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.

Public Health Relevance

Pancreatic cancer has very high mortality partly due to rapid invasion and metastasis. We propose to encapsulate and deliver combination gene constructs for effective treatment of pancreatic cancer. Safe and effective gelatin-based engineered nanovector systems (GENS) specifically made to target the epidermal growth factor receptors (EGFR) on pancreatic cancer will be used to encapsulate and deliver wt-p53 and sFlt-1 expressing genes for maximum therapeutic benefits,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151881-03
Application #
8381582
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$191,785
Indirect Cost
Name
Northeastern University
Department
Type
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Petrenko, Valery A; Gillespie, James W (2017) Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted 'magic bullets' to self-navigated 'magic missiles'. Expert Opin Drug Deliv 14:373-384
Pattni, Bhushan S; Jhaveri, Aditi; Dutta, Ivy et al. (2017) Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG. Int J Pharm 532:149-156
Singh, Amit; Xu, Jing; Mattheolabakis, George et al. (2016) EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model. Nanomedicine 12:589-600
Su, Mei-Ju; Aldawsari, Hibah; Amiji, Mansoor (2016) Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems. Sci Rep 6:30110
Sriraman, Shravan Kumar; Pan, Jiayi; Sarisozen, Can et al. (2016) Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells. Mol Pharm 13:428-37
Gillespie, James W; Wei, Lixia; Petrenko, Valery A (2016) Selection of Lung Cancer-Specific Landscape Phage for Targeted Drug Delivery. Comb Chem High Throughput Screen 19:412-22
Patel, Niravkumar R; Piroyan, Aleksandr; Nack, Abbegial H et al. (2016) Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer. Mol Pharm 13:1996-2009
Zhang, Yilin; Sriraman, Shravan Kumar; Kenny, Hilary A et al. (2016) Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform. Mol Cancer Ther 15:2282-2293
Han, Lei; Liu, Pei; Petrenko, Valery A et al. (2016) A Label-Free Electrochemical Impedance Cytosensor Based on Specific Peptide-Fused Phage Selected from Landscape Phage Library. Sci Rep 6:22199
Sriraman, Shravan Kumar; Salzano, Giusseppina; Sarisozen, Can et al. (2016) Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid. Eur J Pharm Biopharm 105:40-9

Showing the most recent 10 out of 80 publications