Introduction : Pancreatic cancer (PCa) is one of the most lethal malignancies with 5-year survival rate of less than 8%. Current therapies have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from Poly-ADP-ribose polymerase inhibitors (PARPi) due to their unique biological properties. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to the site of the tumor at an adequate concentration is challenging. To address this issue, we have engineered an EGFR targeting, self-assembling amphiphilic peptide nanocarrier (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa.

Methods : 1. Preparation and characterization of targeting-peptide based nanoparticles. 2. Cell viability and apoptosis assays. 3. Immunofluorescence analysis of γ-H2AX. 4. Western blot analysis. 5. Analysis of FITC-labeled nanoparticle uptake by capan-1 cells. 6. Circulation time and biodistribution of nanoparticles in vivo. 7. In vivo pharmacokinetics and tumor drug concentrations. 8. Anti-tumor effects in vivo.

Results : The GENP nanocarrier was stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs. Gemcitabine and olaparib showed strong synergistic actions in vitro. In vivo, the nanocarrier prolonged the half-life of both drugs and resulted in their accumulation at the tumor site at the optimal therapeutic ratio. The drug-loaded nanocarrier was able to significantly suppress tumor growth in a murine PCa model with minimal side effects.

Conclusions : Drug co-delivery via the GENP nanocarrier represents a promising approach for therapy of BRCA mutant pancreatic cancers.