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，女性第十一常见癌症。此外，百分之七十的患者在手术治疗后会出现疾病复发。因此，开发针对这种病理的有效疗法是当务之急。该项目的长期目标是开发一种策略，利用治疗佐剂卡介苗（BCG）中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。事实上，我们最近表明，多价 FAP 纳米载体形成的纤连蛋白：整合素复合物的微簇可诱导人膀胱肿瘤细胞在类似膀胱的条件下摄取纳米载体。在这里，我们将测试这样的假设：负载拓扑替康的 FAP 纳米载体的多价和膜融合特性分别控制其摄取和细胞毒性。将使用培养的膀胱肿瘤细胞和原位小鼠模型来实现以下具体目标： 1.确定多价对膀胱肿瘤细胞内化 FAP-纳米载体的影响。 2. 确定具有不同融合特性的负载拓扑替康的 FAP 纳米载体在膀胱肿瘤细胞中的细胞毒性。该项目具有创新性，因为利用来自 BCG 的新型高效靶向剂 FAP 来开发针对膀胱癌的治疗策略。此外，我们设计了一种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 摄取。此外，我们的方法比其他更传统的纳米载体策略（例如使用 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，因为它与预先存在的纤连蛋白：整合素复合物结合。事实上，我们的策略导致溶酶体靶向和假定的纤连蛋白：整合素信号复合物的降解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera.

一种利用 EGF-炭疽毒素嵌合体治疗 Her2 阳性和阴性膀胱癌的新型、安全、快速和有效的治疗方法。

DOI：
发表时间：
2020-01-15
期刊：
影响因子：
6.4
作者：
Jack, Sherwin;Madhivanan, Kayalvizhi;Ramadesikan, Swetha;Subramanian, Sneha;Edwards 2nd, Daniel F;Elzey, Bennett D;Dhawan, Deepika;McCluskey, Andrew;Kischuk, Erin M;Loftis, Alexander R;Truex, Nicholas;Santos, Michael;Lu, Mike;Rabideau, Amy;P
通讯作者：
P

The Information Content of Glutamine-Rich Sequences Define Protein Functional Characteristics.

富含谷氨酰胺序列的信息内容定义了蛋白质的功能特征。