Abstract 4484: Anti-cancer treatments delivered by antibody guided PLGA nanoparticles
Authors: Wu Shuta , Fowler Anthony , Ogle Craig , Mukherjee Pinku 
Published: May 2015

Background Pancreatic Cancer is (PC) is the 4th leading cause of cancer-related deaths in the United States with 94% of PC patients dying within 5 years of diagnosis. There are limited treatment options

for PC patients since PC is often diagnosed at a late stage, leaving only chemotherapy or a combination of chemotherapy with radiation as a viable treatment. Standard dosages are usually based on a calculated body surface area (BSA) measurement that correlates with patient blood volume. This type of dosing can lead to suboptimal dosages which can cause overdosing or ineffective treatments. Due to

systemic delivery of drugs, current chemotherapies have off-target effects leading to major complications. There is a need to target the delivery of anti-cancer treatments at optimal dosages to avoid adverse side-effects in patients. Pancreatic Ductal Adenocarcinoma (PDA) represents 90% of PCs and over 80% of PDAs over-express tumor-associated Mucin-1 (MUC1), a membrane-tethered glycoprotein protein. Tumor-associated MUC1 exhibits changes to its glycosylation pattern that expose its protein core, thus making it identifiable to the TAB004, a specific antibody we synthesize and have shown to only recognizes this form of MUC1. Poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) are an attractive drug delivery tool. 1) NPs are biodegradable and biocompatible in vivo and are FDA approved, 2) NPs are adaptable to multiple types of drugs/treatments, 3) NPs have the ability to protect drugs from degradation in vivo and allow sustained release, and have modifiable surface properties, which enable site specific targeting. Thus, we hypothesize that PLGA NPs with TAB004 covalently attached as a targeting mechanism will enable the use of highly cytotoxic anti-cancer treatments at localized concentrations that would make the treatment more effective at lower doses, increasing its therapeutic index.

Methods We determined the viability of several MUC1-expressing PDA cell lines in vitro in response to treatment with paclitaxel or γ-secretase inhibitor-loaded NPs, drugs alone, and NPs alone, using the MTT assay. Internalization of fluorescein diacetate-NPs (fNPs) was determined using confocal microscopy.

Results Efficient internalization of fNPs was observed within 30min of treatment and was saturated at 1hr post treatment. Drug loaded NPs were highly effective in killing MUC1-expressing human and mouse PDA cells lines in vitro and displayed comparable results to drug alone while blank NPs and DMSO controls showed negligible cytotoxicity. The results will be confirmed in vivo in an appropriate mouse model of PDA that expresses human MUC1 transgene.

Conclusion TAB004 guided NPs are a promising drug-delivery method for treatment of MUC1-positive PDA. Given that MUC1 is associated with aggressive form of PDA and patients with MUC1-positive PDA have poor prognosis, these results are significant and clinically relevant.

Citation Format: Shuta Wu, Anthony Fowler, Craig Ogle, Pinku Mukherjee. Anti-cancer treatments delivered by antibody guided PLGA nanoparticles. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4484. doi:10.1158/1538-7445.AM2014-4484