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Qiutang Li, Subhash Gaddipati, M. Clarke Miller, John Trent, Henry Kaplan, Qingxian Lu; IKK2 Inhibition Using TPCA-1/PLGA Microspheres Attenuates the Laser Induced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2179.
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IKK2 is a key kinase in activation of transcriptional factor NF-kappaB that regulates multiple cellular processes including inflammation, stress response, cell death and angiogenesis. Neovascularization is a hallmark of wet AMD. The present study aims to assess the therapeutic effect of IKK2 inhibitor, TPCA1, on the laser-induced choroid neovascularization (CNV) using biodegrable poly-lactide-co-glycolide (PLGA) microsphere delivery vehicle.
(1) The water-insoluble small molecule, TPCA-1, was loaded into PLGA microspheres by packaging 10 mg of TPCA-1 into 100 mg of PLGA, average MW 7,000-17,000 lactide:glycolide (50:50). The sphere size and TPCA-1 encapsulation efficiency were measured to meet the pharmaceutical applicable standard. (2) TPCA-1 release from polymers in vitro was tested by dialysis of TPCA-1-PLGA polymers (10 mg/0.5 ml PBS-Tween80) against 50 ml of external media that were replaced daily. The released TPCA-1 in the dialysis medium was extracted with dichloromethane and quantified by HPLC. (3) In vivo releasing, tissue distribution, safety, and inflammatory response to TPCA-1 was tested on the wild type C57BL/6 mice after bilateral retrobulbar injections of TPCA-1-PLGA (10 mg of microspheres loaded with 1 mg TPCA-1 suspended in 100 μL PBS) and sham-loaded PLGA microspheres (10 mg of microspheres suspended in 100 μL PBS). (4) The development of CNV after laser photocoagulation in TPCA-1-PLGA treated mice and controls was quantified by scoring the fluorescence leakage and isolectin-B4-594 stain areas.
TPCA-1 encapsulation efficiency into the microspheres reached to more than 95%, with average PLGA bead size of 2 microns in diameter. TPCA-1-loaded beads showed consistent cumulative drug release in vitro and in vivo for up to a month. Histologic analysis and OKR testing showed no cellular and functional toxicity. In addition, laser-induced choroid neovascularization was significantly attenuated by retrobulbar injection of TPCA-1-PLGA microspheres.
Retrobulbar injection of small molecular IKK2 inhibitor, TPCA-1, delivered by biogradable PLGA microsphere, can achieve a sustained and controllable drug release into choroid/retina tissues and attenuate the laser-induced CNV development without the systemic toxicity. Our results suggest IKK2 inhibition is an innovative therapeutic approach for treating wet AMD.
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