Citrus Peels-Derived Polymethoxyflavones (PMFs) Nanoformulation for the Management of Cushing’s Syndrome: A Novel Phytochemical-Nanomedicine Approach

چکیده

Cushing’s Syndrome (CS), a debilitating endocrine disorder characterized by chronic hypercortisolism, remains therapeutically challenging due to significant off-target toxicities associated with conventional steroidogenesis inhibitors. This article presents a paradigm-shifting approach utilizing Polymethoxyflavones (PMFs)—a subclass of bioactive flavonoids abundantly present in citrus peels (Citrus sinensis and Citrus reticulata)—as novel therapeutic agents for CS. We critically review the pathophysiology of adrenal hypercortisolism and identify key molecular targets, including 11β-hydroxylase (CYP11B1) and the glucocorticoid receptor (GR), which are amenable to modulation by PMFs. Specifically, nobiletin, tangeretin, and 5-demethylnobiletin exhibit potent inhibitory activity against CYP11B1 and exert anti-inflammatory effects without complete adrenal suppression. However, the poor aqueous solubility, rapid hepatic metabolism, and limited oral bioavailability of PMFs necessitate an advanced delivery system. We propose a nanotechnology-based platform utilizing Poly (Lactic-co-Glycolic Acid) (PLGA) nanoparticles and phospholipid-based solid lipid nanoparticles (SLNs) encapsulating standardized citrus PMF extracts. The nanoencapsulation enhances PMF stability in gastrointestinal fluids, promotes lymphatic absorption, and enables sustained release, thereby achieving therapeutic cortisol reduction with a wider safety margin. Detailed synthesis protocols (solvent evaporation and high-pressure homogenization), physicochemical characterization (DLS, zeta potential, HPLC-PDA, TEM, and encapsulation efficiency), and in-vitro validation using H295R adrenocortical cells are presented. We demonstrate that PMF-loaded nanoparticles (PMF-NPs) significantly reduce cortisol secretion compared to free PMF extracts while preserving aldosterone synthesis—a critical advantage over existing therapies. Toxicological profiling confirms the safety of the nanocarrier system. Finally, we discuss the regulatory pathways for botanical drug substances and the potential for synergistic formulations combining multiple citrus PMFs. This work establishes citrus-derived PMFs, delivered via nanocarriers, as a viable, naturally-sourced, and safer alternative for long-term CS management.