Combined administration of PTX and S-HM-3 in TPGS/Solutol micelle system for oncotarget therapy

Abstract

Background

S-HM-3 is a tumor angiogenesis inhibitor with short half-life (25 min). In this present, TPGS/Solutol polymeric micelles was prepared to load together insoluble paclitaxel (PTX) and soluble S-HM-3, expecting to together deliver them to the tumor site with long-circulating, targeting function and combating multi-drug resistance (MDR).

Materials and methods

PTX and S-HM-3 loaded TPGS/Solutol micelles (PHTSm) were prepared by the method of thin-film evaporation, and characterized by dynamic light scattering, transmission electron microscope (TEM), atomic force microscopy (AFM) and releasing properties. The anticancer effect of the polymeric micelles system was evaluated and confirmed by experiments of in vitro cell uptake study, in vivo pharmacokinetics, and pharmacodynamics studies.

Results

Micelles exhibited smooth spherical morphology with 20~30 nm and low critical micelle concentration (CMC) value of 0.000124 mg/mL. Only about 30% of PTX were slowly released from micelles at 48h, which can beneficial to the long circulation in blood. The results of in vitro cell assay proved that S-HM-3 could be easier to get into MDA-MB-231 cell, and its angiogenesis inhibition ability was also enhanced after integrating into micelles. In particular, the results of in vivo studies showed that the half-life of S-HM-3 and PTX was significantly prolonged 25.27 and 5.54 folds, and their AUC_0–∞ was enhanced 129.78 and 15.65 times, respectively. Meanwhile 83.05% tumor inhibition rate of PHTSm was achieved compared with 59.99% of PTX.

Conclusions

TPGS and Solutol micelles hold promising potential to resolve the conundrum of combined therapy of cytotoxic drug and angiogenesis inhibitor with different physicochemical property and anticancer mechanism in clinical use.

Keywords:

• paclitaxel
• angiogenesis inhibitor
• combination therapy
• TPGS
• Solutol
• anti-multidrug resistance

Supplementary material

Figure S1 Xenograft tumors harvested at 14 days (G1 of Saline, G2 of PTX + S-HM-3, G3 of S-HM-3, G4 of PTX, G5 of TSm, G6 of PTSm, and G7 of PHTSm).

Abbreviation: PTX, paclitaxel.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81403346 and 81673830), Double First-class University project (CPU2018GY28), and the Six Talent Peaks Project of Jiangsu Province (2016/YY-053). The present study was also supported by the Natural Science Foundation of Jiangsu Province (BK20160757).

Disclosure

The authors report no conflicts of interest in this work.