Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma.
Treatment efficacy of a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, was determined in xenograft models of non-small-cell lung carcinoma. The short-term impact of local hyperthermia (HT) on tumor morphology, microvessel density and local inflammatory response was also evaluated. The HTLC formulation in combination with local HT resulted in a significant advantage in therapeutic effect in comparison with free drug and a non-thermosensitive liposome formulation of CDDP (i.e. LipoplatinTM) when administered at their maximum tolerated doses. Local HT-induced widespread cell necrosis and a significant reduction in microvessel density in the necrotic regions of tumors. CD11b-expressing innate leukocytes were demonstrated to infiltrate and reside preferentially at the necrotic rim of tumors, likely as a means to phagocytose-damaged tissue. Colocalization of CD11b with a marker of DNA damage (i.e. γH2AX) revealed a small portion of CD11b-expressing leukocytes that were possibly undergoing apoptosis as a result of HT-induced damage and/or the short lifespan of leukocytes. Overall, HT-induced tissue damage (i.e. at 24-h post-treatment) alone did not result in significant improvements in treatment effect, rather, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes.
a Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada.
Yannan Nancy
YN
Dou
a Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada.
Michael
M
Dunne
b Dalla Lana School of Public Health, University of Toronto , Toronto , ON , Canada.
Huang
H
Huang
c Techna Institute, University Health Network , Toronto , ON , Canada.
Trevor
T
Mckee
d Department of Pathology and Laboratory Medicine , Mount Sinai Hospital , Toronto , ON , Canada.
Martin C
MC
Chang
c Techna Institute, University Health Network , Toronto , ON , Canada.|e Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto , ON , Canada.|f Department of Radiation Oncology , University of Toronto , Toronto , ON , Canada.
David A
DA
Jaffray
a Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada.|e Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto , ON , Canada.|g Department of Chemical Engineering and Applied Chemistry , University of Toronto , Toronto , ON , Canada.
Christine
C
Allen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D064593:Heterografts; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000628:therapy*; D011897:Random Allocation
D000970:Antineoplastic Agents; D008081:Liposomes; D002945:Cisplatin
Drug delivery; hyperthermia; immune response; non-small-cell lung cancer; thermosensitive liposomes; tumor microenvironment