期刊
ACTA PHARMACEUTICA SINICA B
卷 12, 期 3, 页码 1148-1162出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.09.024
关键词
Folic acid; Gemcitabine; Polymeric micelles; Breast cancer; Dual targeting; Tumor associated macrophages; Ultrasmall nanocarrier; Doxorubicin
资金
- National Institute of Health [R01CA174305, R01CA219399, R01CA223788, R21CA249649]
- Shear Family Foundation
Combining passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. In this study, ultra-small-sized gemcitabine-based nanoparticles were combined with folic acid conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages. The co-delivery system showed small particle size and achieved significant reduction of tumor growth in a breast cancer model.
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 w10 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 FAPGEM/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 ex-pressed 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. (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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