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

• 批准号: 8508517
• 负责人: Ruben Claudio Aguilar
• 金额: $ 16.24万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508517
• 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

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出现疾病复发。因此，开发针对这种病理的有效治疗方法是当务之急。本项目的长期目标是开发一种利用治疗佐剂卡介苗中的纤维连接蛋白（FAP）将载药纳米载体靶向膀胱肿瘤细胞的策略。事实上，我们最近发现，在膀胱样条件下，多价fap纳米载体对纤维连接蛋白：整合素复合物的微聚集诱导了人类膀胱肿瘤细胞对纳米载体的摄取。在这里，我们将验证负载拓扑替康的fap纳米载体的多价性和膜致聚变特性分别控制它们的摄取和细胞毒性的假设。使用膀胱肿瘤细胞培养和原位小鼠模型将达到以下具体目的：确定多价性对膀胱肿瘤细胞内化fap纳米载体的影响。2. 在膀胱肿瘤细胞中测定负载拓扑替康的不同促融合特性的fap纳米载体的细胞毒性。该项目具有创新性，因为它利用了一种新颖有效的靶向剂，即来自BCG的FAP，来开发一种治疗膀胱癌的策略。此外，我们设计了一种促进fap -纳米载体被膀胱肿瘤细胞内化的方法。这种基于微聚类的方法通过已知动力学、运输路线和平均囊泡大小的机制诱导FAP摄取。此外，我们的方法比其他更传统的纳米载体策略（如使用RGD肽靶向的策略）更有优势，因为如前所述，FAP在免疫个体中引发抗肿瘤免疫反应。此外，与RGD肽相反，FAP与纤连蛋白：整合素复合物结合，而不是靶向低丰度的游离整合素或与纤连蛋白竞争。此外，FAP不太可能参与整合素信号传导，因为它结合了预先存在的纤维连接蛋白：整合素复合物。事实上，我们的策略导致溶酶体靶向和降解假定的纤维连接蛋白：整合素信号复合物。