Dual-targeting liposomes with active recognition of GLUT5 and αvβ3 for triple-negative breast cancer

Yanchi Pu; Hao Zhang; Yao Peng; Qiuyi Fu; Qiming Yue; Yi Zhao; Li Guo; Yong Wu

doi:10.1016/j.ejmech.2019.111720

Dual-targeting liposomes with active recognition of GLUT₅ and α_vβ₃ for triple-negative breast cancer

Eur J Med Chem. 2019 Dec 1:183:111720. doi: 10.1016/j.ejmech.2019.111720. Epub 2019 Sep 18.

Authors

Yanchi Pu¹, Hao Zhang¹, Yao Peng¹, Qiuyi Fu¹, Qiming Yue¹, Yi Zhao², Li Guo³, Yong Wu⁴

Affiliations

¹ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China.
² Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China; Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
³ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China. Electronic address: guoli@scu.edu.cn.
⁴ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China. Electronic address: wyong@scu.edu.cn.

PMID: 31553933
DOI: 10.1016/j.ejmech.2019.111720

Abstract

At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT₅ and integrin α_vβ₃ were designed and prepared in this work. Firstly, a Y-shaped Fru-RGD-chol ligand, where a fructose and peptide Arg-Gly-Asp (RGD) were covalently attached to cholesterol, was designed and synthesized. Then, the Fru-RGD-Lip was constructed by inserting Fru-RGD-chol into liposomes, while Fru+RGD-Lip was obtained by inserting both Fru-chol and RGD-chol (with the molar ratio of 1:1) into liposomes. The particle size, zeta potential, encapsulation efficiency and serum stability of the paclitaxel-loaded liposomes were characterized. The results indicated that the paclitaxel-loaded Fru-RGD-Lip had the strongest growth inhibition against GLUT₅ and α_vβ₃ overexpressed MDA-MB-231 and 4T1 cells. The cellular uptake of Fru-RGD-Lip on MDA-MB-231 cells and 4T1 cells was 3.19- and 3.23-fold more than that of the uncoated liposomes (Lip). The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively. The mechanism study demonstrated that the cellular uptake of both dual-targeting liposomes was likely to be recognized and mediated by GLUT₅ and α_vβ₃ firstly, then endocytosed through comprehensive pathways in an energy-dependent manner. Moreover, Fru-RGD-Lip displayed the maximum accumulation, which was 2.62-fold higher than that of Lip for instance, at the tumor sites compared to other liposomes using in vivo imaging. Collectively, the liposomes co-modified by fructose and RGD have enormous potential in the development of targeted TNBC treatment, especially the covalently modified Fru-RGD-Lip, making it a promising multifunctional liposome.

Keywords: Dual-targeting; Fructose; Liposome; RGD peptide; TNBC.

MeSH terms

Animals
Antineoplastic Agents, Phytogenic* / administration & dosage
Antineoplastic Agents, Phytogenic* / chemistry
Cell Line, Tumor
Female
Fructose / chemistry
Glucose Transporter Type 5 / metabolism*
Humans
Integrin alphaVbeta3 / metabolism*
Liposomes* / chemistry
Mice, Inbred BALB C
Molecular Targeted Therapy
Oligopeptides / metabolism
Paclitaxel* / administration & dosage
Paclitaxel* / chemistry
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / metabolism

Substances

Antineoplastic Agents, Phytogenic
Glucose Transporter Type 5
Integrin alphaVbeta3
Liposomes
Oligopeptides
Fructose
arginyl-glycyl-aspartic acid
Paclitaxel