Department of Clinical and Translational Research, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal, India.
Cellular Immunology Laboratory, Department of Zoology, The University of Burdwan, Bardhaman 713104, India.
ACS Appl Bio Mater. 2021 Mar 15;4(3):2628-2638. doi: 10.1021/acsabm.0c01599. Epub 2021 Mar 4.
Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer-temozolomide conjugate, suggesting the suitability of the construct for therapy. Besides growth inhibition and direct killing, the dendrimer-temozolomide construct induced extensive apoptosis not only in parental Dalton lymphoma tumor cells but also in the doxorubicin-resistant form of the tumor cells. Dendrimer-temozolomide conjugation significantly reduced the solid tumor growth and increased the lifespan with better prognosis, including improved histopathology of the treated mice, while untreated littermates developed extensive metastasis and succumbed to death.
使用接枝有替莫唑胺的树枝状聚合物来治疗实验性淋巴瘤，在肿瘤部位实现了增强的药物定位和最小的毒性，该研究将替莫唑胺开发为一种实体瘤药物。在此，我们构建了一种聚酰胺-胺（PAMAM）树枝状聚合物与替莫唑胺的缀合物，以增强前药替莫唑胺衍生的活性药物代谢物的稳定性。我们的结果表明，活性药物（5-(3-甲基三氮唑-1-基)咪唑-4-甲酰胺）（MTIC）（来自替莫唑胺）从树枝状聚合物-替莫唑胺缀合物中表现出稳定和持续的释放，这表明该结构适合治疗。除了生长抑制和直接杀伤外，树枝状聚合物-替莫唑胺结构还诱导了广泛的细胞凋亡，不仅在亲本道尔顿淋巴瘤肿瘤细胞中，而且在肿瘤细胞的阿霉素耐药形式中也是如此。树枝状聚合物-替莫唑胺缀合物显著减少了实体瘤的生长，延长了生存期并改善了预后，包括改善了治疗小鼠的组织病理学，而未经处理的同窝仔鼠则发生了广泛的转移并死亡。
