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

• 批准号: 8009831
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009831
• 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

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(申请人提供)：通过肿瘤靶向活性药物纳米制剂克服核苷类似物的耐药性细胞毒性核苷类似物(NA)是单药或多药化疗方案的重要组成部分。然而，在肿瘤和病毒感染的治疗中，对治疗性NA的耐药性成为持续的临床挑战。耐药的主要机制包括药物转运不足和依赖于激酶将NA激活为活性药物形式5‘-三磷酸(NatP)。我们的中心假设是，在癌细胞的细胞质中直接输送NatP将足以绕过许多耐药机制，并有效地根除耐药肿瘤。这种方法还可以减少化疗的毒性后果。我们专门设计了纳米载体来包裹NatP，这是一种可生物降解的纳米凝胶阳离子网络，能够可逆地结合NatP，在肿瘤部位的癌细胞内传递和释放活性药物。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-纳米凝胶制剂显示出显著优于NA的治疗效果。通过在纳米尺度上修饰纳米凝胶结构，并在纳米凝胶表面修饰多种与过表达的肿瘤EGF受体或肿瘤淋巴管具有高亲和力的多肽，将优化纳米制剂的体循环和肿瘤蓄积。纳米凝胶在组织中随着无毒聚合物偶合物的形成而降解。NatP-纳米凝胶制剂保留了它们的特性，并可以以冷冻干燥的形式储存。这种方法通过给药两个具有不同细胞靶点的NA分子，为耐药肿瘤的多药化疗提供了额外的前景。建议对多肽修饰的纳米凝胶进行全身给药，以增强药物在播散性转移瘤中的蓄积和对转移瘤的治疗效果。我们的具体目标1是开发高效的肿瘤靶向纳米凝胶载体，这种载体可以优化系统地将NatP输送到肿瘤。具体目的2是评价药物纳米制剂在收集NA耐药细胞系中的体外细胞毒作用。收集对NA具有特定耐药机制的细胞系将使我们能够确定载体、载体和药物的最有效组合，以消除耐药癌细胞。在具体目标3中，我们将通过在人乳腺癌和淋巴瘤异种移植动物模型中选择纳米制剂来实现对耐药肿瘤的有效治疗，并评估使用两种具有不同细胞靶点的NatP进行多化疗方法的可行性。简而言之，这种方法开发了一种基于纳米技术的治疗耐药肿瘤的新策略。 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产生耐药性，这是化疗面临的一个非常严重的临床挑战。细胞毒性核苷类似物是单药和多药治疗癌症的一线药物，其耐药性包括药物转运和细胞药物对核苷5‘-三磷酸激活的缺陷。在此，我们建议直接应用肿瘤靶向的纳米凝胶包裹的核苷5‘-三磷酸(NanNAP)来将活性药物输送到癌细胞内，克服癌细胞绕过耐药机制的防御。研究发现，NanoNatP可使耐药癌细胞对核苷类似物的敏感性恢复数百至数千倍。这一应用包括彻底的化学工程和通过肿瘤结合肽对纳米载体进行表面修饰，以增加它们在肿瘤部位和转移中的积聚。建议的纳米NatP配方提供了一种额外的治疗选择，用于系统地给药一到两种协同药物，用于治疗难以治疗的癌症。这将极大地提高患者的生活质量；他们将只接受一次低剂量，而不是接受高剂量或两次不同药物的注射。这项应用开发了治疗耐药肿瘤的创新纳米技术方法。