Kadam Rajendra S, Williams Jason, Tyagi Puneet, Edelhauser Henry F, Kompella Uday B
Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Mol Vis. 2013 May 30;19:1198-210. Print 2013.
First, to determine the influence of drug lipophilicity (using eight beta-blockers) and molecular weight (using 4 kDa and 40 kDa fluoroscein isothiocyanate [FITC]-dextrans) on suprachoroidal delivery to the posterior segment of the eye by using a rabbit ex vivo eye model. Second, to determine whether drug distribution differs between the dosed and undosed side of the eye following suprachoroidal delivery. Third, to compare the suprachoroidal delivery of sodium fluorescein (NaF) with the intracameral and intravitreal routes by using noninvasive fluorophotometry.
Using a small hypodermic 26G needle (3/8") with a short bevel (250 µm), location of the suprachoroidal injection in an ex vivo New Zealand white rabbit eye model was confirmed with India ink. Ocular tissue distribution of NaF (25 µl of 1.5 µg/ml) at 37 °C was monitored noninvasively using the Fluorotron Master(TM) at 0, 1, and 3 h following suprachoroidal, intravitreal, or intracameral injections in ex vivo rabbit eyes. For assessing the influence of lipophilicity and molecular size, 25 µl of a mixture of eight beta-blockers (250 µg/ml each) or FITC-dextran (4 kDa and 40 kDa, 30 mg/ml) was injected into the suprachoroidal space of excised rabbit eyes and incubated at 37 °C. Eyes were incubated for 1 and 3 h, and frozen at the end of incubation. Ocular tissues were isolated in frozen condition. Beta-blocker and FITC-dextran levels in excised ocular tissue were measured by liquid chromatography-tandem mass spectrometry and spectrofluorometry, respectively.
Histological sections of India ink-injected albino rabbit eye showed the localization of dye as a black line in the suprachoroidal space. Suprachoroidal injection of NaF showed signal localization to the choroid and retina at 1 and 3 h post injection when compared with intravitreal and intracameral injections. Drug delivery to the vitreous after suprachoroidal injection decreased with an increase in solute lipophilicity and molecular weight. With an increase in drug lipophilicity, drug levels in the choroid-retinal pigment epithelium (RPE) and retina generally increased with some exceptions. Beta-blockers and FITC-dextrans were localized more to the dosed side when compared to the opposite side of the sclera, choroid-RPE, retina, and vitreous. These differences were greater for FITC-dextrans as compared to the beta-blockers.
The suprachoroidal route of injection allows localized delivery to the choroid-RPE and retina for small as well as large molecules. Suprachoroidal drug delivery to the vitreous declines with an increase in drug lipophilicity and molecular weight. Drug delivery differs between the dosed and opposite sides following suprachoroidal injection, at least up to 3 h.
第一，通过兔离体眼模型，确定药物亲脂性（使用8种β受体阻滞剂）和分子量（使用4 kDa和40 kDa异硫氰酸荧光素[FITC] -葡聚糖）对脉络膜上腔给药至眼后段的影响。第二，确定脉络膜上腔给药后，给药侧与未给药侧的药物分布是否存在差异。第三，通过无创荧光光度法，比较荧光素钠（NaF）经脉络膜上腔给药与经前房和玻璃体腔给药的情况。
使用带有短斜面（250 µm）的小型26G皮下注射针（3/8"），在离体新西兰白兔眼模型中，用印度墨水确认脉络膜上腔注射的位置。在37°C下，于脉络膜上腔、玻璃体腔或前房注射后0、1和3小时，使用Fluorotron Master(TM)对离体兔眼中NaF（25 µl，1.5 µg/ml）的眼组织分布进行无创监测。为评估亲脂性和分子大小的影响，将25 µl的8种β受体阻滞剂混合物（每种250 µg/ml）或FITC -葡聚糖（4 kDa和40 kDa，30 mg/ml）注入离体兔眼的脉络膜上腔，并在37°C下孵育。眼睛孵育1和3小时，并在孵育结束时冷冻。在冷冻状态下分离眼组织。分别通过液相色谱 - 串联质谱法和荧光分光光度法测量离体眼组织中β受体阻滞剂和FITC -葡聚糖的水平。
注射印度墨水后的白化兔眼组织学切片显示，染料在脉络膜上腔定位为一条黑线。与玻璃体腔和前房注射相比，脉络膜上腔注射NaF后1和3小时，信号定位于脉络膜和视网膜。脉络膜上腔注射后向玻璃体的药物递送随着溶质亲脂性和分子量的增加而减少。随着药物亲脂性增加，脉络膜 -视网膜色素上皮（RPE）和视网膜中的药物水平通常会升高，但有一些例外。与巩膜、脉络膜 - RPE、视网膜和玻璃体的对侧相比，β受体阻滞剂和FITC -葡聚糖更多地定位于给药侧。与β受体阻滞剂相比，FITC -葡聚糖的这些差异更大。
脉络膜上腔注射途径可实现小分子和大分子向脉络膜 - RPE和视网膜的局部递送。脉络膜上腔给药至玻璃体的量随着药物亲脂性和分子量的增加而下降。脉络膜上腔注射后，给药侧与对侧的药物递送存在差异，至少在3小时内如此。
