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（由申请人提供）：有效地在癌症和病毒感染的核苷类似物（NA）中有效实际上是“前药”，必须首先将其在体内转化为5'-单磷酸核苷，最后转化为药物的活性形式，核苷5'-三磷酸盐。它们有效地终止了DNA合成，并且对增殖的癌细胞具有细胞毒性。但是，以5'-三磷酸盐形式的治疗性NA被认为是不稳定的药物形式，无法直接用于癌症化学疗法中。基于初步数据，在该提案中评估的假设是，在亚微米聚合物载体中，具有保护性和靶向特性的抗增殖性NA的5'-三磷酸盐的封装将导致一种新型的旧药物的治疗形式。所提出的配方和递送系统基于在5'-三磷酸核苷和称为“纳米凝胶”的核苷和阳离子载体之间形成的自组装的多回合复合物。该载体由阳离子聚乙烯亚胺的交联网络和聚乙二醇）或洛氨基醇块共聚物组成。纳米凝胶在水性培养基中载有三磷酸核苷酸的纳米凝胶形成小纳米颗粒。 Na的主动三磷酸盐被制成用于全身给药的颗粒，通常以冷冻干燥的形式存储，然后在注射前易于分散。纳米凝胶可以保护循环中的三磷酸核苷酸免受酶促降解，并大大增加阴离子核苷酸的细胞内转运，否则这是无效的。 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.将研究一组代表性的NA和癌细胞系，并将使用鼠Lewis肺癌模型来验证在体外结果中获得的。长期循环的聚合物核苷酸复合物可以表现出更好的肿瘤积累，因为“渗透性增强和保留”效果。它们也可以通过与表面受体亲和力的载体配体在积极增殖的癌细胞上的亲和力来改变，以增强肿瘤或转移性淋巴结中细胞毒性Na的选择性积累。药物形式的应用可能有助于防止许多已知的化学疗法副作用。这些研究中积累的数据可直接用于设计细胞毒性核苷酸药物的更好的系统性制剂。