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）：膀胱癌是男性中第四大常见的癌症，在女性中最常见。此外，手术治疗后，有70％的患者患有疾病复发。因此，针对这种病理学的有效治疗剂的发展是一个很高的优先级。该项目的长期目的是制定一种策略，以使用纤连蛋白附着蛋白（FAP）靶向药物负载的纳米载体，从治疗辅助芽孢杆菌Calmets Calmette-Guerin（BCG）中靶向膀胱肿瘤细胞。实际上，我们最近表明，在类似膀胱状的条件下，多价FAP纳米载体对人膀胱肿瘤细胞诱导纳米载体的摄取的纤连蛋白复合物的微聚类：整联蛋白复合物。在这里，我们将测试以下假设：托普甘替克载体的Fap-nanocarrier分别控制其摄取和细胞毒性的多价和膜融合特性。将使用培养基中的膀胱肿瘤细胞和原位小鼠模型来追求以下特定目标：1。确定多价性对膀胱肿瘤细胞的FAP纳米载体内在化的影响。 2。在膀胱肿瘤细胞中确定具有不同融合特性的替托克甘拓托管的FAP-纳米载体的细胞毒性。该项目具有创新性，因为利用新颖有效的靶向剂BCG的FAP来开发针对膀胱癌的治疗策略。此外，我们设计了一种通过膀胱肿瘤细胞促进FAP纳米载体内在化的方法。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（例如使用RGD肽进行靶向）更有优势，因为如前所述，FAP在免疫个体中引起了抗肿瘤免疫响应。同样，与RGD肽相比，FAP与纤连蛋白结合：整联蛋白复合物，而不是靶向低丰度的无丰度整合素或竞争纤连蛋白。此外，FAP不太可能有助于整联蛋白的信号，因为它结合了先前存在的纤连蛋白：整联蛋白复合物。实际上，我们的策略会导致假定纤连蛋白的溶酶体靶向和降解：整联蛋白信号传导复合物。