A nanoparticle-based approach to improve the outcome of cancer active immunotherapy with lipopolysaccharides

Drug Delivery

Maryam A. Shetab Boushehri¹  Alf Lamprecht²  Mona M. A. Abdel-Mottaleb³  Arnaud Béduneau⁴  Yann Pellequer⁴ 

[1] Department of Pharmaceutics, University of Bonn, Bonn, Germany;Department of Pharmaceutics, University of Bonn, Bonn, Germany;Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France;Department of Pharmaceutics, University of Bonn, Bonn, Germany;Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France;Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egyp;Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France;

关键词: Lipopolysaccharide (LPS);    nanoparticles;    pathogen-mimicking properties;    localized necrosis;    cancer immunotherapy;   

DOI  :  10.1080/10717544.2018.1469684

来源: publisher

【 摘 要 】

This study sought to develop a simple nanoparticle-based approach to enhance the efficiency and tolerability of lipopolysaccharide (LPS), a potent ligand of Toll-like Receptor 4 (TLR4), for immunotherapy in cancer. Despite holding promise within this context, the strong pro-inflammatory properties of LPS also account for its low tolerability given localized and systemic side effects, which restrict the administrable dosage. Herein, we investigated the effect of LPS decoration as a surface-active molecule on a polymeric matrix upon its efficiency and tolerability. The LPS-decorated nanoparticles (LPS-NP) were about 150 nm in size, with slightly negative zeta potential (about −15 mV) and acceptable LPS incorporation (about 70%). In vitro, the particles accounted for a higher induction of apoptosis in tumor cells cultured with murine splenocytes compared to LPS solution. When used for the treatment of a murine syngeneic colorectal tumor model, higher intratumoral deposition of the particle-bound LPS was observed. Furthermore, unlike LPS solution, which accounted for localized necrosis at high concentrations, treatment of tumor-bearing animals with equivalent doses of LPS-NP was well tolerated. We propose that the observed localized necrosis can be Shwartzman phenomenon, which, due to modulated 24-h post-injection systemic TNF-α and LPS concentrations, have been avoided in case of LPS-NP. This has in turn enhanced the therapeutic efficiency and enabled complete tumor regression at concentrations at which LPS solution was intolerable. The findings indicate that nanoparticles can serve as beyond carriers for the delivery of superficially decorated LPS molecules, but impact their overall efficiency and tolerability in cancer therapy.

【 授权许可】

CC BY