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 model of cancers. 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. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo.
Subject(s)
Drug Carriers/pharmacokinetics , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/pharmacokinetics , Nanoparticles/administration & dosage , Peritoneal Neoplasms/drug therapy , Animals , Disease Models, Animal , Mesothelioma/drug therapy , Mice, Inbred C57BL , Treatment OutcomeABSTRACT
This review presents in a comprehensive ways the chemical methods used to functionalize gold nanoparticles with focus on anti-cancer applications. The review covers the parameters required for the synthesis gold nanoparticles with defined shapes and sizes, method for targeted delivery in tumours, and selected examples of anti-cancers compounds delivered with gold nanoparticles. A short survey of bioassays for oncology based on gold nanoparticles is also presented.
Subject(s)
Gold/chemistry , Gold/therapeutic use , Metal Nanoparticles , Neoplasms/diagnosis , Neoplasms/drug therapy , Theranostic Nanomedicine/methods , Gold/pharmacokinetics , HumansABSTRACT
We report the synthesis of acid-responsive polymeric nanoparticles (NPs) consisting of a polymer-histone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-alkyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis.
Subject(s)
Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Histone Deacetylase Inhibitors/chemistry , Nanoparticles , Phenylenediamines/chemistry , Polyethylene Glycols/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzamides , Cell Line, Tumor , Drug Carriers/toxicity , Drug Liberation , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydrogen-Ion Concentration , Particle Size , Phenylenediamines/pharmacology , PolymerizationABSTRACT
In vivo histone deacetylase (HDAC) inhibition by vorinostat under clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of nontoxic pH-responsive delivery system has been synthesized by ring-opening metathesis polymerization, allowing for the selective distribution of vorinostat in mesothelioma tumors in vivo and subsequent histone reacetylation. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. Although vorinostat alone at 50 mg/kg in mice showed no effect, our new delivery system with 2 mg/kg vorinostat promoted histone reacetylation in tumors without side effects, demonstrating that our strategy improves the activity of this HDAC inihibitor in vivo.
Subject(s)
Drug Delivery Systems , Hydroxamic Acids/pharmacology , Nanoparticles/chemistry , Polymers/pharmacology , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Click Chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydrogen-Ion Concentration , Hydroxamic Acids/chemistry , Mesothelioma/drug therapy , Mice , Mice, Nude , Polymers/chemistry , Transfection , VorinostatABSTRACT
Inhibitors of epigenetic targets have entered clinical trials with some success, in particular for combined therapies. Like many other chemotherapeutics these new classes of molecules have dose-limiting toxicities and highly active metabolism in vivo resulting in lower efficacy than expected. This review presents drug delivery strategies proposed to prolong epigenetic inhibitor effects while reducing toxicities and metabolic clearance. Inspired from the work done in cancer-targeted strategies, prodrugs and nanoparticle-based drug delivery systems are discussed in a comprehensive way, detailing the chemical and physiological principles of the selected releasing method and, when available, how epigenetic chemistry can be exploited.
Subject(s)
Drug Delivery Systems , Drug Design , Epigenesis, Genetic , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Dose-Response Relationship, Drug , Humans , Nanoparticles , Neoplasms/drug therapy , Neoplasms/genetics , ProdrugsABSTRACT
The aim of this study was to develop clickable prodrugs bearing a tunable pH responsive linker designed for acidic pH-mediated release of histone deacetylase inhibitors. HDACi are an important class of molecules belonging to the epigenetic modulators used for innovative cancer strategies. The behavior of these prodrugs was determined by a bioluminescence resonance energy transfer assay in living tumor cells. This work demonstrated that this innovative type of clickable prodrugs entered cancer cells and showed restored anti proliferative properties attributed to the effective release of the HDAC inhibitors. A correlation between kinetic studies, dose responses, and biological activities was obtained, making such clickable prodrugs good candidates for new strategies in epigenetic-oriented anticancer therapies.
