Polymer-Nucleotide Complexes with Cytotoxic Activity

具有细胞毒活性的聚合物-核苷酸复合物

• 批准号: 7033004
• 负责人: SERGUEI V VINOGRADOV
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033004
• 关键词: antineoplastics; cell line; cytotoxicity; drug delivery systems; drug design /synthesis /production; laboratory mouse; lung neoplasms; neoplasm /cancer pharmacology; neoplastic cell; nucleoside triphosphate; nucleotide analog; pharmacokinetics; polymers; transmission electron microscopy

DESCRIPTION (provided by applicant): Effective in chemotherapy of cancer and viral infections nucleoside analogues (NA) are actually 'prodrugs', which must be first converted in vivo into nucleoside 5'-monophosphates and, finally, into the drug's active form, nucleoside 5'-triphosphates. They efficiently terminate DNA synthesis and are cytotoxic for the proliferating cancer cells. However, therapeutic NAs in the form of 5'-triphosphates are considered too unstable as a drug form to be used directly in cancer chemotherapy. Based on preliminary data, the hypothesis being evaluated in this proposal is that encapsulation of 5'-triphosphates of antiproliferative NA in a submicron polymeric carrier with protective and targeting properties will result in a novel therapeutic form of the old drugs. The proposed formulation and delivery system is based on self-assembled polyionic complexes formed between nucleoside 5'-triphosphates and cationic carrier called 'Nanogel'. This carrier consists of a cross-linked network of cationic polyethylenimine and poly (ethylene glycol) or Poloxamer block copolymers. Nanogel loaded with triphosphate nucleotides in aqueous media forms small nanosized particles. Formulated into the particles for systemic administration, active triphosphates of NA can be conventionally stored in freeze-dried form and then readily dispersed before injection. Nanogel can protect triphosphate nucleotides in circulation against enzymatic degradation and drastically increase intracellular transport of anionic nucleotides, which otherwise is not effective. Specific aims of the proposal are to: (1) formulate polymer-nucleotide complexes with increased dispersion stability and enzymatic resistance, (2) Determine whether the polymer-nucleotide complexes can increase the cytotoxic effects of nucleotide analogues, and (3) Examine how the polymer-nucleotide complexes can enhance the systemic therapy of tumors in vivo. A panel of representative NA and cancer cell lines will be studied, and a murine Lewis lung carcinoma model will be used to verify obtained in vitro results. The long circulating polymer-nucleotide complexes can display better tumor accumulation because of the 'enhanced permeability and retention' effect. They can also be modified by vector ligands with affinity to surface receptors on actively proliferating cancer cells in order to enhance selective accumulation of the cytotoxic NA in tumors or metastatic nodes. Application of the drug forms may help to prevent many of the known chemotherapy side effects. Data accumulated in these studies can be directly used for design of better systemic formulations of cytotoxic nucleotide drugs.

描述(申请人提供)：在癌症和病毒感染的化疗中有效的核苷类似物(NA)实际上是‘前药’，必须首先在体内转化为核苷5‘-单磷酸，最后转化为药物的活性形式，核苷5’-三磷酸。它们有效地终止DNA合成，并对增殖的癌细胞具有细胞毒性。然而，5‘-三磷酸形式的治疗性NAS被认为作为一种药物形式太不稳定，不能直接用于癌症化疗。根据初步数据，这项建议中评估的假设是，将抗增殖NA的5‘-三磷酸包裹在具有保护和靶向特性的亚微米聚合物载体中将导致旧药物的一种新的治疗形式。所提出的制剂和递送系统是基于核苷5‘-三磷酸盐和被称为纳米凝胶的阳离子载体之间形成的自组装多离子络合物。该载体由阳离子聚乙烯亚胺和聚乙二醇或泊洛沙姆嵌段共聚物组成的交联网络组成。在水介质中负载三磷酸核苷酸的纳米凝胶形成了纳米尺寸的小颗粒。NA的活性三磷酸盐配制成颗粒用于全身给药，通常可以冷冻干燥的形式储存，然后在注射前容易分散。纳米凝胶可以保护循环中的三磷酸核苷酸免受酶降解，并显著增加阴离子核苷酸在细胞内的转运，否则这是无效的。该提案的具体目的是：(1)制备具有更高分散稳定性和酶抵抗力的聚合物-核苷酸复合体，(2)确定聚合物-核苷酸复合体是否可以增加核苷酸类似物的细胞毒作用，以及(3)研究聚合物-核苷酸复合体如何增强体内肿瘤的系统治疗。将研究一组具有代表性的NA和癌细胞株，并将使用小鼠Lewis肺癌模型来验证在体外获得的结果。长循环的聚合物-核苷酸复合体可以表现出更好的肿瘤聚集，因为它具有增强渗透性和保留性的作用。它们还可以通过与活跃增殖的癌细胞表面受体具有亲和力的载体配体进行修饰，以增强细胞毒NA在肿瘤或转移结节中的选择性积聚。药物形式的应用可能有助于防止许多已知的化疗副作用。这些研究中积累的数据可以直接用于设计更好的细胞毒性核苷酸药物的系统配方。