Improved safety and efficacy of a lipid emulsion loaded with a paclitaxel-cholesterol complex for the treatment of breast tumors

Abstract

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 2.25‑fold 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.

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

“…To clarify the connection between LDLR expression and cytotoxicity, MCF7 and MDA-MB-231 cells, which have 27 than in MCF7 cells (IC 50 8.37 ng/mL) ( Figure S2). …”

“…26,27 cell lines and cell culture H9c2 (2-1), MDA-MB-231, and MCF7 were supplied by the Cell Resource Center, Peking Union Medical College (Beijing, People's Republic of China). H9c2 (2-1) and MCF7 cells were cultured in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 µg/mL streptomycin.…”

“…26 Furthermore, PTX-CH Emul shows superior in vitro antitumor efficacy, higher specificity and efficiency in intratumoral accumulation, better safety profiles, and superior antitumor efficacy in vivo against TNBC compared to the conventional PTX Emul and Taxol. 27 Although PTX-CH Emul shows great potential as a drug carrier for PTX in clinical applications involving TNBC therapy, 26,27 intracellular trafficking and its underlying mechanisms have not been investigated. In order to improve the therapeutic potential of PTX-CH Emul for the treatment of TNBC further, it is important to make a comparative evaluation of the antineoplastic effects of PTX-CH Emul on TNBC and non-TNBC cells.…”

“…26 Compared with the tumor-targeting LDE-PTX loaded with PTX and cholesteryl ester reported previously, 21 substitution of the PTX-CH complex for PTX and cholesteryl ester of LDE-PTX has the following advantages: the PTX-CH complex not only greatly improves PTX solubility in the oil phase but can also function as a component of LDL-CH. 27 The resulting lipid emulsion (PTX-CH Emul) exhibits an ideal particle size, high drug-loading capability, high drugencapsulation efficiency, and excellent stability (12 months at 6°C). 26 Furthermore, PTX-CH Emul shows superior in vitro antitumor efficacy, higher specificity and efficiency in intratumoral accumulation, better safety profiles, and superior antitumor efficacy in vivo against TNBC compared to the conventional PTX Emul and Taxol.…”

Investigation of Effect of Phospholipids on Physical and Functional Characterization of Paclitaxel Liposomes

“…As per as anticancer activity is concerned, PT exclusively binds to the β-tubulin subunit through N-terminal side chain with 31 amino acid, in the microtubules [4][5] causing depolymerization of β-tubulin subunit, with inhibition of mitosis and this combined effect can be directed to induction of cell apoptosis [6]. Based on previous reports, PT shows anticancer activities towards breast cancer [7], ovarian cancer [8], lung cancer [9] and pancreatic cancer [10]. Supportive to this, previously published reports by Mullins et al [11], shows that PT gives antitumor activity by a formation of macrophage IL-12 through nitric oxide, which further caused to dysregulation of IL-12 p40 expression and finally reduces the tumor growth.…”