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.

Ginsenoside F1 Ameliorates Endothelial Cell Inflammatory Injury and Prevents Atherosclerosis in Mice through A20-Mediated Suppression of NF-kB Signaling

“…The MPO in vivo biodistribution was performed according to a previous study ( Hong et al, 2016 ). Briefly, mice were given an intraperitoneal injection of probe at a dose of 150 mg/kg for 15 min.…”

Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice

“…As none of ACGs effective components had ultraviolet or fluorescent absorption able to provide ACGs with a sensitive in vivo quantitative analysis method (Hong et al., 2016 ), DiR was incorporated in ACGs-NSps to estimate the in vivo distribution behavior of ACGs in HeLa tumor-bearing mice. Whatever for FA-PEG-ACGs/DiR-NSps or for PEG-ACGs/DiR-NSps, ACGs and DiR were slow but nearly synchronously released in the in vitro experiment ( Figure S4 ).…”

“…FA-PEG-ACGs-NSps were prepared using a precipitation-ultra sonication method as described in our previous study (Hong et al., 2016 ). Briefly, 6 mg of ACGs, 3 mg of DSPE-PEG-FA and 3 mg of SPC were co-dissolved in 0.5 mL of methanol, then the mixed solution was injected dropwise into 6 mL of deionized water at 28 °C ± 2 °C under ultra-sonication at 250 W for 10 min (Kun Shan Ultrasonic Instruments Co., Ltd, Kunshan, PR China), followed by evaporation of methanol under vacuum at 40 °C until no organic solvent remained.…”

“…In our previous research, we have prepared ACGs-NSps stabilized by PEG2000-PCL2000 or self-assembled cyclodextrins–SPC complex. The resultant ACGs-NSps showed a small size, good stability, stronger in vitro cytotoxicity and significantly improved in vivo antitumor efficacy than traditional ACGs oil solution (Aditya et al., 2015 ; Hong et al., 2016 ). Nowadays, folic acid (FA) has become the most widely used tumor targeting ligand with a high affinity to folate receptor (FR)-positive cells (Leamon & Low, 1991 ; Leamon & Reddy, 2004 ; Reddy et al., 2006 ).…”

Folate-modified Annonaceous acetogenins nanosuspensions and their improved antitumor efficacy

“…The ratio of the fluorescence intensity in the tumor to the fluorescence intensity in the liver was used as an index to evaluate the targeting efficiency (Te to liver ) of drug delivery systems. 45 Figure 7C demonstrated that the Te of FA-ACGs-NSps was 2.5-fold greater than that of ACGsNSps (P,0.001). It was clear that FA arrangement provides ACGs-NSps with good active tumor targeting ability in FR-positive tumors.…”