Abstract 1720: Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles

Abstract

Abstract The prognosis of pancreatic ductal adenocarcinoma (PDAC) patients remains poor, and new effective therapies are urgently needed. Cytotoxic gemcitabine (GEM) is currently used as a standard-of-care drug for PDAC treatment but its efficacy is greatly compromised mainly due to quick metabolism in the body and drug resistance. Here we introduce a new simple approach to effectively deliver GEM to PDAC-derived tumors through the combination of a prodrug strategy, nanoparticle formulation, and PDAC-specific targeting strategy. By covalently conjugating GEM with a hydrophobic moiety (i.e. linoleic acid) via amide linkage, the resulting GEM prodrug was conferred with an amphiphilic feature and showed spontaneously self-assembling behavior in aqueous solution. The self-assembled nanoparticles were spherical and monodispersed in water with a diameter less than 100 nm. To optimize the nanoparticles for the in vivo use, DSPE-PEG2k was used to co-assemble with the prodrug. A PDAC-specific peptide was further decorated on the particle surface to endow the nanoparticles with PDAC targeting effect. In vitro assays on PDAC cell lines showed that the modified GEM nanoparticles exhibited superior efficacy than free GEM, and the conjugation of the targeting peptide significantly facilitated the internalization of the nanoparticles into the targeted cancer cells. Furthermore, in vivo evaluation in xenograft-bearing animal models derived from either established cancer cells or patient tumor tissues showed that these GEM nanoparticles were remarkably effective to inhibit tumor growth with alleviated side effects. These data confirmed the effectiveness of our self-assembling GEM prodrug strategy. Moreover, this cost-effective strategy can potentially be applied broadly to many other chemotherapeutic drugs that are insufficiently effective because of pharmacologic obstacles. Citation Format: Zhang Fu. Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1720.