Pearl Moharil, Zhuoya Wan, Apurva Pardeshi, Jiang Li, Haozhe Huang, Zhangyi Luo, Sanjay Rathod, Ziqian Zhang, Yuang Chen, Bei Zhang, Christian A. Fernandez, Jingjing Sun, Song Li. Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1148-1162

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages
Pearl Moharil, Zhuoya Wan, Apurva Pardeshi, Jiang Li, Haozhe Huang, Zhangyi Luo, Sanjay Rathod, Ziqian Zhang, Yuang Chen, Bei Zhang, Christian A. Fernandez, Jingjing Sun, Song Li
Center for Pharmacogenetics, Department of Pharmaceutical Science, School of Pharmacy, University of Pittsburgh, PA 15261, USA
Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. However, most reported polymeric systems have sizes above 100 nm, which limits effective extravasation into tumors that are poorly vascularized and have dense stroma. This will, in turn, limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting. In this study, we combined the passive targeting via ultra-small-sized gemcitabine (GEM)-based nanoparticles (NPs) with the active targeting provided by folic acid (FA) conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages (TAMs). We developed an FA-modified prodrug carrier based on GEM (PGEM) to load doxorubicin (DOX), for co-delivery of GEM and DOX to tumors. The co-delivery system showed small particle size of ~10 nm in diameter. The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile. The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor (FR), but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR. Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model. Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2, which was selectively expressed on TAMs. Thus, targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.
Key words:    Folic acid    Gemcitabine    Polymeric micelles    Breast cancer    Dual targeting    Tumor associated macrophages    Ultrasmall nanocarrier    Doxorubicin   
Received: 2021-05-10     Revised: 2021-07-29
DOI: 10.1016/j.apsb.2021.09.024
Funds: This work was supported by National Institute of Health grants R01CA174305, R01CA219399, R01CA223788 (Song Li, USA), R21CA249649 (Jingjing Sun, USA) and a grant from Shear Family Foundation (Song Li, USA).
Corresponding author: Jingjing Sun,;Song Li,;
Author description:
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Pearl Moharil
Zhuoya Wan
Apurva Pardeshi
Jiang Li
Haozhe Huang
Zhangyi Luo
Sanjay Rathod
Ziqian Zhang
Yuang Chen
Bei Zhang
Christian A. Fernandez
Jingjing Sun
Song Li

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