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William R. Freeman, Michael Sailor, Michelle Chen, Lingyun Cheng; Nanostructured Porous Silicon Dioxide Microparticles as an Intravitreal Injectable Drug Delivery System for Avastin (Bevacizumab) Lasting Six Months. Invest. Ophthalmol. Vis. Sci. 2012;53(14):456.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal anti-VEGF therapy has become the standard of care in treatment of CNV, diabetic macular edema and other conditions. Most studies suggest that injections of Avastin (bevacizumab) every 4 weeks may be the optimal treatment although some interruption in therapy may be possible. The goal of our study was to develop a long-acting intravitreally injectable form of Avastin bound in a nanostructured porous silicon dioxide microparticles and to show the ability of these Avastin-loaded microparticles to release drug over many months.
Porous silicon dioxide was prepared by electrochemical etch of a single crystal silicon wafer in hydrofluoric acid and then oxidized. Microparticles were prepared by ultrasonic fracture. Commercial Avastin was loaded into the nanopores, which had mean diameters of ~ 100 nm. The porous silicon dioxide carrier prepared in this fashion had previosuly been shown to be non-toxic after intravitreal injection. Elution of drug into phosphate buffered saline (PBS) solution at pH 7.4 was determined by placing 5 mg of drug loaded microparticles into tightly capped glass vials containing 1.5 mL PBS and gently reciprocating the vials at 37°C. Free Avastin released from the microparticles was measured using a micro BCA protein test (Pierce).
The mass loading efficiency of Avastin in the porous silicon dioxide microparticles was 137 ug Avastin/mg porous silicon dioxide. Elution experiments were initially performed with a drug load of 700 ug. Avastin release was nearly linear with a steady-state free (released) drug concentration between 10 and 30 ug/mL (therapeutic is >> 0.06 ug/mL). The free drug concentration remained > the therapeutic concentration for 5.5 months.
Commercial Avastin can be loaded into nanoporous silicon dioxide. We loaded a total of 1 mg of Avastin into a 0.1 cc injection volume (50% particles/ 50% dextrose). Drug releases in a linear manner maintaining a therapeutic concentration for 5.5 months (165 days). Optimized Avastin loading can increase the load to 4.7 mg per 0.1 cc injection and would result in a therapeutic effect for over six months. A clinical trial with an Avastin-loaded porous silicon dioxide formulation is anticipated with in the next 12 months.
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