Targeting the tumor microenvironment with liposomes

Cancer is the leading cause of morbidity and mortality in developed countries. A tumor tissue is composed of cancer cells and of non-cancerous stromal cells, here termed the microenvironment. Recent studies have demonstrated that there is a direct link between the tumor microenvironment and the ability of cancer cells to invade adjacent tissues and metastasize. Furthermore, there is increasing evidence that environmental changes within the tumor tissue can lead to drug resistance and consequently to treatment failure (1-3). Therefore, our hypothesis is that a multi-targeting drug strategy, which targets the cancer cells as well as key components of the tumor microenvironment, will significantly improve the clinical outcomes.

In our research, we designed liposomes that interfere with primary metabolic processes of the tumor microenvironment, including acidification, by delivering alkaline buffers to the tumor. We examine how such a treatment affects tumor progression and sensitivity to medicine.

We found that combined targeting of the cancer cells and the tumor microenvironment by liposomal bicarbonate and doxorubicin enhances tumor response to doxorubicin compared to applying doxorubicin as the only treatment. We found that the enhanced activity of doxorubicin is owed to the increased uptake of doxorubicin into 4T1 triple negative breast cancer cells in the presence of bicarbonate.

1. Lorusso, G. & Ruegg, C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochemistry and cell biology 130, 1091-1103, doi:10.1007/s00418-008-0530-8 (2008).
2. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500-504, doi:10.1038/nature11183 (2012).
3. Upreti, M., Jyoti, A. & Sethi, P. Tumor microenvironment and nanotherapeutics. Translational cancer research 2, 309-319, doi:10.3978/j.issn.2218-676X.2013.08.11 (2013).