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

• Main Authors: Ruby Maharjan (Author), Laxman Subedi (Author), Rudra Pangeni (Author), Saurav Kumar Jha (Author), Seo Hee Kang (Author), Kwan-Young Chang (Author), Youngro Byun (Author), Jeong Uk Choi (Author), Jin Woo Park (Author)
• Format: Book
• Published: Taylor & Francis Group, 2021-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1071-7544; 1521-0464; 10.1080/10717544.2021.1995077
• Keywords: pemetrexed; colloidal dispersion; oral metronomic chemotherapy; immunogenic cell death; antitumor immunity; immunotherapy; Therapeutics. Pharmacology; RM1-950
• Source: Drug Delivery, Vol 28, Iss 1, Pp 2313-2328 (2021)

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.