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.

Highlights

  • Despite important progress being made to treat different types of cancers, acquired resistance and some forms of aggressive or less frequent cancers are still waiting for efficient strategies

  • In the group of epigenetic proteins over-expressed in cancer cells, histones deacetylases (HDAC) have been thoroughly studied with the development of their inhibitors (histone deacetylase inhibitors (HDACi)), with four of them being currently approved by the Food and Drug Administration (FDA) to treat some forms of cancers

  • In another study using belinostat loaded PLGA nanoparticles modified with a cell penetrating polymer, an increased toxicity was obtained associated with a sustained hyperacetylation in bladder cancer cells compared to the free drug

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Summary

Background

Despite important progress being made to treat different types of cancers, acquired resistance and some forms of aggressive or less frequent cancers are still waiting for efficient strategies. In the group of epigenetic proteins over-expressed in cancer cells, histones deacetylases (HDAC) have been thoroughly studied with the development of their inhibitors (histone deacetylase inhibitors (HDACi)), with four of them being currently approved by the Food and Drug Administration (FDA) to treat some forms of cancers. This includes the suberoyl anilide hydroxamic acid SAHA [3]. In the field of targeting and delivery, nanoparticle-based vectors (NPs) are often used for their intrinsic properties to accumulate in the tumor tissues, due to the enhanced permeability and retention effect (EPR) [8] described by Sato et al in tumor blood vessels [9]

Concepts for Delivery of Epigenetic Modulators
Discussion
Biological Effects In Vitro and In Vivo
Passive tumors by by NPs
Anti-tumor activity
Findings
Histological analysis of tissues after mice with decitabine and NPs
Conclusion
Full Text
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