期刊
ACS APPLIED MATERIALS & INTERFACES
卷 14, 期 8, 页码 10102-10116出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c23166
关键词
cancer-associated fibroblasts; MMP-sensitive; sequential delivery of quercetin and paclitaxel; hybrid micelle-in-liposome system; dual-targeting
资金
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-026]
- National Natural Science Foundation of China (China) [82073778]
- Fundamental Research Funds for the Central Universities (China) [3332021044]
This study constructed a sequential drug delivery system to remodel the fibrotic tumor microenvironment and enhance chemotherapy efficacy, showing potential in anti-breast cancer treatment.
Cancer-associated fibroblasts (CAFs), an important type of stromal cells in the tumor microenvironment (TME), are responsible for creating physical barriers to drug delivery and penetration in tumor tissues. Thus, effectively downregulating CAFs to destroy the physical barrier may allow enhanced penetration and accumulation of therapeutic drugs, thereby improving therapeutic outcomes. Herein, a matrix metalloproteinase (MMP)-triggered dual-targeting hybrid micelle-inliposome system (RPM@NLQ) was constructed to sequentially deliver quercetin (Que) and paclitaxel (PTX) for fibrotic TME remodeling and chemotherapy potentiation. Specifically, antifibrotic Que and small-sized RGD-modified micelles containing PTX (RPM) were co-encapsulated into MMP-sensitive liposomes, and the liposomes were further adorned with the NGR peptide (NL) as the targeting moiety. The resulting RPM@NLQ first specifically accumulated at the tumor site under the guidance of the NGR peptide after intravenous administration and then released Que and RPM in response to the extensive expression of MMP in the TME. Subsequently, Que was retained in the stroma to remarkably downregulate fibrosis and decrease the stromal barrier by downregulating Wnt16 expression in CAFs, which further resulted in a significant increase of RPM for deeper tumor. Thus, RPM could precisely target and kill breast cancer cells locally. Consequently, prolonged blood circulation, selective cascade targeting of tumor tissue and tumor cells, enhanced penetration, and excellent antitumor efficacy have been demonstrated in vitro and in vivo. In conclusion, as-designed sequential delivery systems for fibrotic TME remodeling and chemotherapy potentiation may provide a promising adjuvant therapeutic strategy for breast and other CAF-rich tumors.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据