ENS-CNRS UMR 5239, UFR Lyon-Sud, 165 Chemin du Grand Revoyet, BP12 - 69921 Oullins, France.
Int J Pharm. 2010 Aug 16;395(1-2):281-9. doi: 10.1016/j.ijpharm.2010.05.028. Epub 2010 May 24.
One of the major problems in cancer chemotherapy is the fast development of drug resistance to most anticancer therapeutics. Thus, an important cause of the eventual decline in clinical efficacy of cytotoxic nucleoside analogs was the selection of resistant cancer cells with deficiencies in the expression of nucleoside transporters or nucleoside-activating kinases. Here, we present an efficient strategy of overcoming this type of drug resistance by tumor-specific delivery of nanogel-encapsulated active triphosphates of nucleoside analogs (NATP). The small particles of biodegradable cationic nanogels loaded with anionic NATP efficiently interacted with cancer cells and released active drug compounds into the cytoplasm. The potential of novel drug formulations was evaluated in the nucleoside transport-deficient (CEM/araC/C8) or nucleoside activation-deficient (RL7/G) lymphogenic cancer cells. Compared to nucleoside analogs, NATP-loaded nanogels demonstrated increased cytotoxicity, reducing the drug resistance index 250- to 900-fold in CEM/araC/C8 cells and 70- to 100-fold in RL7/G cells. The strong cytotoxic effect of nanoformulations was accompanied by characteristic cell cycle perturbations, usually observed in drug-treated sensitive cells, and resulted in the induction of apoptosis in all studied drug-resistant cells. Efficient cellular accumulation of nanogels and the consequent increase in intracellular levels of NATP were found to be the major factors determining cytotoxic efficacy of nanoformulations. Decoration of nanogels with multiple molecules of tumor lymphatic-specific peptide (LyP1) enhanced the binding efficacy of nanocarriers with lymphogenic cancer cells. The targeted nanoformulation of activated gemcitabine (LyP1-NG-dFdCTP), when injected in subcutaneous RL7/G xenograft tumor model, demonstrated 2-fold more efficient tumor growth inhibition than gemcitabine at a higher dose. Nanogel-drug formulations exhibited no systemic toxicity during the treatment, hence extending the versatility of nucleoside analogs in the treatment of drug-resistant lymphogenic tumors.
癌症化疗的主要问题之一是大多数抗癌治疗药物的耐药性迅速发展。因此，细胞毒性核苷类似物临床疗效最终下降的一个重要原因是选择了核苷转运体或核苷激活激酶表达缺陷的耐药癌细胞。在这里，我们提出了一种通过肿瘤特异性递送包裹核苷类似物活性三磷酸酯的纳米凝胶（NATP）来克服这种类型耐药性的有效策略。负载阴离子 NATP 的生物可降解阳离子纳米凝胶的小颗粒与癌细胞有效相互作用，并将活性药物化合物释放到细胞质中。在核苷转运缺陷型（CEM/araC/C8）或核苷激活缺陷型（RL7/G）淋巴源癌细胞中评估了新型药物制剂的潜力。与核苷类似物相比，负载 NATP 的纳米凝胶显示出更高的细胞毒性，使 CEM/araC/C8 细胞中的耐药指数降低 250-900 倍，RL7/G 细胞中的耐药指数降低 70-100 倍。纳米制剂的强烈细胞毒性作用伴随着通常在药物处理的敏感细胞中观察到的特征性细胞周期扰动，并导致所有研究的耐药细胞诱导凋亡。发现纳米凝胶的有效细胞积累以及随之而来的 NATP 细胞内水平的增加是决定纳米制剂细胞毒性效力的主要因素。用多个肿瘤淋巴管特异性肽（LyP1）分子修饰纳米凝胶增强了纳米载体与淋巴源癌细胞的结合效力。在皮下 RL7/G 异种移植肿瘤模型中注射靶向激活的吉西他滨（LyP1-NG-dFdCTP）纳米制剂，与更高剂量的吉西他滨相比，肿瘤生长抑制效率提高了 2 倍。纳米凝胶药物制剂在治疗过程中没有表现出全身毒性，从而扩展了核苷类似物在治疗耐药性淋巴源肿瘤中的多功能性。
