Overcoming Drug Resistance to Nucleoside Analogs by Tumor-Targeted Active Nanofor

通过肿瘤靶向活性 Nanofor 克服核苷类似物的耐药性

基本信息

批准号：
8204697
负责人：
SERGUEI V VINOGRADOV
金额：
$ 21.93万
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：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204697
关键词：
Adverse effects Affinity Animal Model Antibiotics Antimetabolites Antineoplastic Agents Apoptosis Binding Biodegradation Blood Circulation Breast Lymphoma Bypass Cancer cell line Cell Line Cell model Chemical Engineering Chemotherapy-Oncologic Procedure Clinical Collection Combination Drug Therapy Complex Cytoplasm Cytotoxic Chemotherapy DNA Deaminase Dose Drug Carriers Drug Formulations Drug Transport Drug resistance Encapsulated Epidermal Growth Factor Receptor Family Hematologic Neoplasms Human In Vitro Induction of Apoptosis Liver Lymphatic Lymphatic Vessel Tumors Malignant Neoplasms Mammary Neoplasms Methodology Mitochondria NADP NanoGel Nanotechnology Neoplasm Metastasis Nucleoside Transporter Nucleosides Nucleotides Organ Oxidoreductase Patients Peptides Pharmaceutical Preparations Phosphotransferases Physiological Polymers Preparation Prodrugs Property Purines Pyrimidine Nucleosides Quality of life RNA Regimen Resistance Reticuloendothelial System Ribonucleotides Site Solid Neoplasm Solubility Structure Surface Systemic Therapy Therapeutic Therapeutic Effect Time Tissues Toxic effect Treatment Efficacy Tumor Specific Peptide Virus Diseases Xenograft Model Xenograft procedure base cancer cell cancer therapy cellular targeting chemotherapy comparative cytotoxic cytotoxicity design direct application drug distribution improved innovation malignant breast neoplasm nano nanocarrier nanoformulation nanoscale neoplastic cell novel nucleoside analog overexpression pill public health relevance purine resistance mechanism self assembly tripolyphosphate tumor tumor growth tumor xenograft vector

项目摘要

DESCRIPTION (provided by applicant): Overcoming drug resistance to nucleoside analogs by tumor targeted active drug nanoformulations cytotoxic nucleoside analogs (NA) are important components of single-drug or multidrug chemotherapeutic regimens. However, drug resistance to therapeutic NA became constant clinical challenge in the treatment of tumors and viral infections. The principle mechanisms of resistance include deficiencies in drug transport and kinase-dependent activation of NA into 5'-triphosphates (NATP), an active drug form. Our central hypothesis is that direct delivery of NATP in the cytoplasm of cancer cells would be sufficient to bypass many mechanisms of drug resistance and efficiently eradicate drug-resistant tumors. This approach would also allow for decreasing toxic consequences of chemotherapy. We have specially designed nanocarriers for encapsulation of NATP, biodegradable nanogel cationic networks, which are capable to reversibly bind NATP, deliver and release the active drug inside cancer cells in tumor sites. In preliminary studies, NATP-nanogel formulations demonstrated significantly improved over NA therapeutic effect in many normal and drug-resistant cancer cells and animal models. Systemic circulation and tumor accumulation of nanoformulations will be optimized by modifying nanogel structure on nanoscale and decorating nanogel surface with multiple selected peptides having high affinity to overexpressed tumor EGF receptors or tumor lymphatic vessels. Nanogels degrade in tissues with the formation of non-toxic polymer conjugates. NATP-nanogel formulations retain their properties and can be stored in lyophilized form. This approach provides additional prospects for multidrug chemotherapy of drug-resistant tumors by administration of two NA molecules with different cellular targets. Systemic administration suggested for peptide-decorated nanogels would enhance drug accumulation in disseminated metastases and therapeutic efficacy against metastatic tumors. Our Specific Aim 1 is to develop efficient tumor-targeted nanogel carriers that are optimized for systemic delivery of NATP to tumors. Specific Aim 2 is to evaluate cytotoxic effect of drug nanoformulations in vitro in the collection of resistant to NA cancer cell lines. The collection of cell lines with specific mechanisms of resistance to NA will allow us to determine the most efficient combinations of vector, carrier and drug for elimination of drug-resistant cancer cells. In Specific Aim 3 we are going to achieve efficient therapy of drug-resistant tumors by selected nanoformulations in human breast cancer and lymphoma xenograft animal models and evaluate the feasibility of polychemotherapeutic approach using two NATP having separate cellular targets. Concisely stating, this approach develops a novel nanotechnology-based strategy of treating drug-resistant tumors. PUBLIC HEALTH RELEVANCE: Resistance of many common cancers to therapeutic drugs, including nucleoside analogs, represents a very serious clinical challenge to chemotherapy. The drug resistance to cytotoxic nucleoside analogs, the first line drugs in single- and multidrug cancer therapies, includes deficiencies in drug transport and cellular drug activation to nucleoside 5'-triphosphates. We propose here direct application of tumor-targeted nanogel- encapsulated nucleoside 5'-triphosphates (nanoNATP) to deliver the active drug inside of cancer cells and overcome the cancer cell defense bypassing the drug resistance mechanisms. NanoNATP was found to restore sensitivity of cancer cells resistant to nucleoside analogs in hundreds to thousand times. This application includes thorough chemical engineering and surface decoration of nanocarriers by tumor-binding peptides to increase their accumulation in tumor sites and metastases. The suggested nanoNATP formulations provide an additional therapeutic option for systemic administration of one or two synergistic drugs at the treatment of poorly treatable cancers. This would greatly improve quality of life of patients; instead of receiving high doses or two administrations of different drugs, they would receive only one low dose. This application develops innovative nanotechnological approach to treat drug-resistant tumors.

描述（由申请人提供）：通过肿瘤靶向的活性药物纳米成型的抗核苷类似物的耐药性细胞毒性核苷类似物（NA）是单药或多药化学治疗方案的重要组成部分。然而，对治疗NA的耐药性成为治疗肿瘤和病毒感染的持续临床挑战。抗药性的主要机制包括药物转运和激酶依赖性激活Na到5'-三磷酸盐（NATP）（一种活性药物形式）中的缺陷。我们的中心假设是，NATP在癌细胞的细胞质中的直接递送将足以绕过许多耐药性机制并有效地消除耐药性肿瘤。这种方法还可以减少化学疗法的毒性后果。我们有专门设计的纳米载体，用于封装NATP，可生物降解的纳米凝胶阳离子网络，这些网络能够可逆地结合NATP，在肿瘤部位中递送和释放活性药物。在初步研究中，在许多正常和耐药的癌细胞和动物模型中，NATP纳米凝胶制剂在NA治疗效果上表现出显着改善。通过修饰纳米级上的纳米凝胶结构并用多种选择的纳米凝胶表面修饰纳米凝胶结构，具有高表达过表达肿瘤EGF受体或肿瘤淋巴管的纳米凝胶表面，可以通过修饰纳米凝胶结构并装饰纳米凝胶表面来优化纳米成型的全身循环和肿瘤积累。纳米凝胶在组织中降解，形成了无毒聚合物偶联物。 NATP-Nanogel制剂保留其特性，可以以冻干形式存储。这种方法通过给予两个具有不同细胞靶标的NA分子来提供耐药性肿瘤的多药化疗的额外前景。全身性给药建议对肽的纳米凝胶进行了促进的纳米凝固，这将增强对转移肿瘤的传播转移和治疗功效的药物积累。我们的特定目的1是开发有效的符号肿瘤的纳米凝胶载体，这些纳米凝胶载体已针对全身性NATP递送到肿瘤进行了优化。具体目的2是评估药物纳米成型在体外的细胞毒性作用，从而在收集NA癌细胞系的耐药性中。具有对NA耐药性的特定机制的细胞系收集将使我们能够确定载体，载体和药物的最有效组合，以消除耐药性癌细胞。在特定目标3中，我们将通过在人类乳腺癌和异种淋巴瘤动物模型中精选的纳米构造来实现有效治疗药物耐药性肿瘤，并使用两个具有单独的细胞靶标的NATP来评估多化学治疗方法的可行性。简而言之，这种方法开发了一种基于纳米技术的新型策略，用于治疗药物耐药性肿瘤。公共卫生相关性：许多常见癌症对包括核苷类似物在内的治疗药物的抗性，代表了对化学疗法的非常严重的临床挑战。对细胞毒性核苷类似物的耐药性是单线和多药癌疗法中的第一线药物，包括药物转运和细胞药物激活5'-三磷酸核苷的缺乏。我们在这里提出，直接应用靶向肿瘤的纳米凝胶封装的核苷5'-三磷酸盐（纳米ANONATP）将活性药物输送到癌细胞内部，并克服绕过耐药性机制的癌细胞防御。发现纳米纳州可以恢复癌细胞对核苷类似物的敏感性，数百到千倍。该应用包括通过肿瘤结合肽来彻底的化学工程和纳米载体的表面装饰，以增加其在肿瘤部位和转移酶中的积累。建议的纳米ANONATP配方为全身服用一种或两种协同药物提供了一种额外的治疗选择，以治疗无法治疗的癌症治疗不佳。这将大大改善患者的生活质量；他们不接受高剂量或两种不同药物的施用，而是只会收到一种低剂量。该应用开发了创新的纳米技术方法来治疗耐药性肿瘤。