The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma

Abstract

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.

Keywords: cabazitaxel; liposome; lung adenocarcinoma; paclitaxel resistance; β-elemene.

Figure 1

The chemical structure of β-elemene and cabazitaxel.

Figure 2

Relative tumor volume profiles of studied liposomes. *Compared with the 5% glucose group, there was a statistically significant difference (p < 0.01). Compared with 5% glucose group, the statistics parameter of cabazitaxel injection was t = 7.682, p < 0.01; that of the β-elemene liposome group was t = 7.221, p < 0.01; that of cabazitaxel liposome was t = 8.012, p < 0.01, that of the cabazitaxel-β-elemene complex liposome was t = 8.612, p < 0.01. **Compared with the taxol injection group, there was a statistically significant difference (p < 0.01). Compared with the taxol injection group, the statistics parameter of cabazitaxel injection was t = 7.373, p < 0.01; that of the β-elemene liposome group was t = 6.369, p < 0.01; that of the cabazitaxel liposome was t = 7.469, p < 0.01; and that of the cabazitaxel-β-elemene complex liposome was t = 8.116, p < 0.01. Compared with the cabazitaxel injection group, the statistics parameter of the β-elemene liposome group was t = −1.674, p > 0.05; that of the cabazitaxel liposome was t = 1.067, p > 0.05; that of the cabazitaxel-β-elemene complex liposome was t = −1.051, p > 0.05 (there was no statistically significant difference). Compared with the β-elemene liposome group, the statistics parameter of the cabazitaxel-β-elemene complex liposome group was t = 0.971, p > 0.05 (there was no statistically significant difference).

Figure 3

The relative tumor proliferation rate of these liposomes. *Compared with the 5% glucose group, there was a statistically significant difference (p < 0.01). **Compared with the taxol injection group, there was a statistically significant difference (p < 0.01). Compared with the cabazitaxel injection group, there was no statistically significant difference for the group with cabazitaxel liposome, β-elemene liposome or the complex liposome, respectively. The results of the statistics parameter of the relative tumor proliferation rate were the same as those of the relative tumor volume.

Figure 4

The tumor tissues figure with paclitaxel-resistant lung adenocarcinoma. A, 5% glucose; B, blank liposome; C, taxol injection 10 mg/kg; D, cabazitaxel injection 2.5 mg/kg; E, β-elemene liposome 25 mg/kg; F, cabazitaxel liposome 2.5 mg/kg; G, cabazitaxel-β-elemene complex liposome 0.625 mg/kg after the first 2.5 mg/kg.

Figure 5

The tumor inhibition rate of the liposomes. A, 5% glucose; B, blank liposome; C, taxol injection 10 mg/kg; D, cabazitaxel injection 2.5 mg/kg; E, β-elemene liposome 25 mg/kg; F, cabazitaxel liposome 2.5 mg/kg; G, cabazitaxel-β-elemene complex liposome 0.625 mg/kg after the first 2.5 mg/kg. *Compared with the 5% glucose group, there was a statistically significant difference (p < 0.01). Compared with the 5% glucose group, the statistics parameter of the cabazitaxel injection group was t = −11.870, p < 0.01; that of the β-elemene liposome group was t = −10.095, p < 0.01; that of the cabazitaxel liposome was t = −15.615, p < 0.01; and that of the cabazitaxel-β-elemene complex liposome was t = −11.824, p < 0.01. **Compared with the taxol injection group, there was a statistically significant difference (p < 0.01). Compared with the taxol injection group, the statistics parameter of the cabazitaxel injection was t = −8.294, p < 0.01; that of the β-elemene liposome group was t = −5.648, p < 0.01; that of the cabazitaxel liposome was t = −10.461, p < 0.01; that of the cabazitaxel-β-elemene complex liposome was t = −7.091, p < 0.01. Compared with the cabazitaxel injection group, the statistics parameter of the cabazitaxel-β-elemene complex liposome group was t = 1.842, p > 0.05, there was no statistically significant difference. Compared with the β-elemene liposome group, the statistics parameter of the cabazitaxel-β-elemene complex liposome group was t = −1.669, p > 0.05, there was no statistically significant difference. The tumor inhibition rates of group B, C, D, E, F, G were 13.53% ± 9.81%, 24.33% ± 10.67%, 58.40% ± 5.81%, 47.62% ± 6.25%, 63.46% ± 3.27%, and 52.71% ± 7.18%, respectively.