Preclinical evaluation of an innovative anti-TAM approach based on zoledronate-loaded erythrocytes

In tumor microenvironment, tumor-associated macrophages (TAMs) are implicated in cancer sustainment, metastasis, and drug resistance, raising a growing interest as targets in cancer therapy. Since the bisphosphonate zoledronate has proven to affect TAMs’ functions, the anti-tumor effect of single or repeated administrations of red blood cells (RBCs) encapsulating zoledronate was evaluated in a mouse model of mammary carcinoma. The obtained results showed that loaded RBCs, but not free zoledronate, caused a significant (p < 0.01) and time-lasting reduction of TAMs’ extent in tumor mass of Balb/C mice inoculated with murine mammary carcinoma T41 cells; in addition, a significant reduction (p < 0.05) of tumor growth rate has been obtained only following repeated administrations of zoledronate-loaded RBCs. The anti-tumor effect was secondary to the early depletion of spleen macrophages. Moreover, by assessing the IgG2a/IgG1 ratio, a prevalence of Th1 cytotoxic response in tumor-bearing mice receiving zoledronate by means of RBCs has been observed. These encouraging findings provide further evidence for the central role played by macrophages in tumor setting and highlight the suitability of zoledronate-loaded RBCs as pharmacological agents in depleting, even if indirectly, TAMs and, thus, their eligibility as part of a therapeutic strategy in cancer treatment.