Folic Acid Receptor-Mediated Targeting Enhances the Cytotoxicity, Efficacy, and Selectivity of Withania somnifera Leaf Extract: In vitro and in vivo Evidence.

Yue Yu,Renu Wadhwa,Jia Wang,Sunil C Kaul,Eijiro Miyako

doi:10.3389/fonc.2019.00602

Abstract

Nanomedicine holds great potential for drug delivery to achieve more effective and safer cancer treatment. Earlier, we reported that the alcoholic extract of Withania somnifera leaves (i-Extract) has selective cancer cell killing activity. Herein, we developed a folate receptor-targeting i-Extract nanocomplex (FRi-ExNC) that suspends well in water and possesses enhanced selective anticancer activity in both in vitro and in vivo assays. Comparative analyses of folate receptor (FR)-positive and -negative cells revealed that FRi-ExNC caused a stronger decrease in Cyclin D/Cdk4 and anti-apoptotic protein Bcl-2, as well as a higher increase in the growth arrest regulating protein p21WAF1 and pro-apoptotic protein PARP-1, in FR-enriched cancer cells. Our results demonstrate that FRi-ExNC could be a natural source-based nanomedicine for targeted cancer therapy.

Highlights

Withania somnifera is a popular herb used in Indian traditional Ayurvedic medicine and health tonics
We designed the encapsulation of i-EX in FRPEG-lipid using the polymeric micelle system, examined its characteristics as well as anticancer effects in in vitro and in vivo assays
The polymeric micelles containing FRi-ExNC can be synthesized through a simple self-assembly technique without any complicated multistep processes. i-ExNC- or FRi-ExNC-supplemented (i-Ex) was encapsulated in the inner core of micelles that were composed of phospholipid-polyethylene glycol (PEG) (DSPE-PEG)

Summary

INTRODUCTION

Withania somnifera is a popular herb ( called Indian ginseng) used in Indian traditional Ayurvedic medicine and health tonics. Withaferin-A and Withanone were found to possess anticancer activity; whereas i-Extract and Withanone have been shown to be selectively cytotoxic to cancer cells, Withaferin-A causes toxicity to normal cells as well [1,2,3,4,5]. Both bioinformatics and wet lab studies have demonstrated that both Withaferin-A and Withanone cause death of cancer cells through multi-target mechanisms [6,7,8,9,10,11]. We developed a folate receptor-targeting i-Extract nanocomplex that possesses enhanced selective cancer cell killing activity. The amount of i-Ex in pellets (Wnonencapsulated) was determined based on the absorption at 660 nm by reference to its calibration curve

MATERIALS AND METHODS

RESULTS AND DISCUSSION

ETHICS STATEMENT