Liposomal co-delivery system encapsulating celastrol and paclitaxel displays highly enhanced efficiency and low toxicity against pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreas cancer and difficult to treat. Various combination strategies have been utilized to improve the poor therapeutic effect and serious systemic toxicity of clinical PDAC treatments. Here, we report a new combination therapy strategy against PDAC using a liposomal carrier co-loading with anti-inflammatory agent celastrol (CLT) and chemotherapeutic drug paclitaxel (PTX). First, the synergistic effect of CLT and PTX was verified and it is discovered that this effect peaks at 1:2 (CLT/PTX, mol/mol). Then, the co-delivery system CP-Lip with high loading capabilities (97.48% ± 1.14 for CLT, 86.29% ± 3.03 for PTX), sustained release profile and favorable long-circulating feature was fabricated. Tumor-specific accumulation of CP-Lip was significantly improved compared with that of free drug. Moreover, CP-Lip showed comparable cytotoxicity with free CLT and PTX (CLT/PTX) on Pan02 cells in vitro and significantly improved anti-tumor efficacy in vivo with a ∼4-fold increase of tumor inhibition rate compared to single drug treatment in mice model. Furthermore, safety evaluation found no significant damages induced by CP-Lip. Therefore, CLT-PTX combined treatment has good clinic potential, and the simple and effective CP-Lip system fabricated here offers a promising candidate for future development.