Peptide-Targeted High-Density Lipoprotein Nanoparticles for Combinatorial Treatment against Metastatic Breast Cancer

作者全名："Jiang, Chuli; Wang, Xingyue; Teng, Biyun; Wang, Zhe; Li, Fenghe; Zhao, Yu; Guo, Yuan; Zeng, Qiu"

作者地址："[Jiang, Chuli; Teng, Biyun; Wang, Zhe; Li, Fenghe; Zhao, Yu; Zeng, Qiu] Chongqing Med Univ, Dept Vasc Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Wang, Xingyue; Guo, Yuan] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China"

通信作者："Zeng, Q (corresponding author), Chongqing Med Univ, Dept Vasc Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Guo, Y (corresponding author), Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：ACS APPLIED MATERIALS & INTERFACES

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000683741400002

JCR分区：Q1

影响因子：9.5

年份：2021

卷号：13

期号：30

开始页：35248

结束页：35265

文献类型：Article

关键词：triple-negative breast cancer; reconstituted high-density lipoprotein; cell-penetrating peptide; sonic hedgehog signaling pathway; metastasis

摘要："The sonic hedgehog (SHH) signaling pathway exhibits aberrant activation in triple-negative breast cancer (TNBC), wherein it regulates several malignant phenotypes related to tumor metastasis. GANT61, an inhibitor of the SHH signaling pathway, may offer promise when administered in combination with conventional chemotherapy to treat metastatic TNBC. However, poor bioavailability and substantial off-target toxicity limit its clinical application. To address these limitations, we designed a peptide-functionalized dual-targeting delivery system encapsulating paclitaxel and GANT61 in tLyP-1 peptide-modified reconstituted high-density lipoprotein nanoparticle (tLyP-1-rHDL-PTX/GANT61 NP) for metastatic TNBC treatment. The apolipoprotein A-1 and tLyP-1 peptide modified on the surface of nanoparticles enable the delivery system to target tumor cells by binding to the overexpressed scavenger receptor B type I and neuropilin-1 receptor. Moreover, the tLyP-1 peptide also enables the deep tumor penetration of nanoparticles further facilitating paclitaxel and GANT61 delivery. Increased cellular uptake of the nanoparticles was observed in both MDA-MB-231, BT-549 tumor cells, and their 3D tumor spheroids. A series of in vitro experiments reveal that GANT61 was able to suppress key metastasis-related tumor cell activities including angiogenesis, migration, invasion, and stemness. Owing to more effective drug administration, the metastasis suppression efficiency of GANT61 was significantly enhanced by the dual-targeting tLyP-1-rHDL delivery system. Meanwhile, the codelivery of paclitaxel and GANT61 by dual-targeting tLyP-1-rHDL nanoparticles demonstrated superior efficiency of disrupting proliferation and inducing apoptosis in tumor cells compared with drug solutions. In a spontaneous metastasis breast cancer NCG mice model, the tLyP-1-rHDL-PTX/ GANT61 nanoparticles exhibited highly tumor-specific distribution and result in significant inhibition of the primary tumor growth and dramatic reduction of lung metastasis without obvious side effects. The present work suggests that a combination of the SHH signaling pathway suppression and chemotherapy assisted by peptide-functionalized targeting tLyP-1-rHDL nanoparticles may provide a promising strategy for metastatic TNBC treatment."

基金机构：National Natural Science Youth Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81800417]

基金资助正文：We sincerely acknowledge the financial support by the National Natural Science Youth Foundation of China (no. 81800417).