基于聚（β-L-苹果酸）的多功能纳米载体向肿瘤细胞递送替莫唑胺。
Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid).
机构信息
Department of Neurosurgery, Cedars-Sinai Medical Center, 8631 W. Third Street, Suite 800E, Los Angeles, California 90048, USA.
出版信息
Pharm Res. 2010 Nov;27(11):2317-29. doi: 10.1007/s11095-010-0091-0. Epub 2010 Apr 13.
PURPOSE
Temozolomide (TMZ) is a pro-drug releasing a DNA alkylating agent that is the most effective drug to treat glial tumors when combined with radiation. TMZ is toxic, and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity.
METHODS
Multifunctional targetable nanoconjugates of TMZ hydrazide were synthesized using poly(β-L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL), for pH-dependent endosomal membrane disruption, and PEG for protection.
RESULTS
The water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and ζ potentials in the range of -6.3 to -17.7 mV. Fifty percent degradation in human plasma was observed in 40 h at 37°C. TMZ conjugated with polymer had a half-life of 5-7 h, compared with 1.8 h for free TMZ. The strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody. TMZ-resistant cancer cell lines were sensitive to TMZ nanoconjugate treatment.
CONCLUSIONS
TMZ-polymer nanoconjugates entered the tumor cells by receptor-mediated endocytosis, effectively reduced cancer cell viability, and can potentially be used for targeted tumor treatment.
目的
替莫唑胺（TMZ）是一种前体药物，释放出一种 DNA 烷化剂，与放射治疗联合使用时是治疗神经胶质瘤最有效的药物。TMZ 具有毒性，治疗剂量受到严重副作用的限制。因此，需要靶向递送以提高效率并降低非肿瘤组织毒性。
方法
使用聚（β-L-马来酸）平台合成了 TMZ 酰肼的多功能靶向纳米复合物，其中包含针对转铁蛋白受体（TfR）的单克隆抗体、三亮氨酸（LLL）用于 pH 依赖性内涵体膜破坏以及 PEG 用于保护。
结果
水溶性 TMZ 纳米复合物的水动力学直径在 6.5 至 14.8nm 范围内，ζ 电位在-6.3 至-17.7mV 范围内。在 37°C 下，40 小时内人血浆中观察到 50%的降解。与游离 TMZ 的 1.8 小时相比，与聚合物偶联的 TMZ 的半衰期为 5-7 小时。含有 LLL 和抗 TfR 抗体的 TMZ 纳米复合物版本可最大程度地降低人脑和乳腺癌细胞活力。TMZ 耐药癌细胞系对 TMZ 纳米复合物治疗敏感。
结论
TMZ-聚合物纳米复合物通过受体介导的内吞作用进入肿瘤细胞，有效降低了癌细胞活力，并且可能可用于靶向肿瘤治疗。
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