Development and In Vitro Efficacy of Macrophage-Targeted Nanoparticles Encapsulating Vitamin E Derivatives Garcinoic Acid and α‑13′-Carboxychromanol

Abstract

Garcinoic acid (GA), a phytomolecule and long-chain metabolite of δ-tocotrienol, and its analogue α-13′-carboxychromanol (α-13′-COOH), derived from α-tocopherol metabolism, are bioactive compounds involved in the regulation of various processes, including immune function and inflammatory responses. Pharmacological properties of these compounds are constrained by the rapid metabolism and the poor target selectivity in distinct tissue or cell types, including macrophages, a main player in the inflammatory response. To overcome these limitations, in this study, the DSPE-PEG-S2P conjugate containing a stabilin-2 receptor-specific S2P peptide was synthesized and utilized for the preparation of nanoparticles (NPs) for macrophage targeting. Also, GA or α-13′-COOH were loaded into nontargeted or macrophage-targeted NPs, and their delivery efficiency was compared against bone marrow-derived macrophages (BMDMs). These NPs exhibited stability for at least 2 days at room and body temperature and provided pH-responsive drug release. Moreover, macrophage-targeted NPs demonstrated a linear dose-dependent increase of cellular levels for both metabolites, whereas nontargeted NPs induced dose-independent accumulation, which emphasizes the targeting ability of the S2P peptide. Additionally, both NPs had no adverse effect on cell morphology and viability. Present findings confirmed the improving effect of S2P-decorated NPs for delivering GA or α-13′-COOH metabolites specifically into these inflammatory cells via targeting macrophages. Cell selectivity and efficacy of this delivery system deserve further preclinical investigation in models of acute and chronic inflammation.