Recent Progress in the Hesperetin Delivery Regimes: Significance of Pleiotropic Actions and Synergistic Anticancer Efficacy.

Background: In the plant kingdom, flavonoids are widely distributed with multifunctional immunomodulatory actions. Hesperetin (HST) remains one of the well-studied compounds in this domain, initially perceived in citrus plants as an aglycone derivative of hesperidin (HDN).

Observations: Natural origin, low toxicity, and pleiotropic functional essence are the foremost fascinations for HST use as an anticancer drug. However, low aqueous solubility accompanied with a prompt degradation by intestinal and hepatocellular enzymes impairs HST physiological absorption.

Motivation: Remedies attempted herein comprise the synthesis of derivatives and nanocarrier (NC)-mediated delivery. As the derivative synthesis aggravates the structural complexity, NC-driven HST delivery has emerged as a sustainable approach for its sustained release. Recent interest in HST has been due to its significant anticancer potential, characterized inhibited cell division (proliferation), new blood vessel formation (angiogenesis), forceful occupation of neighboring cell's space (invasion), migration to erstwhile physiological locations (metastasis) and apoptotic induction. The sensitization of chemotherapeutic drugs (CDs) by HST is driven stoichiometrically regulated synergistic actions. Purpose and Conclusion: This article sheds light on HST structure-function correlation and pleiotropic anticancer mechanisms, in unaided and NC-administered delivery in singular and with CDs synergy. The discussion could streamline the HST usefulness and long-term anticancer efficacy.