Annonaceous acetogenins nanosuspensions stabilized by PCL-PEG block polymer: significantly improved antitumor efficacy

Abstract

Annonaceous acetogenins (ACGs) have shown superior antitumor activity against a variety of cancer cell lines, but their clinical application has been limited by their poor solubility. In this study, ACGs-nanosuspensions (NSps) were successfully prepared by a precipitation ultrasonic method using monomethoxypoly (ethylene glycol)2000–poly (ε-caprolactone)2000 (mPEG2000–PCL2000) as a stabilizer. The resultant ACGs-NSps had a mean particle size of 123.2 nm, a zeta potential of −20.17 mV, and a high drug payload of 73.68%. ACGs-NSps were quite stable in various physiological solutions, and they exhibited sustained drug release. Compared to free drug, ACGs-NSps exhibited stronger cytotoxicity against 4T1, MCF-7, and HeLa cells. An in vivo real-time biodistribution investigation after labeling with 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide, a noninvasive near-infrared fluorescence probe, demonstrated that ACGs-NSps could effectively accumulate in tumor. An in vivo antitumor activity study in 4T1 tumor-bearing mice revealed that ACGs-NSps achieved much better therapeutic efficacy than the traditional dosage form (oil solution) even at 1/10 of the dose (74.83% vs 45.53%, P<0.05), demonstrating that NSp was a good dosage form for ACGs to treat cancer.

Keywords:

• annonaceous acetogenins
• mPEG2000–PCL2000
• near–infrared fluorescence
• biodistribution
• antitumor efficacy

Supplementary materials

Figure S1 HPLC chromatograms of total ACGs.

Notes: The mobile phase was composed of acetonitrile and water (70/30, v/v) and ran at a flow rate of 1 mL/min. The detection wavelength was set at 210 nm.

Abbreviations: ACGs, annonaceous acetogenins; HPLC, high-performance liquid chromatography.

Figure S2 The particle size of ACGs/DiR solution measured by DLS.

Notes: ACGs/DiR solution was prepared by dissolving 10 mg ACGs and 0.25 mg DiR in 1.0 mL of DMSO/Tween 80 (1:1, v/v) mixed solution, then being diluted to 10 mL with saline before use. The particle size was 19.5 nm.

Abbreviations: ACGs, annonaceous acetogenins; DiR, 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide; DMSO, dimethyl sulfoxide; DLS, dynamic light scattering.

Figure S3 The particle size of DiR solution measured by DLS.

Notes: DiR solution was prepared by dissolving 0.25 mg DiR in 0.5 mL DMSO and then being diluted with saline to 10 mL before use. The particle size was 128.3 nm.

Abbreviations: DiR, 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide; DMSO, dimethyl sulfoxide; DLS, dynamic light scattering.

Table S1 Characterization of ACGs-NSps prepared by block copolymer of mPEG–PCL with different molecular weights

Table S2 Changes in the zeta potential of ACGs-NSps and ACGs/DiR-NSps in plasma at 37°C

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (number U1401223) and the Youth Research Fund of Peking Union Medical College (number 3332015050).

Disclosure

The authors report no conflicts of interest in this work.