Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents

• Published in: Molecular pharmaceutics 2018-11, Vol.15 (11), p.5162-5173
• Main Authors: Chen, Yichao, Sun, Jingjing, Huang, Yixian, Lu, Binfeng, Li, Song
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Cell Line, Tumor; Drug Carriers - chemistry; Female; Imidazoles - administration & dosage; Immunologic Factors - administration & dosage; Immunotherapy - methods; Isoindoles - administration & dosage; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred BALB C; Micelles; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Paclitaxel - administration & dosage; Polyethylene Glycols - chemistry; Sunitinib - administration & dosage; Tissue Distribution; Treatment Outcome
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00717

It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for co-delivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX). Although antitumor immune responses were enhanced with a PTX-loaded nanocarrier, the accumulation of myeloid-derived suppressor cells (MDSCs) was also significantly increased, which may limit the overall efficacy of therapy. In the present work, we developed an improved dual-functional nanocarrier (PEG5k-Fmoc-NLG2) to co-load PTX and sunitinib (SUN, a multitarget receptor tyrosine kinase inhibitor) for improved cancer immunochemotherapy. We found that the recruited MDSCs negatively impacted the overall antitumor activity of the PTX-loaded PEG-NLG nanocarrier. Mechanistic study suggests that this is likely attributed to the PTX-mediated induction of a number of chemokines that are involved in the recruitment of MDSCs. We have further shown that the induction of these chemokines was drastically blocked by SUN. Co-delivery of PTX and SUN via the PEG5k-Fmoc-NLG9192 nanocarrier led to a further improvement in the therapeutic efficacy with a concomitant reduction in MDSCs.