Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, Pennsylvania 19104, USA.
Pharm Res. 2013 Aug;30(8):2087-96. doi: 10.1007/s11095-013-1065-9. Epub 2013 May 18.
To demonstrate the feasibility of a novel macromolecular delivery system for doxorubicin (DOX) which combines pH dependent DOX release with a high molecular weight and biodegradable gelatin carrier.
DOX was conjugated to gelatin using an acid labile hydrazone bond and a glycylglycine linker. The gelatin-doxorubicin conjugate (G-DOX) was evaluated for hydrazide and DOX content by spectrophotometry, molecular weight by HPLC-SEC, in vitro DOX release at various pH, and cell growth inhibition using EL4 mouse lymphoma and PC3 human prostate cells.
G-DOX hydrazide and DOX content was 47% and 5-7%, respectively of theoretical gelatin carboxylic acid sites. During preparation of G-DOX, the molecular weight decreased to 22 kDa. DOX release was 48% in pH 4.8 phosphate buffer, 22% at pH 6.5, but 10% at pH 7.4. The G-DOX IC50 values in EL4 and PC3 cells were 0.26 μM and 0.77 μM, respectively; the latter value 3 times greater than that of free DOX.
A 22 kDa macromolecular DOX conjugate containing 3.4-5.0% w/w DOX has been prepared. The pH dependent drug release in combination with a biodegradable gelatin carrier offer potential therapeutic advantages of enhanced tumor cell localization and reduced systemic toxicities of the drug.
展示一种新型的阿霉素（DOX）大分子递药系统的可行性，该系统将 DOX 的 pH 依赖性释放与高分子量和可生物降解的明胶载体相结合。
通过酸不稳定的腙键和甘氨酰甘氨酸接头将 DOX 与明胶偶联。通过分光光度法评估明胶-阿霉素缀合物（G-DOX）的酰肼和 DOX 含量、高效液相色谱-SEC 的分子量、不同 pH 下的体外 DOX 释放以及使用 EL4 小鼠淋巴瘤和 PC3 人前列腺细胞的细胞生长抑制。
G-DOX 酰肼和 DOX 含量分别为理论明胶羧酸部位的 47%和 5-7%。在制备 G-DOX 期间，分子量降至 22 kDa。在 pH 4.8 的磷酸盐缓冲液中 DOX 释放 48%，在 pH 6.5 时释放 22%，但在 pH 7.4 时释放 10%。G-DOX 在 EL4 和 PC3 细胞中的 IC50 值分别为 0.26 μM 和 0.77 μM，后者是游离 DOX 的 3 倍。
已经制备了一种包含 3.4-5.0%w/w DOX 的 22 kDa 大分子 DOX 缀合物。这种 pH 依赖性药物释放与可生物降解的明胶载体相结合，为增强肿瘤细胞定位和降低药物的全身毒性提供了潜在的治疗优势。
