Codelivery of Doxorubicin/PI3K Inhibitor Nanomicelle Linked with Phenylboronic Acid for Enhanced Cytotoxicity to Pancreatic Cancer

Abstract

Multidrug combination therapy for pancreatic cancer is widely applied in clinical practice. In this study, we used phenylboronic acid and polyethylene glycol as materials of nanomicelles, loaded with the PI3K/mTORC1 dual inhibitor PF04691502 (PF) to inhibit the resistance and metastasis of pancreatic cancer and increase the sensitivity of doxorubicin (DOX). We prepared the PPD nanoparticles (NPs) with a small PDI and a uniform morphology by controlling the DOX substitution degree (size of $164.8\pm 3.6$  nm and zeta potential of $-16.9\pm 0.4$  mV). We determined the rates of PF and materials through the combination experiment of free drugs and the obtained PF@PPD NPs (size of $200.8\pm 2.6$  nm and zeta potential of $-13.9\pm 0.3$  mV). The drug loadings of DOX and PF in the nanomicelle were $14.8\pm 0.4\%$ and $9.5\pm 0.3\%$ , respectively. And the drug release in vitro was slow ( $29.17\pm 2.00\%$ for DOX and $39.22\pm 2.49\%$ for PF). The cell assay showed that the NPs had a good curative effect and migration on BxPC-3 cells, and it could be continuously taken up by cells. The PF@PPD NPs displayed a dose-dependent cytotoxicity with less cell viability ( $20.38\pm 1.11\%$ ) and higher uptake in BxPC-3 cells compared with the free drug. The combined medication or PF@PPD NPs reduced tumor metastasis, indicating that PF@PPD NPs had the potential for clinical application.