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

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，治疗性NA的耐药成为肿瘤和病毒感染治疗的持续临床挑战。耐药的主要机制包括药物运输缺陷和激酶依赖的NA活化成5'-三磷酸（NATP），一种活性药物形式。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传递和释放活性药物。在初步研究中，natp纳米凝胶配方在许多正常和耐药癌细胞和动物模型中显示出明显优于NA的治疗效果。通过在纳米尺度上修饰纳米凝胶结构，并选择对过表达的肿瘤EGF受体或肿瘤淋巴管具有高亲和力的多肽修饰纳米凝胶表面，可以优化纳米制剂的体循环和肿瘤蓄积。纳米凝胶在组织中降解，形成无毒的聚合物偶联物。natp纳米凝胶配方保留了它们的特性，可以以冻干形式储存。这种方法通过给药两种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。经多肽修饰的纳米凝胶可增强弥散性转移瘤的药物蓄积，提高对转移性肿瘤的治疗效果。我们的具体目标1是开发高效的肿瘤靶向纳米凝胶载体，优化其对肿瘤的全身递送。特异性目的2是评估药物纳米制剂在体外收集耐NA癌细胞系中的细胞毒性作用。收集对NA具有特定抗性机制的细胞系将使我们能够确定最有效的载体、载体和药物组合，以消除耐药癌细胞。在Specific Aim 3中，我们将通过选择纳米制剂在人类乳腺癌和淋巴瘤异种移植动物模型中实现对耐药肿瘤的有效治疗，并评估使用两种具有单独细胞靶点的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新的基于纳米技术的治疗耐药肿瘤的策略。

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.