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Huiyuan Hou, Alejandra Nieto, Feiyan Ma, Su-Na Lee, Kaihui Nan, William Freeman, Michael Sailor, Lingyun Cheng; Tunable sustained intravitreal drug delivery system for daunorubicin using oxidized porous silicon. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5069.
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© ARVO (1962-2015); The Authors (2016-present)
Daunorubicin (DNR) is a potent therapeutic agent for unwanted proliferative ocular diseases. However, it has a narrow therapeutic window and short vitreous half-life. We have previously shown that covalent bonding DNR to functionalized porous silicon (pSi) can extend DNR vitreous stay from days to months. Current study is to investigate the feasibility and capacity of regulating DNR release by quantitatively altering nano pore size of this unique delivery system.
Porous silicon microparticles were prepared by electrochemical etches followed by ultrasonication. Three different etching parameters were used to acquire three nano-pore sizes (15nm, 26nm, and 43nm). pSi particles were oxidized at 800°C and in vitro degradation was examined at 37°C in a closed system by quantitate silicon using ICP-OES. For in vivo drug release study, the oxidized pSi particles were further silanized for daunorubicin loading. DNR was loaded into the pSi particles by covalent attaching. Three milligrams of each type of DNR loaded particle was intravitreally injected into 4 rabbits eyes. Only one eye of each animal was used. After the injection, the eyes were examined at day 1, 3, 7 and 14 by slit lamp biomicroscopy, indirect ophthalmoscopy, and tonometry. All rabbits were sacrificed at day 14 and vitreous was dissected out. The supernatant of the vitreous was subjected to HPLC/MS/MS for daunorubicin quantitation.
The 32-day in vitro degradation studies showed that degradation rate of pSi was associated with pore sizes; with the larger pore being faster degraded. The mean degradation rate of pSi with 46nm pores was significantly larger than that of the other two pore sizes (44.2 vs 25.7 or 21.2 ug/mL, p<0.0001). In vivo drug release study demonstrated that free daunorubicin in vitreous at post-injection day 14 was 12ng/mL for 43nm pore pSi, 3ng/mL for 26nm pore pSi, and 1ng/mL for 15nm pore pSi. Pore expansion from 15nm to 43nm led to a 12 folds increase of daunorubicin release (p<0.0001). Clinical monitoring and fundus photographs did not reveal any ocular toxicity or visually difference in amount of the particles in rabbit vitreous.
The current study demonstrated the feasibility to regulate daunorubicin release from porous silicon through pore size manipulation. The capacity of this regulating seems promising and further study is warrantied.
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