Using Targeted Lipid Nanoparticles to Deliver Chemotherapeutic Agents againstPancreatic Cancer

PROJECT SUMMARY/ABSTRACT
Pancreatic cancer continues to be a devastating disease with less than 10% 5-year survival. Pancreatic cancer
is aggressive and there are no good tools for early detection. By the time of diagnosis, the tumor is often surgically
unresectable. At this stage, patients are often treated with different chemotherapeutic agents or their
combination, which while potent, have significant side-effects, limiting their dose. There is critical and an unmet
need to selectively and precisely target the tumor only and deliver high doses of chemotherapy while sparing the
surrounding healthy tissue from the deleterious effects of the chemotherapeutics. Pancreatic cancer cells depend
on extracellular cystine/cysteine for growth and survival. The cystine molecules are transported into the
pancreatic cancer cell through the xCT cystine transporter. Pancreatic cancer is characterized by an
overexpression of surface xCT transporters compared to the healthy pancreas. Doric Pharma LLC’s patented
drug delivery system uses targeted liposomal nanoparticles, TLNs, carry the anticancer drug as cargo and have
specially designed surface molecules that target xCT transporters. Our studies show that TLNs selectively co-
localize to pancreatic cancer cells in mice with orthotopic pancreatic tumors and reduce both orthotopic and
subcutaneous pancreatic tumors. DoricPharma will examine if TLNs delivering gemcitabine spare other organs
and tissues from its toxicity. In Aim 1 we will (a) characterize the physicochemical properties of TLNs loaded with
gemcitabine and (b) determine the pharmacokinetics and biodistribution of gemcitabine encapsulated in TLNs
after a single IV dose given to mice with orthotopic human pancreatic tumors. In Aim 2 we will determine the
antitumor efficacy and reduced toxicity of gemcitabine encapsulated in TLNs for primary and metastatic tumors.
We envision the TLNs system becoming a gold-standard for the delivery of chemotherapeutics because it
selectively delivers anticancer drugs to cancer cells which improves activity and reduces toxicity. This Phase I
STTR will determine if TLNs offer a superior and more efficacious treatment for pancreatic cancer. In addition,
this project will position TLNs for IND- enabling studies (SBIR Phase II), after which DoricPharma LLC will seek
partnerships for human phase I clinical trials. Overall, TLNs represent a paradigm shift for chemotherapy by
selectively delivering agents to the tumor which will increase antitumor efficacy and reduce toxicity. Overall,
TLNs will enhance the life span and the quality of life in cancer patients.Project Narrative
This proposal develops targeted drug carriers for precise delivery of anticancer drugs to
pancreatic cancers. These carriers achieve high drug concentrations in tumors and minimal
concentrations in healthy tissues, resulting in enhanced tumor destruction and reduction of
adverse effects of anticancer drugs. These drug carriers extend the lifespan and enhance the
quality of patients’ life.