The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Abstract

Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

Histone Deacetylase Inhibition in Non-small Cell Lung Cancer: Hype or Hope?

“…Given the heterogeneity of various HDACs and their role in regulating genes involved in different cellular pathways, development of more selective HDACi, preferably HDAC class I inhibitors, with potent anti-tumor activity and more favorable side effect profile is desirable. Recent development of technologies to utilize nanocarriers, such as polymeric nanoparticles, PEG-coated nanoparticles, colloid carrier systems, PLGA nanoparticles, and albumin microspheres, are being investigated in clinical studies to deliver HDACi with enhanced solubility, tumor specificity and less toxicity ( Enriquez et al, 2013 ; Martin et al, 2013 ; Goswami et al, 2018 ; Bertrand et al, 2019 ; Lee et al, 2019 ). Moreover, the optimum timing of administration of HDACi with other treatments remains unknown.…”

Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment

“…Epigenetic modulators are another category of molecules that might benefit from the development of NP-based delivery strategies. For example, histone deacetylase inhibitors (HDACi) have been implemented within tumor-targeting particles showing significant inhibitory effects on tumor growth ( Bertrand et al, 2019 ; Lee S. Y. et al, 2019 ). Studies evaluating the effects on the TIME of targeted HDACi therapy should be encouraged after the effects observed by selective HDACi in an NP-free treatment ( McCaw et al, 2019 ).…”

Supramolecular behaviour and fluorescence of rhodamine-functionalised ROMP polymers

“…[8][9][10][11] The living nature of the ROMP reaction allows for the preparation of a vast array of copolymers with excellent control over chain length, functional density, and monomer variety, and has led to the preparation of a wide range of biorelated and therapeutic ROMP polymers. [12][13][14][15][16][17][18][19][20][21][22] In a wider context, ROMP also allows for the incorporation of dyes that are not suitable for free radical polymerisation processes, and the control ROMP affords can deliver polymer conjugates below 45 kDa, as required to allow renal clearance in eventual in vivo applications. 8 We here report the synthesis and analysis of a new fluorophore-rich block copolymer prepared by ROMP.…”