Combining doxorubicin with stearylamine-bearing liposomes elicits Th1 cytokine responses and cures metastasis in a mouse model

Abstract

Surface exposed phosphatidylserine (PS) of cancer aids it to evade immune surveillance and thereby results in tumor progression. Earlier, we reported that PS targeting cationic liposomes, phosphatidylcholine-stearylamine (PC-SA), alone and in combination with doxorubicin can result in complete remission of B16F10 melanoma in C57BL/6 mice without signs of toxicity. Inducing an immunogenic response is highly crucial for any cancer therapy as it is essential in improving the tumor microenvironment for any drug to act. Herein, we demonstrate that PC-SA, besides having tumor reducing ability, elicits a strong immune response. The combination therapy (PC-SA-DOX) is superior to free DOX in enhancing the anti-tumor immune effect on CD4-positive and CD8-positive T cells for IFN-γ, IL-2 and TNF-α production in sera and splenic culture supernatants of B16F10 tumor-induced mice. An upregulation of IL-12 and NO production is evidenced in spleen cultures of these mice, thereby showing a promising role of both Th1 type and innate immune response for host anti-tumor activity. Complete elimination of cancer is sometimes accomplished by surgery, but its effectiveness is often limited due to the propensity of cancers to spread to distant organs by metastasis. In our present study, we show that in PC-SA-DOX treated mice, the elevated Th1 cytokine levels create an immuno-protective environment which thereby facilitates in curing lung metastasis. Our results, therefore, warrant the need of effective immune stimulation by anticancer formulations for inhibition of solid tumors and metastasis, demonstrated by the liposomal DOX formulation.