Dual-Targeting of Tumor Cells and Tumor-Associated Macrophages by Palmitic Acid Modified Albumin Nanoparticles for Antitumor and Antimetastasis Therapy

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.

Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment

“…The synthesis of PSA was based on the method previously explored in our laboratory. , Briefly, 350 mg PA-NASE was dissolved in 1 mL dimethylformamide (DMF), then slowly added to 10 mL NaHCO 3 (pH 8.5) buffer containing 3.3 g HSA, stirred at 37 °C for 24 h, and then dialyzed in ultrapure water for 3 days. After centrifugation three times at 8000 rpm for 5 min each time until no insoluble agents were produced, PSA was obtained by freeze-drying.…”

Scavenger receptor A-mediated nanoparticles target M1 macrophages for acute liver injury

“…PSA was synthesized as the previous reports [29 , 30] . Briefly, 6.6 g HSA powder was added to 20 ml NaHCO 3 buffer (pH 8.4–8.6) in a 37 °C water bath.…”

“…Then PSA lyophilized powder was obtained by a freeze-dried method. Moreover, the PSA and HSA were characterized by circular dichroism and fluorescence spectra [29 , 30] . Briefly, PSA and HSA powder were dissolved in PBS (pH 7.27) to form 0.2 mg/ml solution, respectively.…”

“…SchB-PSA/HSA NPs were prepared [29 , 30] . 300 µl dichloromethane (Cdkelong, Chengdu, China) was used to dissolve SchB (10 mg) and MCT (35 mg).…”

“…Scavenger receptors are highly expressed in the liver [27] . Specifically, the SR-A receptor, also named macrophage scavenger receptor 1 (MSR1) [28] , is strongly and specifically expressed on activated macrophages, and its distribution in normal tissues is insignificant [29 , 30] . In our previous studies, Palmitic acid-modified serum albumin (PSA) NPs showed a more remarkable targeting effect on M1 macrophages via SR-A, which has been demonstrated to be stronger than the targeting effect of CS-modified NPs via CD44, whether in vitro or in vivo [29] .…”