Institute of Microbiology AS CR, v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
Bioconjug Chem. 2009 Nov;20(11):2090-7. doi: 10.1021/bc900212k.
The main limitation of contemporary anticancer chemotherapy remains to be the insufficient specificity of the drugs for tumor tissue, which decreases the maximum tolerated dose due to severe side effects. Micellar drug delivery systems based on amphiphilic block copolymers with a very narrow size distribution (10 to 100 nm in diameter) is a novel innovative approach. Here, we report biological and pharmacological properties of polymeric micellar conjugate containing doxorubicin (DOX) covalently bound via hydrolytically cleavable hydrazone bonds to the micelle core. The system had a very low systemic toxicity (almost 20 times lower than free DOX) and long circulation in the bloodstream (with half of the dose after 24 h). Significant accumulation of tested micelles within the tumor was confirmed by fluorescent whole body imaging. Our new micellar system showed promising therapeutic activity against established murine EL-4 T-cell lymphoma; it was found that it is able to completely cure about 75% of tumor-bearing mice (with doses of either 1 x 150 mg DOX kg(-1) or 2 x 75 mg DOX kg(-1), administered i.v.). Moreover, treatment with micelles in cured mice induced tumor-specific resistance. Up to 80% of these mice survived rechallenge with original but not with distinct tumor cells.
当代抗癌化疗的主要局限性仍然是药物对肿瘤组织的特异性不足，这会由于严重的副作用而降低最大耐受剂量。基于具有非常窄的尺寸分布（直径为 10 至 100nm）的两亲嵌段共聚物的胶束药物递送系统是一种新颖的创新方法。在这里，我们报告了通过水解可裂解的腙键共价结合到胶束核的阿霉素（DOX）的聚合物胶束缀合物的生物学和药理学特性。该系统具有非常低的全身毒性（比游离 DOX 低近 20 倍）和在血液中的长循环（24 小时后有一半剂量）。通过荧光全身成像证实了测试的胶束在肿瘤内的大量积累。我们的新型胶束系统对已建立的小鼠 EL-4 T 细胞淋巴瘤表现出有希望的治疗活性；发现它能够完全治愈约 75%的荷瘤小鼠（剂量为 1x150mg DOX/kg 或 2x75mg DOX/kg，静脉内给药）。此外，在治愈的小鼠中用胶束治疗会诱导肿瘤特异性耐药性。高达 80%的这些小鼠在接受原始但不是不同的肿瘤细胞的再挑战时存活下来。
