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: 8403796
• 负责人: SERGUEI V VINOGRADOV
• 金额: $ 20.62万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403796
• 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.

描述（由申请人提供）：通过肿瘤靶向活性药物纳米制剂克服对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缺陷和NA转化为活性药物形式5 '-三磷酸（NATP）的激酶依赖性活化。我们的中心假设是，在癌细胞的细胞质中直接递送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。我们专门设计了用于封装NATP的纳米载体，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递送和释放活性药物。在初步研究中，NATP-nanogel制剂在许多正常和耐药癌细胞和动物模型中表现出比NA显著改善的治疗效果。纳米制剂的全身循环和肿瘤蓄积将通过在纳米级上修饰纳米凝胶结构和用对过表达的肿瘤EGF受体或肿瘤淋巴管具有高亲和力的多种选择的肽装饰纳米凝胶表面来优化。纳米凝胶在组织中降解，形成无毒的聚合物缀合物。NATP-纳米凝胶制剂保留了它们的性质，并且可以以冻干形式储存。这种方法提供了额外的前景，多药化疗的耐药肿瘤，通过管理两个NA分子与不同的细胞目标。肽修饰纳米凝胶的全身给药建议将增强药物在播散性转移灶中的蓄积和对转移性肿瘤的治疗功效。我们的具体目标1是开发有效的肿瘤靶向纳米凝胶载体，这些载体被优化用于将NATP全身递送到肿瘤。具体目标2是在体外评估药物纳米制剂在收集对NA耐药的癌细胞系中的细胞毒性作用。收集具有NA抗性的特定机制的细胞系将使我们能够确定用于消除耐药癌细胞的载体、载体和药物的最有效组合。在具体目标3中，我们将在人类乳腺癌和淋巴瘤异种移植动物模型中通过选定的纳米制剂实现对耐药肿瘤的有效治疗，并评估使用具有单独细胞靶点的两种NATP的多重化疗方法的可行性。简而言之，这种方法开发了一种新的基于纳米技术的治疗耐药肿瘤的策略。

项目成果

Efficient overcoming of drug resistance to anticancer nucleoside analogs by nanodelivery of active phosphorylated drugs.

• DOI: 10.1016/j.ijpharm.2010.05.028
• 发表时间: 2010-08-16
• 期刊: INTERNATIONAL JOURNAL OF PHARMACEUTICS
• 影响因子: 5.8
• 作者: Galmarini, Carlos M.;Warren, Galya;Senanayake, Madapathage T.;Vinogradov, Serguei V.
• 通讯作者: Vinogradov, Serguei V.

Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors.

• DOI: 10.1021/bc300632w
• 发表时间: 2013-04-17
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 作者: Wei, Xin;Senanayake, Thulani H.;Warren, Galya;Vinogradov, Serguei V.
• 通讯作者: Vinogradov, Serguei V.

Curcumin-encapsulating Nanogels as an Effective Anticancer Formulation for Intracellular Uptake.

• DOI: 10.4255/mcpharmacol.15.04
• 发表时间: 2015
• 期刊: Molecular and cellular pharmacology
• 作者: Reeves A;Vinogradov SV;Morrissey P;Chernin M;Ahmed MM
• 通讯作者: Ahmed MM

Macrophages associated with tumors as potential targets and therapeutic intermediates.

• DOI: 10.2217/nnm.14.13
• 发表时间: 2014-04
• 期刊: Nanomedicine (London, England)
• 作者: Vinogradov S;Warren G;Wei X
• 通讯作者: Wei X

Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.

• DOI: 10.1016/j.jconrel.2013.01.020
• 发表时间: 2013-04-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Senanayake TH;Warren G;Wei X;Vinogradov SV
• 通讯作者: Vinogradov SV