title: Mild hyperthermia enhances transport of liposomal gemcitabine and improves in vivo therapeutic response.
abstract: Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery, and antitumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment leads to a threefold increase in accumulation of 80-nm liposomes and enhances spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment lead to a threefold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg kg(-1) Gem Lip leads to a twofold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect is confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg kg(-1) Gem Lip achieves similar therapeutic efficacy as the use of 60 mg kg(-1) free gemcitabine. In conclusion, improvements in vivo efficacy are demonstrated resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines.
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.
authors.forename: Dickson K
authors.initials: DK
authors.lastname: Kirui
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.|Department of Pharmacy, University of Chieti - Pescara "G. d'Annunzio", Chieti, 66013, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Celia
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.|Department of Health Sciences, University of Catanzaro "Magna Graecia", Germaneto - Catanzaro, 88100, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Molinaro
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Bansal
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Germaneto - Catanzaro, 88100, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cosco
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Germaneto - Catanzaro, 88100, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fresta
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.|Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of NanoMedicine, Houston Methodist Research Institute, 6670, Bertner Avenue, Houston, TX, 77030, USA.|Department of Biomedical Engineering in Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems / Q000379:methods; D005334:Fever / Q000503:physiopathology*; D006046:Gold / Q000008:administration & dosage; D006979:Hyperthermia, Induced / Q000379:methods; D008081:Liposomes / Q000008:administration & dosage*; D051379:Mice; D043942:Nanotubes; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000628:therapy*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D003841:Deoxycytidine; D006046:Gold; D000093542:Gemcitabine
keywords: biological barriers; cancer nanotherapeutics; cancer therapy; liposomal gemcitabine; mild hyperthermia