(M1230-03-18) Using Targeted Lipid Nanoparticles to Deliver Chemotherapy to Pancreatic Cancer

Purpose: Pancreatic cancer continues to be a devastating disease with less than 10% 5-year survival. Cisplatin is a very effective chemotherapeutic agent but has serious dose-limiting adverse-effects. The purpose of this study is to address this need by developing targeted lipid nanoparticles (TLNs), that target the xCT transporter which is upregulated in pancreatic cancer and selectively deliver cisplatin to pancreatic cancer only, thereby avoiding the normal tissues and the adverse effects and improving treatment response.

Methods: The cellular uptake and cytotoxicity of TLNS was evaluated in the Panc-1 GFP cell line using the MTS assay (NOVUS Biologicals) and flow cytometry (Accuri BD C6). The antitumor effect of cisplatin in TLNs was evaluated using a mouse model of orthotopic pancreatic cancer. Mice (NCI Athymic NCr-nu/nu purchased from Charles River Labs) were injected orthotopically (in the pancreas) with 3x10⁶ PANC-1GFP cells. Three weeks later, four different groups of mice were administered IV bi-weekly with 3.5 mg/kg cisplatin encapsulated in TLNs, cisplatin in non-targeted lipid nanoparticles, free cisplatin, and PBS control. We evaluated the tumor progression by assessing the tumor fluorescence using a small animal imager (UVP). The survival rate and tumor volume at the time the animal was euthanized were also evaluated.

Results: The cellular uptake of TLNs by PANC-1GFP is significantly higher compared to non-targeted lipid nanoparticles (p < 0.0008) or free drug (p < 0.0001). Regarding cytotoxicity, TLNs show the lowest IC₅₀ compared to non-targeted lipid nanoparticles or free cisplatin with 10-fold and 14-fold lower values, respectively. The tumor progression six weeks after the start of the treatment was significantly less in mice treated with cisplatin in TLNs compared to mice treated with cisplatin in nontargeted lipid nanoparticles (p < 0.0138), free cisplatin (p < 0.0089), or PBS control (p < 0.0172). Furthermore, mice treated with cisplatin in TLNs showed a significantly better survival rate and smaller tumor volume at the end-point compared to the three other groups (p < 0.0001), that is, mice received cisplatin in nontargeted lipid nanoparticles, free cisplatin and PBS.

Conclusion: Cisplatin encapsulated in TLNs shows better in-vitro uptake by pancreatic cancer cell comparted to the drug encapsulated in nontargeted lipid nanoparticles, or free drug. Moreover, mice treated with cisplatin in TLNs have better survival rates and smaller tumor volume compared to those received cisplatin in nontargeted lipid nanoparticles, free cisplatin or PBS.

Acknowledgements: We thank NCI for the award, R41CA247009 (MPL).