Novel anticancer polymeric conjugates of activated nucleoside analogues.
Novel anticancer polymeric conjugates of activated nucleoside analogues.
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DOI：
10.1021/bc200173e
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发表时间：
2011-10-19
影响因子：
4.7
通讯作者：
Vinogradov, Serguei V.
中科院分区：
文献类型：
--
作者：
Senanayake, Thulani H.;Warren, Galya;Vinogradov, Serguei V.
固有的或治疗诱导的耐药性是癌症治疗中的主要临床挫折。细胞毒性核碱基和核苷类似物在化疗中的广泛使用也导致产生特定的耐药性机制，如核苷转运或活化缺陷。这些药物是前药;并在给药后在癌细胞内转化为活性单磷酸、二磷酸和三磷酸，它们影响核酸合成、核苷酸代谢或对细胞凋亡的敏感性。以前，我们积极推广这样的想法，即活性核苷酸物质的纳米递送，例如核苷类似物的5′-三磷酸，可以提高药物疗效并降低非特异性毒性。在这项研究中，我们报告了一种新型的药物纳米制剂，核苷类似物的聚合物缀合物的发展，这是能够有效的运输和持续释放的磷酸化药物。这些药物缀合物已经合成，从胆固醇改性的粘膜粘附性聚乙烯醇或生物可降解的糊精开始，通过核苷类似物通过四磷酸酯接头的共价连接。胆固醇部分在水性介质中的缔合导致分子内聚合物折叠并形成含有0.5 mmol/g 5′-磷酸化核苷类似物的小纳米凝胶颗粒，例如5-氟-2 ′-脱氧尿苷（5-fluorouracyl，FdU），抗癌药物5-氟尿嘧啶（5-FU）的活性代谢物。聚合物偶联物表现出快速酶促释放的5′-磷酸尿苷和缓慢得多的药物释放在水解条件下（pH 1.0-7.4）。在一组癌细胞系中，与游离药物相比，所有研究的聚合FdU-缀合物在人前列腺癌PC-3、乳腺癌MCF-7和MDA-MB-231细胞中表现出高达50倍的细胞毒性增加，并且对阿糖胞苷抗性人T淋巴瘤（CEM/araC/8）和吉西他滨抗性滤泡性淋巴瘤（RL 7/G）细胞的功效高出100倍以上。在最初的体内筛选中，PC-3和RL 7/G皮下肿瘤异种移植模型均显示出对肿瘤周围注射后聚合物FdU-缀合物的持续药物释放的敏感性增强和显著的肿瘤生长抑制。所有这些数据表明磷酸化核苷类似物的新型聚合物缀合物具有显著的临床潜力，特别是作为针对耐药肿瘤的新治疗剂。
Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogs in chemotherapy also results in the development of specific mechanisms of drug resistance; such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di- and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis. Previously, we have actively promoted the idea that the nanodelivery of active nucleotide species, e.g. 5′-triphosphates of nucleoside analogs, can enhance drug efficacy and reduce nonspecific toxicity. In this study we report the development of a novel type of drug nanoformulations, polymeric conjugates of nucleoside analogs, which are capable of the efficient transport and sustained release of phosphorylated drugs. These drug conjugates have been synthesized, starting from cholesterol-modified mucoadhesive polyvinyl alcohol or biodegradable dextrin, by covalent attachment of nucleoside analogs through a tetraphosphate linker. Association of cholesterol moieties in aqueous media resulted in intramolecular polymer folding and the formation of small nanogel particles containing 0.5 mmol/g of a 5′-phosphorylated nucleoside analog, e.g. 5-fluoro-2′-deoxyuridine (floxuridine, FdU), an active metabolite of anticancer drug 5-fluorouracyl (5-FU). The polymeric conjugates demonstrated rapid enzymatic release of floxuridine 5′-phosphate and much slower drug release under hydrolytic conditions (pH 1.0–7.4). Among the panel of cancer cell lines, all studied polymeric FdU-conjugates demonstrated an up to 50 times increased cytotoxicity in human prostate cancer PC-3, breast cancer MCF-7 and MDA-MB-231 cells, and more than 100 times higher efficacy against cytarabine-resistant human T-lymphoma (CEM/araC/8) and gemcitabine-resistant follicular lymphoma (RL7/G) cells as compared to free drugs. In the initial in vivo screening, both PC-3 and RL7/G subcutaneous tumor xenograft models showed enhanced sensitivity to sustained drug release from polymeric FdU-conjugate after peritumoral injections and significant tumor growth inhibition. All these data demonstrate a remarkable clinical potential of novel polymeric conjugates of phosphorylated nucleoside analogs, especially as new therapeutic agents against drug-resistant tumors.
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影响因子：
5.7
作者：
Galmarini CM;Warren G;Kohli E;Zeman A;Mitin A;Vinogradov SV
通讯作者：
Vinogradov SV
影响因子：
6.5
作者：
Galmarini, CM;Thomas, X;Dumontet, C
通讯作者：
Dumontet, C
影响因子：
5.5
作者：
Magnani, M;Rossi, L;DeFlora, A
通讯作者：
DeFlora, A
影响因子：
14
作者：
ULBRICH, K;STROHALM, J;KOPECEK, J
通讯作者：
KOPECEK, J
影响因子：
41.2
作者：
Nochi, Tomonori;Yuki, Yoshikazu;Kiyono, Hiroshi
通讯作者：
Kiyono, Hiroshi