Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer

Abstract

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA) 4 ) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.

Redox-sensitive iodinated polymersomes carrying histone deacetylase inhibitor as a dual-functional nano-radiosensitizer for enhanced radiotherapy of breast cancer

“…In this study, we designed redox-sensitive iodinated polymersomes (RIP) carrying SAHA, as a dual-functional nano-radiosensitizer for enhanced breast cancer radiotherapy ( Scheme 1 ). RIP is disulfide-crosslinked to improve its stability and accelerate intracellular drug release, as reported previously for delivery of different drugs (Liu et al., 2020 ; Fu et al., 2021 ; Gong et al., 2021 ). RIP not only possesses a high iodine content of 55.4 wt.% but also efficiently loads and delivers SAHA into tumor cells.…”

The Use of Phytochemicals to Improve the Efficacy of Immune Checkpoint Inhibitors: Opportunities and Challenges

“…The researchers observed T-lymphocyte-based immune activation and removal of immune exhaustion via a decrease in the intratumoral myeloid-suppressor cells, leading to increased survival [27]. Later studies most frequently used curcumin, a non-flavonoid polyphenol, as the experimental phytochemical [28][29][30][31] and primarily focused on the colorectal cancer models [28,30,31,36], followed by NSCLC [33,38,39]. The intratumoral expansion of CD8+ or CD4+ lymphocytes and the increased levels of IFN-γ were consistent findings throughout the studies [34,42].…”

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

“…Micelles represent a novel drug vehicle; with respect to other nanocarriers, polymeric micelles generally have a smaller size, present easier preparation and sterilization processes [ 296 ], and allow high bioavailability of poorly water-soluble drugs [ 297 ]. Thanks to their good solubilization properties, micelles appeared to help in IBD [ 121 ] and colon cancer treatments [ 298 , 299 ], with notable advantages, such as reduced risk of systemic toxicity, improved selectivity for specific tissues due to stimuli-sensitive polymeric materials, incremented storage stability, and resilience against dilution. Xu et al designed a micelle-based oral nanoparticle formulation formed by curcumin-conjugated hydroxyethyl starch.…”