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Targeting of Bladder Tumor Cells by Nanocarriers Bearing bacillus Calmette-Guerin

携带卡介苗的纳米载体靶向膀胱肿瘤细胞

基本信息

批准号：
8639496
负责人：
Ruben Claudio Aguilar
金额：
$ 18.98万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639496
关键词：
Adjuvant Therapy Affect Antineoplastic Agents Bacteria Binding Biological Assay Bladder Bladder Neoplasm Blood Circulation Calmette-Guerin Bacillus Cancer Model Carcinoma Cell Adhesion Molecules Cells Characteristics Complex Cytoplasm Cytotoxic agent Development Disease Drug Delivery Systems Drug Targeting Endocytosis Fibronectins Foundations Glycosaminoglycans Human Immune response Individual Inflammatory Response Integrins Intravesical Instillation Kinetics Life Ligands Liposomes Malignant Neoplasms Malignant neoplasm of urinary bladder Measurable Measures Mediating Membrane Methods Modeling Monitor Morbidity - disease rate Mus Mycobacterium Infections Normal Cell Operative Surgical Procedures Pathology Patients Periodicals Permeability Pharmaceutical Preparations Physiological Positioning Attribute Preparation Property Protein Binding Protein Chemistry Proteins RGD (sequence)Recurrence Risk Route Signal Transduction Surface Systemic infection Technology Testing Therapeutic Thick Time Topotecan Undifferentiated Urine Urothelium Vesicle Woman base cytotoxic cytotoxicity density design fluorexon innovation men mouse model nanocarrier neoplastic cell novel novel therapeutic intervention public health relevance residence seal targeted delivery trafficking tumor uptake wasting

项目摘要

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in men and eleventh most common in women. In addition, seventy percent of patients suffer disease recurrence after surgical treatment. Therefore, the development of efficient therapeutics against this pathology is a high priority. The long-term objective of this project is to develop a strategy to target drug- loaded nanocarriers to bladder tumor cells using Fibronectin Attachment Protein (FAP) from the therapy adjuvant Bacillus Calmette-Guerin (BCG). Indeed, we recently showed that microclustering of Fibronectin:Integrin complexes by multivalent FAP-nanocarriers induced nanocarrier uptake by human bladder tumor cells under bladder-like conditions. Here, we will test the hypothesis that multivalency and membrane fusogenic properties of topotecan-loaded FAP-nanocarriers control their uptake and cytotoxicity, respectively. The following specific aims will be pursued using bladder tumor cells in culture and an orthotopic mouse model: 1. Determine the effect of multivalency on FAP-nanocarrier internalization by bladder tumor cells. 2. Determine in bladder tumor cells the cytotoxicity of topotecan-loaded FAP-nanocarriers with different fusogenic characteristics. This project is innovative because utilizes novel and efficient targeting agent, FAP from BCG, for the development of a therapeutic strategy against bladder cancer. Further, we devised a method for promoting the internalization of FAP-nanocarriers by bladder tumor cells. This microclustering-based approach induces FAP uptake through a mechanism with known kinetics, trafficking route and average vesicle-size. In addition, our approach is more advantageous than other more conventional nanocarrier strategies (like the ones using RGD peptides for targeting) because, as previously described, FAP elicits an anti-tumor immunoresponse in immunized individuals. Also, as opposed to RGD peptides, FAP binds to Fibronectin:Integrin complexes rather than targeting low abundance free Integrins or competing off Fibronectin. Further, FAP is not likely to contribute to Integrin-signaling as it binds pre-existing Fibronectin:Integrin complexes. In fact, our strategy leads to lysosomal targeting and degradation of putative Fibronectin:Integrin signaling complexes.

描述（由申请人提供）：膀胱癌是男性第四大常见癌症，女性第十一大常见癌症。此外，70%的患者在手术治疗后复发。因此，开发针对这种病理学的有效疗法是一个高度优先事项。该项目的长期目标是开发一种使用来自治疗佐剂卡介苗（BCG）的纤连蛋白附着蛋白（FAP）将载药纳米载体靶向膀胱肿瘤细胞的策略。事实上，我们最近表明，纤连蛋白：整合素复合物的多价FAP-纳米载体的微簇诱导的人膀胱肿瘤细胞在膀胱样条件下的纳米载体摄取。在这里，我们将测试负载托泊替康的FAP纳米载体的多价性和膜融合性分别控制其摄取和细胞毒性的假设。将使用培养的膀胱肿瘤细胞和原位小鼠模型追求以下具体目标：1.确定多价性对膀胱肿瘤细胞的FAP-纳米载体内化的影响。2.在膀胱肿瘤细胞中测定具有不同融合特性的负载托泊替康的FAP纳米载体的细胞毒性。该项目是创新的，因为利用新型和有效的靶向剂，FAP从BCG，用于开发膀胱癌的治疗策略。此外，我们设计了一种用于促进膀胱肿瘤细胞内化FAP纳米载体的方法。这种基于微簇的方法通过具有已知动力学、运输途径和平均囊泡大小的机制诱导FAP吸收。此外，我们的方法比其他更常规的纳米载体策略（如使用RGD肽进行靶向的策略）更有利，因为如前所述，FAP在免疫个体中激发抗肿瘤免疫应答。此外，与RGD肽相反，FAP结合纤连蛋白：整合素复合物，而不是靶向低丰度游离整合素或竞争纤连蛋白。此外，FAP不太可能有助于整合素信号传导，因为它结合预先存在的纤连蛋白：整合素复合物。事实上，我们的策略导致溶酶体靶向和降解推定的纤连蛋白：整合素信号复合物。