Dual-Targeting of Tumor Cells and Tumor-Associated Macrophages by Palmitic Acid Modified Albumin Nanoparticles for Antitumor and Antimetastasis Therapy
Jiaxing Feng, Ling Xiang, Changlong Fang, Yulu Tan, Yan Li, Ting Gong, Ting Gong, Qingsi Wu, Tao Gong, Tao Gong, Zhirong Zhang
Abstract
Tumor-associated macrophages (TAMs), the most abundant immune cells in the tumor microenvironment (TME), profoundly affect the occurrence and development of tumors. To overcome the common limitations of TAMs-targeted delivery systems, such as off-target toxicity, high cost, and transformation probability, we fabricated pirarubicin (THP)-loaded palmitic acid modified human serum albumin nanoparticles (THP-PSA NPs) for dual-targeting of tumor cells and TAMs via acidic secretory proteins rich in cysteine (SPARC) and scavenger receptor-A (SR-A), respectively. In vitro, the THP-PSA NPs exhibit stronger cytotoxicity against 4T1 and M2 macrophages compared with THP-loaded human serum albumin nanoparticles (THP-HSA NPs). In vivo, the infiltration of myeloid-derived suppressor cells (MDSCs) and the secretion of immunosuppressive cytokines significantly decrease after effective elimination of the TAMs through the THP-PSA NPs treatment; this is accompanied by an increase in the immunostimulatory cytokine expression level. Moreover, the antitumor and antimetastasis experimental results indicate that the tumor volumes in mice treated with the THP-PSA NPs are effectively controlled, resulting in an inhibition rate of 81.0% and almost no metastases in the lung tissues. Finally, in terms of biological safety, the THP-PSA NPs perform similar to THP-HSA NPs, causing no damage to the liver or kidney.