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Multi-Modal Gene Therapy for Pancreatic Cancer using Targeted Nanovectors

使用靶向纳米载体对胰腺癌进行多模式基因治疗

基本信息

批准号：
7984276
负责人：
Mansoor M Amiji
金额：
$ 19.9万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984276
关键词：
Acute Adenocarcinoma Cell Adverse effects Amino Acids Animals Apoptosis Apoptotic Binding Biodistribution Blood Circulation Blood Platelets Body Weight Changes Breast Adenocarcinoma Bystander Effect Cancer Patient Cells Clinic Combined Modality Therapy Cryoultramicrotomy DNA DNA Maintenance Development Drug Formulations Encapsulated Engineering Enzyme-Linked Immunosorbent Assay Enzymes Epidermal Growth Factor Receptor Flow Cytometry Future Gelatin Gene Combinations Gene Delivery Genes Harvest Head of pancreas Hepatic Mass Histopathology Human In Vitro Incubated Intracellular Transport Label Lead Liver Malignant neoplasm of pancreas Mammary Neoplasms Measurement Measures Microscopy Modeling Morphology Mus Neoplasm Metastasis Nodule Nude Mice Pancreatic Adenocarcinoma Peptides Plasma Plasmids Prevention Radio Radiolabeled Relative (related person)Resistance Safety Skeletal Muscle Staging Staining method Stains Structure of parenchyma of lung Sulfhydryl Compounds Surface Survival Analysis System TP53 gene Technology Therapeutic Time Tissues Transfection Treatment Efficacy Tumor Volume Tumor Weights Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Western Blotting White Blood Cell Count procedure Xenograft Model Xenograft procedure base combination gene therapy cytotoxicity density effective therapy engineering design gene therapy in vivo male mortality nanocarrier nanovector neoplastic cell novel outcome forecast plasmid DNA prevent radiotracer subcutaneous targeted delivery therapeutic gene tumor tumor growth tumor xenograft uptake

项目摘要

Multi-Modal Gene Therapy For Pancreatic Cancer Using Targeted Nanovectors Pancreatic cancer is associated with very poor prognosis partly due to rapid invasion and metastasis Novel clinically-translatable therapeutic strategies are necessary in order to effectively treat advanced stage pancreatic cancer. Although several gene therapy strategies have been tried, the major limitation is in the development of safe and effective delivery system for systemic administration. To overcome systemic gene delivery challenges, we have developed novel non-condensing gelatin based engineered nanovector systems (GENS) that can encapsulate plasmid DNA, protect against degradation in the systemic circulation and during intracellular transport, and efficiently transfect in vitro and in vivo in an orthotopic human breast tumor xenograft model. The expressed soluble Flt-1 (VEGF-R1) was therapeutically effective in the treatment of orthotopic human breast adenocarcinoma. Based on these impressive preliminary observations, we propose to use epidermal growth factor receptor (EGFR)-targeted long-circulating GENS encapsulated with wt-p53 and sFlt-1 encoding plasmids for single and combination gene therapy in pancreatic cancer. EGFR is over-expressed in approximately 50% pancreatic cancer and is a predictive indicator of tumor metastasis and resistance to chemo- and radio-therapy. Our hypothesis is that wt-p53 transfection will suppress tumor growth, induce apoptosis, and provide the "bystander effect", while the expressed sFlt-1 will lead to anti-angiogenic effect and prevent secondary metastasis. This combination therapy, delivered with safe EGFR-targeted GENS, will be especially beneficial in advanced stages of pancreatic cancer without the harmful side effects. The specific aims of this proposal are to: (1) formulate, using engineering design criteria, EGFR-targeted GENS for systemic p53 and sFlt-1 gene delivery; (2) evaluate uptake, cytotoxicity, and transfection in pancreatic adenocarcinoma (Panc-1 and Capan-1) cells; (3) examine the biodistribution, tumor uptake, and transfection in pancreatic adenocarcinoma-bearing nude mice upon systemic administration; (4) examine the therapeutic efficacy and prevention of metastasis in subcutaneous and orthotopic pancreatic adenocarcinoma-bearing nude mice, and (5) determine acute safety profile of systemically administered GENS. The results from this study are critical in order to adapt this clinically-translatable technology into the clinic for benefit to pancreatic cancer patients in the near future.

靶向纳米载体多模式基因治疗胰腺癌胰腺癌的预后非常差，部分原因是其侵袭和转移速度快为了有效治疗晚期胰腺癌，需要新的临床可转化的治疗策略。虽然已经尝试了几种基因治疗策略，但主要限制在于开发安全有效的全身给药递送系统。为了克服系统性基因递送的挑战，我们开发了新型非冷凝明胶，基于工程纳米载体系统（GENS），可以封装质粒DNA，本发明提供了一种在体循环中和在细胞内转运期间有效地抑制乳腺癌细胞的生长和降解，并且在原位人乳腺肿瘤异种移植模型中在体外和体内有效地抑制乳腺癌细胞的生长和降解。表达的可溶性Flt-1（VEGF-R1）对原位人乳腺癌的治疗有效。基于这些令人印象深刻的初步观察，我们建议使用表皮生长因子受体（EGFR）为靶点的长循环GENS封装与wt-p53和sFlt-1编码质粒的单一和组合基因治疗胰腺癌。EGFR在大约50%的胰腺癌中过表达，并且是肿瘤转移和对化疗和放疗的抗性的预测指标。我们的假设是，wt-p53转染将抑制肿瘤生长，诱导凋亡，并提供“旁观者效应”，而表达的sFlt-1将导致抗血管生成作用，防止继发转移。这种联合治疗，与安全的EGFR靶向GENS一起提供，将特别有益于晚期胰腺癌，而不会产生有害的副作用。本提案的具体目标是：（1）使用工程设计标准，制定EGFR靶向GENS用于系统性p53和sFlt-1基因递送;（2）评估胰腺癌的摄取、细胞毒性和转染（3）检测全身给药后胰腺腺癌荷瘤裸鼠的生物分布、肿瘤摄取和转染;（4）检查皮下和原位胰腺腺癌荷瘤裸鼠的治疗功效和转移预防，和（5）确定全身施用GENS的急性安全性特征。这项研究的结果对于在不久的将来将这种临床可翻译的技术应用于临床以造福胰腺癌患者至关重要。