ABSTRACT
Multidrug resistance (MDR) is a major obstacle for clinical application of paclitaxel (PTX). Recent studies have suggested that baicalein (BA) might be a potent MDR reversal agent with the ability of P-glycoprotein inhibition and oxidative stress augmentation. Herein, we co-encapsulated PTX and BA in nanoemulsions (PTX/BA NE) for overcoming MDR in breast cancer. Paclitaxel-cholesterol complex and baicalein-phospholipid complex were prepared to improve the liposolubility of PTX and BA. The cytotoxicity of the combination of PTX and BA with different weight ratios were evaluated and the combination with a weight ratio of 1/1 exhibited the strongest synergistic effect. In vitro cytotoxicity study indicated that PTX/BA NE had a better antitumor efficacy in MCF-7/Tax cells than other PTX formulations. Studies on cellular uptake demonstrated that the PTX/BA NE could effectively accumulate in cancer cells. Mechanism research showed that PTX/BA NE could significantly increase the cellular reactive oxygen species (ROS), decrease cellular glutathione (GSH), and enhance caspase-3 activity in MCF-7/Tax cells. More importantly, in vivo antitumor study demonstrated that PTX/BA NE exhibited a much higher antitumor efficacy than other PTX formulations. These findings suggest that co-delivery of PTX and BA in nanoemulsions might provide us a potential combined therapeutic strategy for overcoming MDR.
Subject(s)
Breast Neoplasms/drug therapy , Flavanones/administration & dosage , Oxidative Stress/drug effects , Paclitaxel/administration & dosage , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/pathology , Chemistry, Pharmaceutical , Cholesterol/chemistry , Drug Delivery Systems , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Emulsions , Female , Flavanones/pharmacology , Humans , MCF-7 Cells , Mice, Inbred BALB C , Mice, Nude , Nanoparticles , Paclitaxel/pharmacology , Phospholipids/chemistry , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Lipids/chemistry , Paclitaxel/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cholesterol/chemistry , Drug Screening Assays, Antitumor , Emulsions/chemistry , Emulsions/pharmacokinetics , Female , Humans , Lipids/administration & dosage , Lipids/pharmacokinetics , MCF-7 Cells/drug effects , Mice, Inbred BALB C , Paclitaxel/chemistry , Paclitaxel/pharmacokinetics , Receptors, LDL/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Xenograft Model Antitumor AssaysABSTRACT
The aim of the present study was to develop a lipid emulsion loaded with a paclitaxel-cholesterol complex (PTX-CH Emul) in order to improve the safety and efficacy of paclitaxel (PTX) and evaluate its antitumor activity against commercially available formulation Taxol®. PTX-CH Emul resembling a low density lipoprotein lipid structure, exhibited an ideal particle size, high drug loading capability, high drug encapsulation efficiency and excellent stability. PTX-CH Emul showed superior in vitro anticancer efficacy against triple-negative MDA-MB-231 breast cancer cells when compared with a paclitaxel emulsion (PTX Emul) and Taxol. The IC70 value of PTX-CH Emul was almost 1.5- and 2.4-fold lower than that of PTX Emul and Taxol, respectively. Compared with PTX Emul and Taxol, PTX-CH Emul exhibited stronger and more rapid inhibitory effects on 3D tumor spheroids of MDA-MB-231 cells. Additionally, in vivo tumor-targeting study showed that PTX-CH Emul had higher specificity and efficiency in intratumoral accumulation as compared to PTX Emul. Finally, the maximum tolerated dose (MTD) of PTX-CH Emul was 2.25fold higher than that of Taxol, suggesting that PTX-CH Emul exhibited better safety profiles in vivo than Taxol. At the MTDs, PTX-CH Emul exhibited superior antitumor efficacy in nude mice bearing MDA-MB-231 xenografts in comparison to Taxol. Therefore, PTX-CH Emul as reported here showed high potential as a drug carrier for PTX in clinical applications involving the targeting of triple-negative breast cancer.
