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J Control Release. 2018 Apr 10;275:117-128. doi: 10.1016/j.jconrel.2018.02.024. Epub 2018 Feb 20.

Anti-tumor efficacy of hyaluronan-based nanoparticles for the co-delivery of drugs in lung cancer.

Author information

1
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France.
2
Laboratoire de Chimie des Polymères Organiques, CNRS UMR5629, Pessac, France.
3
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: morgane.couvet@inserm.fr.
4
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: laetitia.vanwonterghem@univ-grenoble-alpes.fr.
5
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: maxime.henry@univ-grenoble-alpes.fr.
6
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: chloe.didier@univ-grenoble-alpes.fr.
7
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: Julien.Vollaire@univ-grenoble-alpes.fr.
8
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: veronique.josserand@univ-grenoble-alpes.fr.
9
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: jean-luc.coll@univ-grenoble-alpes.fr.
10
Laboratoire de Chimie des Polymères Organiques, CNRS UMR5629, Pessac, France. Electronic address: schatz@enscbp.fr.
11
Laboratoire de Chimie des Polymères Organiques, CNRS UMR5629, Pessac, France. Electronic address: lecommandoux@enscbp.fr.
12
Cancer Target and Experimental Therapeutics, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Univ. Grenoble Alpes, Grenoble, France. Electronic address: amandine.hurbin@inserm.fr.

Abstract

Combinations of therapeutic agents could synergistically enhance the response of lung cancer cells. Co-delivery systems capable of transporting chemotherapeutics with different physicochemical properties and with the simultaneous release of drugs remain elusive. Here, we assess the ability of nanoparticles of 30-nm diameter obtained from the self-assembly of hyaluronan-based copolymer targeting CD44 receptors to encapsulate both gefitinib and vorinostat for effective combinational lung cancer treatment. Drug loading was performed by nanoprecipitation. Drug release experiments showed a slow release of both drugs after 5 days. Using two- and three-dimensional lung adenocarcinoma cell cultures, we observed that the nanoparticles were mostly found at the periphery of the CD44-expressing spheroids. These drug-loaded nanoparticles were as cytotoxic as free drugs in the two- and three-dimensional systems and toxicity was due to apoptosis induction. In mouse models, intravenous injection of hyaluronan-based nanoparticles showed a selective delivery to subcutaneous CD44-overexpressing tumors, despite a significant liver capture. In addition, the systemic toxicity of the free drugs was reduced by their co-delivery using the nanoparticles. Finally, intrapulmonary administration of drug-loaded nanoparticles, to avoid a possible hepatic toxicity due to their accumulation in the liver, showed a stronger inhibition of orthotopic lung tumor growth compared to free drugs. In conclusion, hyaluronan-based nanoparticles provide active targeting partially mediated by CD44, less-toxic drug release and improved antitumor efficiency.

KEYWORDS:

Drug co-delivery; Gefitinib; Lung cancer; Polymer nanoparticles; Spheroids; Vorinostat

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