Journal of Nanomedicine & Nanotechnology

Targeted nano-based proteostasis-inhibition for controlling lung cancer pathogenesis & progression

2^nd International Conference on Nanotek and Expo

December 3-5, 2012 DoubleTree by Hilton Philadelphia Center City, USA

Neeraj Vij and Changhoon Ji

Scientific Tracks Abstracts: J Nanomed Nanotechol

Abstract:

We recently identified valosin-containing protein (VCP)/p97-retrograde translocation as a novel proteostasis mechanism involved in non-small cell lung cancer (NSCLC) pathogenesis and progression. Since VCP is involved in homeostatic processes (proteostasis), we developed a nano-based targeted proteostasis-inhibitor delivery system for targeting lung tumors as a novel selective proteostasis-inhibition strategy to control NSCLC progression and metastasis. We identified that the PLGA-PEG based bio-degradable nanoparticles (NPs) are safer for selective molecular targeting of proteostasis-inhibitor over polymeric chitosan-dextran sulphate (CS-DS; p<0.02; 24hrs) NPs as they did not inhibit non-tumor lung epithelial (Beas2b) cell proliferation. We encapsulated potent VCP-proteostasis-inhibitor (N 2 , N 4 -dibenzylquinazoline-2, 4-diamine; DBeQ) in PLGA-PEG (PLGA-PEG DBeQ ) NPs for targeted release of the drug without affecting the non-tumor cells. Next, we standardized the efficacy of PLGA-PEG DBeQ NPs (~15μM) to control NSCLC growth and progression. We found that PLGA-PEG DBeQ NPs significantly inhibit NSCLC migration (n=6, p<0.001; 24hrs) and proliferation (n=6, p<0.03; 24hrs & p<0.002; 48hrs) while inducing apoptosis (n=5, p<0.01; 48hrs). Moreover, we evaluated the anti-proliferative, apoptotic and tumor inhibitory efficacy of PLGA-PEG DBeQ NPs in athymic-nude mice (n=6; xenograft-model) injected with GeltrexTM-H1299 (4x10 6 ; day-0) tumors. We observed that PLGA-PEG DBeQ NPs (~15μM; day-10) induce anti-tumor activity within 48hrs, as seen by significant (p<0.005; day- 12) reduction in tumor sizes (~1.44-fold), without any significant body weight loss. The data demonstrates the safety and efficacy of novel PLGA-PEG based selective proteostasis-inhibition strategy (PLGA-PEG DBeQ ) for lung cancer therapy