Drug-loaded microparticles as a novel drug delivery approach against pancreatic cancer

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the United States with only 9% of diagnosed patients surviving 5 years. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. Most PDAC patients are not surgical candidates due to the advanced stage of disease at diagnosis and more than 50% presenting with metastatic disease. Current systemic treatments have proved ineffective at extending the life span of patients as well as increasing the number of surgical candidates, which offers the only possibility of long-term survival. Two recently approved treatments against PDAC, FOLFIRINOX and nab-paclitaxel (nab-PTX) combined with gemcitabine, increase overall median survival by only a few months. Furthermore, systemic delivery of drugs is limited by the associated body-wide toxicities that prevent increasing the drug dose. Therefore, alternative treatment strategies are urgently needed. Polymer-based microparticles (MPs) are a FDAapproved tool for drug delivery with high biocompatibility, flexibility in the encapsulation of drugs and extended drug release. Our hypothesis is that intratumoral delivery of paclitaxel (PTX) and gemcitabine (GEM), encapsulated in MPs (PMPs and GMPs, respectively) should enable higher drug concentrations to be attained inside the tumor, as well as decrease GEM resistance with the sequential treatment of PMPs followed by GMPs, leading to greater efficacy compared to systemic treatment. Our novel approach will allow localizing the MPs inside the tumor where continuous release of drug occurs without the need for more injections. The sequential treatment of PMPs followed by GMPs demonstrated a downregulation of resistance proteins as well as activation of apoptosis in vitro and in vivo. In addition, transcriptome analysis showed differences in expression of chemoresistance genes for the PANC-1 and MIAPaCa-2 human pancreatic cancer cell lines. Using gene expression analysis of treated cells with MPs, I propose a mechanism of action that could explain the resistance modulation observed when using GMPs and PMPs. This therapy can be offered to patients with locally advanced unresectable PDAC or those with borderline resectable disease with use of this treatment to downsize the tumor and potentially present surgery as an option. The described drug delivery method has the potential to be a more efficient local treatment modality than systemic drug against PDAC.