Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

作者：Meraz Ismail M; Savage David J; Segura Ibarra Victor; Li Jeffrey; Rhudy Jessica; Gu Jianhua; Serda Rita E^*

来源：Molecular Pharmaceutics, 2014, 11(10): 3484-3491.

DOI：10.1021/mp5002697

• liposome
• monophosphoryl lipid A
• interleukin-12
• Toll-like receptor
• breast cancer

Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1 beta and tumor necrosis factor (TNF)-alpha. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1 beta, TNF-alpha, and interferon-gamma. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80(+) macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of K-i-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response.

• 出版日期2014-10