible formation of drug-carrying spaces within the material, which was achieved by using Tris (6-isocyanatohexyl) isocyanurate with three soft hexyl arms in this study. A series of novel drug-carrying matrix systems prepared by crosslinking reaction could be candidates for an excellent and smart potential material. When the polymeric networks were established on the surfaces of resulting materials, the developed hydrophilic interpenetrating polymeric structures of HPMC/ polyurethane could provide good wettability to the wound dressings, particularly for moisture healing application. The materials containing HPMC/polyurethane networks using 1% cross-linking agent showed a water uptake value of 5.1% after one hour, which has great potential for use as wound dressings for moisture healing. Furthermore, a new drug delivery system of hydrophilic IPN was successfully designed and established.
