TY - JOUR
T1 - Nanoparticle-Based Combination Therapy Enhances Fulvestrant Efficacy and Overcomes Tumor Resistance in ER-Positive Breast Cancer
AU - Li, Bozhao
AU - Qi, Feilong
AU - Zhu, Fei
AU - Lu, Zefang
AU - Wang, Meiqi
AU - Chu, Tianjiao
AU - Wu, Suying
AU - Wei, Jingyan
AU - Song, Zhenchuan
AU - Sukumar, Saraswati
AU - Zhang, Cheng
AU - Xu, Jiangfei
AU - Li, Suping
AU - Nie, Guangjun
N1 - Funding Information:
S. Sukumar reports grants from The Fetting Fund during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
This work was supported by grants from the Beijing Distinguished Young Scientist program (JQ20037 to S. Li), CAS Interdisciplinary Innovation Team (JCTD-2020-04 to S. Li), CAS Project for Young Scientists in Basic Research (no. YSBR-036 to S. Li), the Key Area R&D Program of Guangdong Province (2020B0101020004 to S. Li), National Basic Research Plan of China (2018YFA0208900 to G. Nie), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB36000000 to G. Nie).
Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/9
Y1 - 2023/9
N2 - Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)–positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.
AB - Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)–positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.
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U2 - 10.1158/0008-5472.CAN-22-3559
DO - 10.1158/0008-5472.CAN-22-3559
M3 - Article
C2 - 37326467
AN - SCOPUS:85169503474
SN - 0008-5472
VL - 83
SP - 2924
EP - 2937
JO - Cancer research
JF - Cancer research
IS - 17
ER -