Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.
Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.
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DOI：
10.1016/j.jconrel.2013.01.020
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发表时间：
2013-04-28
期刊：
影响因子：
--
通讯作者：
Vinogradov SV
中科院分区：
文献类型：
--
作者：
Senanayake TH;Warren G;Wei X;Vinogradov SV
大多数在癌症化疗中显示出前景的纳米胶囊药物都是静脉注射。开发有效的口服纳米制剂是一个非常具有挑战性的医学目标。在这里，我们描述了创新型聚合物纳米凝胶以与活化核苷类似物结合的形式在癌症化疗中口服给药的成功应用。此前，我们报道了两亲性聚乙烯醇和糊精基纳米凝胶与磷酸化5-FU核苷Floxuridine的合成，并证明了它们对常规癌症和耐药癌症的增强活性。在这项研究中，我们合成并评估了受保护的吉西他滨纳米凝胶缀合物的口服应用，该药物从未用于口服疗法。这些缀合物能够通过特定的酶活性快速释放药物的活性形式（吉西他滨5'-单磷酸盐、二磷酸盐和三磷酸盐），或者在水解过程中缓慢释放。吉西他滨缀合物对各种癌细胞（包括对核苷类似物耐药的细胞系）的体外功效比游离药物高出 127 倍。令人惊讶的是，根据 Caco-2 细胞模型的渗透性研究，这些纳米凝胶-药物缀合物在胃部条件下相对稳定，并且能够主动穿透胃肠道屏障。在几种耐药人类癌症的肿瘤异种移植模型中，我们观察到口服治疗的吉西他滨或氟尿苷纳米凝胶缀合物可有效抑制肿瘤生长，并将动物的寿命延长至对照组的 4 倍。因此，我们已经证明了具有活化和稳定的吉西他滨的治疗性纳米凝胶缀合物作为针对吉西他滨耐药和其他耐药肿瘤的成功口服药物形式的潜力。
A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers. In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5′-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 4 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.
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影响因子：
4.7
作者：
Senanayake, Thulani H.;Warren, Galya;Vinogradov, Serguei V.
通讯作者：
Vinogradov, Serguei V.
影响因子：
38.3
作者：
Jiang, Wen;Kim, Betty Y. S.;Chan, Warren C. W.
通讯作者：
Chan, Warren C. W.
影响因子：
5.8
作者：
Galmarini, Carlos M.;Warren, Galya;Senanayake, Madapathage T.;Vinogradov, Serguei V.
通讯作者：
Vinogradov, Serguei V.
影响因子：
10.8
作者：
Mu, L;Feng, SS
通讯作者：
Feng, SS
影响因子：
24
作者：
Jones, Lee W.;Haykowsky, Mark J.;Mackey, John R.
通讯作者：
Mackey, John R.