Sustained Drug Release From Liposomes for the Remodeling of Systemic Immune Homeostasis and the Tumor Microenvironment.

Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. They are consisted of a heterogeneous population of immature myeloid cells including polymorphonuclear MDSC (PMN-MDSC) and monocytes MDSC (M-MDSC) that are found in both the systemic circulation and in the tumor microenvironment (TME). While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy. We aimed in this study to develop a drug encapsulated liposome formulation L-ATRA with sustained release properties and examined the immuno-modulation effects. We showed that the actively loaded L-ATRA achieved stable encapsulation and enabled controlled drug release and accumulation in the tumor tissues. In vivo administration of L-ATRA promoted the remodeling of the systemic immune homeostasis as well as the tumor microenvironment. They were found to promote MDSCs maturation into DCs and facilitate immune responses against cancer cells. When used as a single agent treatment, L-ATRA deterred tumor growth, but only in immune-competent mice. In mice with impaired immune functions, L-ATRA at the same dose was not effective. When combined with checkpoint inhibitory agents, L-ATRA resulted in greater anti-cancer activities. Thus, L-ATRA may present a new IO strategy targeting the MDSCs that needs be further explored for improving the immunotherapy efficacy in cancer.

Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy.

Ursolic acid (UA) is a potent triterpenoid compound found in plants and fruits with activities modulating key cell signaling pathways involving STATs, NF-κB, and TRAIL. But it's highly hydrophobic and very poorly soluble in nature. It had been prepared as nanocrystals, solid dispersion and loaded in nanoparticles but the achieved systemic exposure and circulation half-life were not ideal. We reported the development of UA-liposomes made by HPßCD assisted active loading. Compared to lipid suspensions of UA (Lipid-UA) with similar lipid composition, the novel process enabled the formation of UA-Ca crystalline structures inside the liposomes and therefore sustained release of UA in vivo. While the UA-liposomes were not generally toxic towards 4T1 triple negative breast cancer cells, they could effectively modulate CD4+CD25+Foxp3+ T cells from 4T1 tumor bearing mouse by inhibiting STAT5 phosphorylation and IL-10 secretion. In vivo administration of UA-liposomes at 10 mg/kg dose led to reduced numbers of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) residing in tumor tissues. These changes signified the correction of the tumor mediated immune-suppressive microenvironment. The UA-liposomes treatment alone was already effective in deterring tumor growth. Such a formulation may be highly promising as an immunotherapy agent and be combined with chemotherapeutics or targeted drugs.