Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity

Drug Delivery

Jeong Uk Choi¹  Saurav Kumar Jha²  Laxman Subedi²  Jin Woo Park³  Rudra Pangeni⁴  Kwan-Young Chang⁵  Seo Hee Kang⁵  Youngro Byun⁶  Ruby Maharjan⁶ 

[1] College of Pharmacy, Chonnam National University, Gwangju, South Kore;Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan-gun, South Kore;Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan-gun, South Kore;College of Pharmacy, Natural Medicine Research Institute, Mokpo National University, Muan-gun, South Kore;Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, US;Global R&D Center, IcureBNP, Seoul, South Kore;Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Kore;

关键词: Pemetrexed;    colloidal dispersion;    oral metronomic chemotherapy;    immunogenic cell death;    antitumor immunity;    immunotherapy;   

DOI  :  10.1080/10717544.2021.1995077

来源: Taylor & Francis

【 摘 要 】

In this study, we developed oral pemetrexed (PMX) for metronomic dosing to enhance antitumor immunity. PMX was electrostatically complexed with positively charged lysine-linked deoxycholic acid (DL) as an intestinal permeation enhancer, forming PMX/DL, to enhance its intestinal permeability. PMX/DL was also incorporated into a colloidal dispersion (CD) comprised of the block copolymer of poly(ethylene oxide) and poly(propylene oxide), and caprylocaproyl macrogol-8 glycerides (PMX/DL-CD). CD-containing PMX/DL complex in a 1:1 molar ratio [PMX/DL(1:1)-CD] showed 4.66- and 7.19-fold greater permeability than free PMX through the Caco-2 cell monolayer and rat intestine, respectively. This resulted in a 282% improvement in oral bioavailability in rats. In addition, low-dose metronomic PMX led to more immunogenic cell death in CT26.CL25 cells compared to high PMX concentrations at the maximum tolerated dose. In CT26.CL25 tumor-bearing mice, oral metronomic PMX/DL-CD elicited greater antitumor immunity not only by enhancing the number of tumor-infiltrating lymphocytes but also by suppressing T cell functions. Oral PMX/DL-CD substantially increased programmed cell death protein ligand-1 (PD-L1) expression on tumor cells compared to the control and PMX-IV groups. This increased antitumor efficacy in combination with anti-programmed cell death protein-1 (aPD-1) antibody in terms of tumor rejection and immunological memory compared to the combination of PMX-IV and aPD-1. These results suggest that oral metronomic scheduling of PMX/DL-CD in combination with immunotherapy has synergistic antitumor effects.

【 授权许可】

CC BY