期刊
JOURNAL OF CONTROLLED RELEASE
卷 275, 期 -, 页码 117-128出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.02.024
关键词
Drug co-delivery; Polymer nanoparticles; Spheroids; Lung cancer; Gefitinib; Vorinostat
资金
- National Research Agency (ANR) [Nanoluc ANR-11-BSV5-0018]
- La Ligue Contre le Cancer comite de l'Isere [R15HURBIN]
- Region Rhone-Alpes [ARC 2012-ADR]
- Association for Research on Cancer
- French Ministry Enseignement Superieur et Recherche
- Region Rhone-Alpes (Contrat de projets Etat-Region Exploration du vivant, Imagerie biomedicale)
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.
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