Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma^*

Abstract

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. Lipoplatin^TM) 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.

Keywords:

• Drug delivery
• hyperthermia
• immune response
• non-small-cell lung cancer
• thermosensitive liposomes
• tumor microenvironment

Acknowledgements

The authors acknowledge the STTARR Innovation Center and University Health Network Pathology Research Program for tissue staining, and image acquisition and analysis. The authors thank Dr. Robert Weersink and Dr. Brian Wilson’s laboratory for sharing the laser equipment, Meegan Larsen for histological analysis, and Dr. Jack Uetrecht for helpful discussions and input on the manuscript.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding information

Yannan Nancy Dou is the recipient of an Ontario Graduate Scholarship. Michael Dunne is the recipient of a Dean’s Fund Scholarship and an Ontario Graduate Scholarship. This research was funded by an operating grant from the Canadian Institute of Health Research [grant number 102569] to Christine Allen and David A. Jaffray. Christine Allen acknowledges a Chair in Pharmaceutics and Drug Delivery from GSK Inc