Drug Resistance in Cancer Therapy

癌症治疗中的耐药性

基本信息

批准号：
7405692
负责人：
VINOD D LABHASETWAR
金额：
$ 14.25万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-12 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7405692
关键词：
Animals Antineoplastic Agents Binding Biodistribution Breast Cancer Cell Breast Cancer Model Bypass Cancer cell line Cell Nucleus Cells Class Cytoplasm Cytoplasmic Vesicles DDAB DNA Development Disease regression Dose Doxorubicin Drug Delivery Systems Drug Formulations Drug resistance Drug usage Emulsions Encapsulated Exocytosis Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Inhibitory Concentration 50 Intravenous Localized Lysosomes MCF7 cell Malignant Neoplasms Measures Membrane Modeling Multi-Drug Resistance Mus NIH Program Announcements Nuclear Oils Organic solvent product P-Glycoprotein P-Glycoproteins Pharmaceutical Preparations Polymers Polyvinyl Alcohol Property Proteins Rate Research Project Grants Resistance Route Site Solutions Surface Testing Therapeutic Tissues Treatment Efficacy Vesicle Water biomaterial compatibility cancer cell cancer therapy chemotherapeutic agent chemotherapy drug efficacy efflux pump evaporation in vivo interfacial intravenous administration malignant breast neoplasm nanoparticle polylactic acid-polyglycolic acid copolymer response size subcutaneous tumor tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): This aim of this exploratory proposal is to investigate the efficacy of our recently developed nanoparticle formulation to overcome the problem of drug resistance in cancer therapy. Modified nanoparticles are seen to localize in and around the nucleus following their cellular uptake and are retained inside the cells i.e. they do not undergo exocytosis. Hence, it is hypothesized that modified nanoparticles would deliver the encapsulated drug directly to the nucleus without its exposure to the membrane-bound efflux transporters and cytoplasmic factors (e.g., degradation or accumulation of drug in acidic vesicles) that limit the nuclear delivery of antineoplastic agents in resistant cells. Hence, direct nuclear delivery of the drug using modified nanoparticles would overcome the problem of drug resistance and hence the therapy would be more effective in tumor regression. We will use doxorubicin as a model antineoplastic agent because it acts by intercalating with the nuclear DNA. To test the above hypothesis, we will measure the antiproliferative activity (IC50) of the drug in normal and drug resistant breast cancer cell lines and also determine drug levels in various intracellular compartments (nucleus, cytoplasm, endo-lysosomes) to understand the mechanism of greater drug efficacy with modified nanoparticles. To test the suitability of modified nanoparticles for in vivo administration, we will study their biocompatibility, biodistribution, and then determine their efficacy for tumor regression in a murine model of breast cancer progression via intravenous administration. The specific aims of the proposal are: 1) to test the hypothesis that modified nanoparticles are effective in targeting doxorubicin to the nucleus, and hence in overcoming the problem of drug resistance and 2) to demonstrate that modified nanoparticles are effective in tumor regression in a murine model of breast cancer induced using sensitive (MCF-7) and resistant (MCF-7/Adr) cells. The nanoparticle formulation investigated in this proposal could be used as an effective delivery mechanism for several classes of therapeutics for which the target is nucleus.

描述（由申请人提供）：该探索性提案的目的是研究我们最近开发的纳米颗粒制剂的功效，以克服癌症治疗中的耐药性问题。修饰的纳米颗粒被认为在细胞摄取后定位在细胞核内和细胞核周围，并保留在细胞内，即它们不经历胞吐作用。因此，假设修饰的纳米颗粒会将封装的药物直接递送至细胞核，而不暴露于限制抗肿瘤药物的细胞核递送的膜结合外排转运蛋白和细胞质因子（例如，药物在酸性囊泡中的降解或积累）在耐药细胞中。因此，使用修饰的纳米颗粒直接向核递送药物将克服耐药性问题，因此该疗法在肿瘤消退方面将更有效。我们将使用阿霉素作为抗肿瘤药物模型，因为它通过嵌入核 DNA 发挥作用。为了检验上述假设，我们将测量该药物在正常和耐药乳腺癌细胞系中的抗增殖活性（IC50），并测定不同细胞内区室（细胞核、细胞质、内溶酶体）中的药物水平，以了解该药物的作用机制。修饰后的纳米颗粒具有更高的药效。为了测试修饰纳米粒子在体内给药的适用性，我们将研究它们的生物相容性、生物分布，然后确定它们在通过静脉给药的乳腺癌进展小鼠模型中对肿瘤消退的功效。该提案的具体目标是：1) 测试修饰纳米颗粒可有效将阿霉素靶向细胞核，从而克服耐药性问题的假设；2) 证明修饰纳米颗粒可有效抑制肿瘤消退。使用敏感（MCF-7）和耐药（MCF-7/Adr）细胞诱导乳腺癌的小鼠模型。本提案中研究的纳米颗粒制剂可用作几类以细胞核为靶标的治疗药物的有效递送机制。