Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel-cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines.
There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel-cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Jun
J
Ye
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Xuejun
X
Xia
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Wujun
W
Dong
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Huazhen
H
Hao
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Luhua
L
Meng
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Yanfang
Y
Yang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Renyun
R
Wang
School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
Yuanfeng
Y
Lyu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing.
Yuling
Y
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004655:Emulsions / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D061986:MCF-7 Cells / Q000187:drug effects; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011973:Receptors, LDL / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004655:Emulsions; D008055:Lipids; D011973:Receptors, LDL; D002784:Cholesterol; D017239:Paclitaxel
lipid emulsion; low-density lipoprotein; paclitaxel; triple-negative breast cancers; tumor targeting