Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo

Abstract

Multidrug resistance (MDR) is a major impediment to cancer treatment. A promising strategy for treating MDR is the joint delivery of combined anticancer agents to tumor cells in a single nanocarrier. Here, for the first time, Resveratrol (Res) was co-encapsulated with paclitaxel (PTX) in a PEGylated liposome to construct a carrier-delivered form of combination therapy for drug-resistant tumors. The composite liposome had an average diameter of 50 nm with encapsulated efficiencies of above 50%. The studies demonstrated that the composite liposome could generate potent cytotoxicity against the drug-resistant MCF-7/Adr tumor cells in vitro and enhance the bioavailability and the tumor-retention of the drugs in vivo. Moreover, systemic therapy with the composite liposome effectively inhibited drug-resistant tumor in mice (p < 0.01), without any notable increase in the toxicity. These results suggested that the co-delivery of Res and a cytotoxic agent in a nanocarrier may potentially improve the treatment of drug-resistant tumors.

Figure 1. Design and characterization of the composite liposome.

(A) Scheme and the components of the liposome. (B) TEM image of the prepared composite liposome. (C) Size distribution spectrum, as determined by the laser diffraction size detector.

Figure 2

Cumulative release of PTX or Res from the composite liposome at 37 °C in PBS (pH 7.4; n = 3, mean ± standard deviation).

Figure 3

In vitro cytotoxicity on MCF-7 (A,C,E) and MCF-7/Adr (B,D,F) cells of the saline solution, liposome, Res liposome, PTX liposome, and the composite liposome at 24 h (A,B), 48 h (C,D), and 72 h (E,F). The PTX concentration was fixed at 1.5 μg/mL, whereas the Res concentrations varied at 1, 3, 5, and 10 μg/mL. Data represent mean ± standard deviation (n = 6).

Figure 4

Serum concentration–time profiles of Res (A) and PTX (B) in nude mice, after intravenous injection of free and liposomal PTX or Res, as well as the composite liposome with both PTX and Res.

Figure 5

In vivo distribution and accumulation of Res (A to C) and PTX (D to F) in various organ systems of mice at 24 h (A,D), 48 h (B,E), and 2 wk (C,F) after injection of free and liposomal PTX or Rex, as well as the composite liposome with both PTX and Res.

Figure 6

In vivo antitumor effects generated by the saline solution, blank liposome, Res liposome, PTX liposome, or the composite liposome with both Res and PTX. Tumor growth curves of MCF-7 (A) and MCF-7/Adr (B); error bars correspond to 95% confidence intervals. Tumor volumes were measured at 0, 3, 8, 10, and 14 d after tumor cell injection.

Figure 7

Average body weights of mice bearing MCF-7 (A) or MCF-7/Adr (B) tumors during the course of therapy. Animals in the various experiment groups received treatments of the saline solution, blank liposome, Res liposome, PTX liposome, and the composite liposome with Res and PTX. Error bars corresponded to 95% confidence intervals.