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

Abstract

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 (PEG-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 (PEG-Fmoc-NLG) 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 PEG-Fmoc-NLG919 nanocarrier led to a further improvement in the therapeutic efficacy with a concomitant reduction in MDSCs.

PEG-Derivatized Dual-Functional Nanomicelles for Improved Cancer Therapy

“…These micelles, whether loaded with DOX or not, reduced the recruitment of granulocytic MDSC and monocytic MDSCs to tumor tissues. This contrasts with the observation that the same micelles, when loaded with PTX, triggered the counter-productive accumulation of MDSCs (Chen et al, 2018). These differences may reflect the different abilities of DOX and PTX to modulate the immune system.…”

“…Increased numbers of tumor-infiltrating MDSCs often correlate with high tumor burden and metastasis, contributing to poor prognosis (Nagaraj and Gabrilovich, 2008; Malek et al, 2016). To avoid stimulating MDSCs, a dual-functional carrier of PEG linked to NLG919 via an Fmoc moiety was loaded with both PTX and sunitinib (Chen et al, 2018), an FDA-approved tyrosine kinase inhibitor for the treatment of various cancers. Sunitinib reduces the level and activity of MDSCs and Treg cells systemically and in the tumor microenviroment (van Hooren et al, 2016; Motzer et al, 2017).…”

Engineered Multifunctional Nano‐ and Biological Materials for Cancer Immunotherapy

“…The production of chemokines responsible for the recruitment of MDSCs was drastically blocked by sunitinib and helped improve the overall efficiency of the combination therapy. [ 73 ] The recent studies from Rivas's group fabricated phospholipids based micellar nanocarrier to integrate the TLR 4 agonist Xcc lipooligosaccharide, OVA antigen, and iron oxide nanoparticles to facilitate the co‐delivery of immune stimulators. The TLR agonist Xcc lipooligosaccharide induced the immune response by secreting costimulatory molecules on DCs and inflammatory cytokines (TNF‐ α and IL‐12) and helps in creating an immunogenic environment.…”

Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy

“…Other studies have also confirmed that nanomaterials effectively enhance the immunomodulatory effect of sunitinib, and the combination of sunitinib and other drugs achieved better antitumor effects. 92,93 The CSF-1/CSF-1R Pathway Colony stimulating factor-1 (CSF-1) is a cytokine that plays an important role in the survival, proliferation, differentiation, and function of macrophages. 94 Studies have shown that CSF-1 is highly expressed in some tumors and is associated with poor prognosis and distant metastasis.…”