Tunable sustained intravitreal drug delivery system for daunorubicin using oxidized porous silicon.
Tunable sustained intravitreal drug delivery system for daunorubicin using oxidized porous silicon.
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DOI：
10.1016/j.jconrel.2014.01.003
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发表时间：
2014-03-28
期刊：
影响因子：
--
通讯作者：
Cheng L
中科院分区：
文献类型：
--
作者：
Hou H;Nieto A;Ma F;Freeman WR;Sailor MJ;Cheng L
柔红霉素（DNR）是一种有效的新血管形成蛋白的抑制剂，包括VEGF和PDGF。这些生长因子与许多破坏性视网膜疾病的视网膜瘢痕形成直接相关。由于玻璃体半衰期短，治疗窗口窄，DNR在眼内的应用受到限制。研究表明，基于多孔硅（pSi）的输送系统可以将DNR玻璃体的停留时间从几天延长到3个月。在这项研究中，我们探讨了改变硅颗粒的孔径来调节有效载荷释放的可行性。调制蚀刻参数可以控制纳米孔径从15 nm到95 nm。体外实验表明，psio2的降解随孔隙大小的增加而增加，对于给定的颗粒类型，psio2的降解近似恒定。通过观察和归一化平均Si浓度（44.2±8.9 vs 25.7±5.6或21.2±4.2µg/mL, p<0.0001）判断，43 nm孔对pSi O2的降解明显大于其他两种孔径较小的颗粒。体外DNR动态释放结果显示，大孔（43 nm） pSiO2-CO2H:DNR（多孔二氧化硅与柔红霉素共价负载）的DNR水平显著高于孔（15和26 nm）（13.5±6.9 ng/mL vs. 2.3±1.6 ng/mL和1.1±0.9 ng/mL, p<0.0001）。在体外动态释放2个月后，54%的pSiO2-CO2H:DNR颗粒仍按重量留在溶出腔中。体内药物释放研究表明，注射后第14天，95 nm孔径pSiO2-CO2H:DNR时，玻璃体内游离DNR为66.52 ng/mL， 43 nm pSiO2-CO2H:DNR为10.76 ng/mL， 15 nm pSiO2-CO2H:DNR为1.05 ng/mL。孔径从15 nm扩大到95 nm导致DNR释放增加63倍（p<0.0001），证实了活体玻璃体中孔径大小与药物水平直接相关。本研究证明了通过改造pSi的纳米孔径来调节DNR共价负载pSi O2释放DNR的可行性。
Daunorubicin (DNR) is an effective inhibitor of an array of proteins involved in neovascularization, including VEGF and PDGF. These growth factors are directly related to retina scar formation in many devastating retinal diseases. Due to the short vitreous half-life and narrow therapeutic window, ocular application of DNR is limited. It has been shown that a porous silicon (pSi) based delivery system can extend DNR vitreous residence from a few days to 3 months. In this study we investigated the feasibility of altering the pore size of the silicon particles to regulate the payload release. Modulation of the etching parameters allowed control of the nano-pore size from 15 nm to 95 nm. In vitro studies showed that degradation of pSi O2 increased with increasing pore size and the degradation of pSi O2 was approximately constant for a given particle type. The degradation of pSi O2 with 43 nm pores was significantly greater than the other two particles with smaller pores, judged by observed and normalized mean Si concentration of the dissolution samples (44.2±8.9 vs 25.7±5.6 or 21.2±4.2 µg/mL, p<0.0001). In vitro dynamic DNR release revealed that pSiO2-CO2H:DNR (Porous silicon dioxide with covalent loading of daunorubicin) with large pores (43 nm) yielded a significantly higher DNR level than particles with 15 or 26 nm pores (13.5±6.9 ng/mL vs. 2.3±1.6 ng/mL and 1.1±0.9 ng/mL, p<0.0001). After two months of in vitro dynamic release, 54% of the pSiO2-CO2H:DNR particles still remained in the dissolution chamber by weight. In vivo drug release study demonstrated that free DNR in vitreous at post-injection day 14 was 66.52 ng/mL for 95 nm pore size pSiO2-CO2H:DNR, 10.76 ng/mL for 43 nm pSi O2-CO2 H:DNR, and only 1.05 ng/mL for 15 nm pSi O2-CO2 H:DNR. Pore expansion from 15 nm to 95 nm led to a 63 folds increase of DNR release (p<0.0001) and a direct correlation between the pore size and the drug levels in the living eye vitreous was confirmed. The present study demonstrates the feasibility of regulating DNR release from pSi O2 covalently loaded with DNR by engineering the nano-pore size of pSi.
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