权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Polymer-Nucleotide Complexes with Cytotoxic Activity

具有细胞毒活性的聚合物-核苷酸复合物

基本信息

批准号：
7213329
负责人：
SERGUEI V VINOGRADOV
金额：
$ 21.95万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213329
关键词：
Address Adverse effects Affinity Biodistribution Blood Blood Circulation Bypass Cancer cell line Cell Line Cells Chemotherapy-Oncologic Procedure Complex Cytoplasm Cytotoxic agent DNA biosynthesis DNA chemical synthesis Data Disseminated Malignant Neoplasm Dose Drug Formulations Drug Kinetics Ethylene Glycols Freeze Drying In Vitro Injection of therapeutic agent Intracellular Transport Lewis Lung Carcinoma Ligands Malignant Neoplasms Modeling Mus NanoGel Neoplasm Metastasis Nucleosides Nucleotides Permeability Pharmaceutical Preparations Poloxamer Poloxamers Polymers Population Process Prodrugs Proliferating Property Protein Dephosphorylation Range Resistance Serum Site Specificity Structure-Activity Relationship Surface System Systemic Therapy Therapeutic Viral Cancer Virus Diseases analog aqueous base cancer cell cancer type chemotherapy copolymer crosslink cytotoxic cytotoxicity design ethylene glycol improved in vivo nanosized novel therapeutics nucleoside analog nucleotide analog particle prevent programs receptor size submicron targeted delivery three dimensional structure tripolyphosphate tumor vector

项目摘要

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）：核苷类似物（NA）在癌症和病毒感染的化疗中有效，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NA作为药物形式被认为太不稳定而不能直接用于癌症化疗。基于初步数据，本提案中评估的假设是，将抗增殖NA的5 '-三磷酸封装在具有保护和靶向性质的亚微米聚合物载体中将导致旧药物的新治疗形式。所提出的制剂和递送系统是基于核苷5 '-三磷酸和称为“纳米凝胶”的阳离子载体之间形成的自组装聚离子复合物。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的交联网络组成。在水性介质中装载有三磷酸核苷酸的纳米凝胶形成小的纳米尺寸的颗粒。配制成用于全身给药的颗粒，NA的活性三磷酸盐可以常规地以冷冻干燥形式储存，然后在注射前容易地分散。纳米凝胶可以保护循环中的三磷酸核苷酸免受酶降解，并大大增加阴离子核苷酸的细胞内转运，否则是无效的。该提案的具体目标是：（1）配制具有增加的分散稳定性和酶抗性的聚合物-核苷酸复合物，（2）确定聚合物-核苷酸复合物是否可以增加核苷酸类似物的细胞毒性作用，以及（3）检查聚合物-核苷酸复合物如何可以增强体内肿瘤的全身治疗。将研究一组代表性NA和癌细胞系，并将使用鼠刘易斯肺癌模型验证获得的体外结果。由于“增强的渗透性和保留”效应，长循环聚合物-核苷酸复合物可以表现出更好的肿瘤积聚。它们还可以通过对活跃增殖的癌细胞上的表面受体具有亲和力的载体配体进行修饰，以增强细胞毒性NA在肿瘤或转移性淋巴结中的选择性积累。药物形式的应用可能有助于预防许多已知的化疗副作用。在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全身制剂。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cross-linked polymeric nanogel formulations of 5'-triphosphates of nucleoside analogues: role of the cellular membrane in drug release.

核苷类似物 5-三磷酸的交联聚合物纳米凝胶制剂：细胞膜在药物释放中的作用。

DOI：
10.1021/mp0500364
发表时间：
2005
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Vinogradov,SergueiV;Kohli,Ekta;Zeman,ArinD
通讯作者：
Zeman,ArinD

FOLATE-TARGETED POLYFORMULATIONS OF CYTOTOXIC NUCLEOSIDE TRIPHOSPHATES AND PACLITAXEL.

细胞毒性核苷三磷酸酯和紫杉醇的叶酸靶向多制剂。

DOI：
发表时间：
2008
期刊：
Papers presented at the ... meeting. American Chemical Society. Division of Polymer Chemistry
影响因子：
0
作者：
Vinogradov,SergueiV;Mitin,Anton;Warren,Galya
通讯作者：
Warren,Galya

The second annual symposium on nanomedicine and drug delivery: exploring recent developments and assessing major advances. 19-20 August 2004, Polytechnic University, Brooklyn, NY, USA.

第二届纳米医学和药物输送年度研讨会：探索最新进展并评估重大进展。

DOI：
10.1517/17425247.1.1.181
发表时间：
2004
期刊：
Expert opinion on drug delivery
影响因子：
6.6
作者：
Vinogradov,Serguei
通讯作者：
Vinogradov,Serguei

SYNTHESIS OF NANOGEL CARRIERS FOR DELIVERY OF ACTIVE PHOSPHORYLATED NUCLEOSIDE ANALOGUES.

用于递送活性磷酸化核苷类似物的纳米凝胶载体的合成。

DOI：
发表时间：
2004
期刊：
Papers presented at the ... meeting. American Chemical Society. Division of Polymer Chemistry
影响因子：
0
作者：
Vinogradov,SergueiV;Kabanov,AlexanderV
通讯作者：
Kabanov,AlexanderV

Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines.