Dang W, Saltzman W M
Department of Chemical Engineering, Johns Hopkins University, Baltimore, Maryland 21218.
Biotechnol Prog. 1992 Nov-Dec;8(6):527-32. doi: 10.1021/bp00018a009.
Intracranial controlled release polymers may improve drug administration to the brain, where therapy is frequently limited due to the low permeability of brain capillaries to therapeutic agents. On the basis of drug transport and elimination rates, we proposed that high molecular weight, water-soluble molecules would be retained in the brain space following release from an intracranial implant. To test this hypothesis, solid particles of different molecular weight fractions of fluorescein isothiocyanate labeled dextran (FITC-dextran; 4 x 10(3) Da (4 kDa) < weight-averaged molecular weight (Mw) < 150 kDa) or fluorescein were uniformly dispersed in matrices of a polyanhydride copolymer synthesized from a fatty acid dimer and sebacic acid in a 50:50 ratio, P(FAD:SA). When incubated in buffered saline, FITC-dextran fractions of 70 kDa Mw were released from the polymer within 48 h; 4 kDa Mw FITC-dextran and fluorescein were released more slowly. Following implantation of P(FAD:SA) matrices containing either 70 kDa Mw FITC-dextran, 4 kDa Mw FITC-dextran, or fluorescein into the brains of normal rats, fluorescent tracers were continuously released into the brain tissue for 30 days. Tracer concentrations within the brain were significantly higher for large molecular weight tracers (70 kDa Mw FITC-dextran >> 4 kDa Mw FITC-dextran > fluorescein). The rate of elimination, kapp, of each tracer from the brain was determined by comparing experimental data with a model describing tracer diffusion/elimination in the brain extracellular space; kapp decreased with increasing molecular weight (fluorescein > 4 kDa Mw FITC-dextran > 70 kDa Mw FITC-dextran).
颅内控释聚合物可以改善药物向脑部的输送，因为脑毛细血管对治疗药物的低渗透性常常限制了脑部的治疗效果。基于药物转运和消除速率，我们提出高分子量的水溶性分子从颅内植入物释放后会保留在脑间隙中。为了验证这一假设，将不同分子量级分的异硫氰酸荧光素标记葡聚糖（FITC - 葡聚糖；4×10³ Da（4 kDa）＜重均分子量（Mw）＜150 kDa）或荧光素的固体颗粒均匀分散在由脂肪酸二聚体和癸二酸按50:50比例合成的聚酸酐共聚物P（FAD:SA）的基质中。当在缓冲盐水中孵育时，Mw为70 kDa的FITC - 葡聚糖级分在48小时内从聚合物中释放出来；Mw为4 kDa的FITC - 葡聚糖和荧光素释放得更慢。将含有Mw为70 kDa的FITC - 葡聚糖、Mw为4 kDa的FITC - 葡聚糖或荧光素的P（FAD:SA）基质植入正常大鼠脑内后，荧光示踪剂持续释放到脑组织中30天。脑内大分子示踪剂（Mw为70 kDa的FITC - 葡聚糖 >> Mw为4 kDa的FITC - 葡聚糖 > 荧光素）的浓度显著更高。通过将实验数据与描述示踪剂在脑细胞外间隙扩散/消除的模型进行比较，确定了每种示踪剂从脑中的消除速率常数kapp；kapp随分子量增加而降低（荧光素 > Mw为4 kDa的FITC - 葡聚糖 > Mw为70 kDa的FITC - 葡聚糖）。
