Vorinostat–Polymer Conjugate Nanoparticles for Acid-Responsive Delivery and Passive Tumor Targeting

• Published in: Biomacromolecules Vol. 15; no. 12; pp. 4534 - 4543
• Main Authors: Denis, Iza, el Bahhaj, Fatima, Collette, Floraine, Delatouche, Régis, Gueugnon, Fabien, Pouliquen, Daniel, Pichavant, Loic, Héroguez, Valérie, Grégoire, Marc, Bertrand, Philippe, Blanquart, Christophe
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08-12-2014
• Subjects: Animals; Apoptosis - drug effects; Applied sciences; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Chemical Sciences; Click Chemistry; Drug Delivery Systems; Exact sciences and technology; General pharmacology; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydrogen-Ion Concentration; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Medical sciences; Mesothelioma - drug therapy; Mice; Mice, Nude; Nanoparticles - chemistry; Organic polymers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physicochemistry of polymers; Polymers; Polymers - chemistry; Polymers - pharmacology; Polymers with particular properties; Preparation, kinetics, thermodynamics, mechanism and catalysts; Transfection; Biological properties; Antineoplastic agent; Immunohistochemistry; Fluorescent tracer; Triazole derivative copolymer; Intravenous administration; Targeting; Graft copolymer; Nanoparticle; Toxicity; Mesothelioma; Drug carrier; Macromer; Ethylene oxide polymer; Labelled copolymer; Unsaturated copolymer; pH; Tumor cell; Norbornene copolymer; Control release polymer; Rodentia; Prodrug; Ethylene oxide copolymer; Experimental study; Complex catalyst copolymerization; In vitro; Biological activity; In vivo; Vertebrata; Histone deacetylase inhibitor; Mammalia; Metathesis polymerization; Mouse; Animal; Preparation; Vorinostat; Ring opening copolymerization; CELLS; APOPTOSIS; HISTONE DEACETYLASE INHIBITOR; METABOLITES; SUBEROYLANILIDE HYDROXAMIC ACID; IN-VIVO; GROWTH; NANOCARRIERS; MESOTHELIOMA; SERUM
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm501338r

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.