This revised application for an R21 exploratory research grant is in response to PA-11-149 entitled "Nanoscience and Nanotechnology in Biology and Medicine". This project addresses an area of interest of the National Cancer Institute seeking evaluation of nanotechnology-based methods to enable the understanding, prevention, detection, and elimination of metastases. In this exploratory research project we shall validate our recently developed, unique, biodegradable targeted nanoparticle complexed with IL-8 specific siRNA (BDT IL- 8-siRNA nanoplex) for the efficient and prolonged knockdown IL-8 gene expression in CaP cells resulting in their death. A component of this project will allow us to produce sufficient quantities of therapeutic nanoplexes for use in an in vivo animal model of CaP. BDT IL-8-siRNA nanoplexes are built on allyl-functionalized L-lactide monomers, yielding a functionalized polylactic acid (PLA) backbone and are highly biocompatible, making them ideal agents for nanotherapy. In spite of our prior preliminary studies with the PC-3 CaP cell line, we shall use the LNCaP cell line in this proposal because it expresses prostate specific membrane antigen (PSMA) allowing for its selective targeting by customized nanoplexes incorporating monoclonal antibodies (MAb) to PSMA. Initially we shall perform in vitro experiments to determine the effect of treating LNCaP cells with BDT IL-8-siRNA nanoplexes. Nanoplex controls will incorporate a scrambled siRNA. Subsequent in vivo experiments will use our established athymic, nude murine model of human CaP employing orthopic inoculation of LNCaP cells into the prostate allowing formation of a primary tumor and subsequent metastases. Animals will be treated with BDT IL-8-siRNA nanoplexes administered i.v directly into the prostate. Further, BDT IL-8-siRNA nanoplexes coupled to MAb to PSMA will be administered for systemic targeted delivery in vivo. Treated animals will be followed prospectively and we expect to see regression of tumors and metastases compared to controls. Serum and tumor tissue will be analyzed for knockdown of IL-8 expression in treated animals as well as the expression of angiogenic and anti-apoptotic factors. These exploratory studies are designed to establish proof of concept for eventual clinical trials of BDT IL-8-siRNA nanoplexes in patients with CaP.

Public Health Relevance

The goal of this project is to develop a unique and safe, biodegradable nanotherapy for local and metastatic prostate cancer by suppressing the gene for interleukin-8 which is required for their growth and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA167177-02
Application #
8507652
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2012-07-09
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$162,027
Indirect Cost
$59,802
Name
State University of New York at Buffalo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Chen, Chih-Kuang; Law, Wing-Cheung; Aalinkeel, Ravikumar et al. (2014) Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells. Nanoscale 6:1567-72