Hyaluronic acid-poly(lactic-co-glycolic acid) nanoparticles with a ruthenium photosensitizer cargo for photokilling of oral cancer cells

Abstract

• Enhanced photodynamic effect by Ru(II) complex through both Type I and II mechanisms. • Synthesis of Ru(II) complex with 2,2’-biimidazole for PDT of oral cancer. • Ru(II) complex encapsulation in HA-PLGA NPs for improved solubility and selectivity. • High intracellular uptake of Ru(II) complex mediated by HA targeting of CD44. • Preferential accumulation of Ru(II) complex in the mitochondria. Photodynamic therapy (PDT), a combination of light, molecular oxygen and a photosensitizing dye, has gained attention as a promising technique to treat various types of cancers. Among all the photosensitizers reported so far, ruthenium(II) polypyridyl complexes exhibit unique photophysical and photobiological features owing to their photostability, μs triplet excited states, and ability to undergo both ‘type I’ and ‘type II’ reactions in their photodynamic action. We report the synthesis of a novel Ru(II) complex containing one 2,2'-biimidazole (bim) and two tetramethylphenanthroline (tmp) ligands that sensitizes the simultaneous production of superoxide anion (O 2 • - ) and singlet oxygen ( 1 O 2 ) upon irradiation with blue-green light. To improve its solubility and bioavailability, a zero-order degradation-controlled release formulation based on self-assembled hyaluronic acid (HA)–poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was prepared for its topical application in oral cancer cells (TR146 cell line). These NPs (152 nm diameter) showed 70% Ru-complex encapsulation efficiency, high physiological stability, low polydispersity index (0.12), and a sensitizer release enhanced by the hyaluronidase enzyme overexpressed in many cancer cells. Both the free complex and its nanocarrier are internalized by the TR146 cells, displaying >90% in vitro cytotoxicity under 470 nm activation (50 J cm -2 ), highlighting their potential as PDT agents. The Ru(II) complex loaded nanocarrier developed in this study can be potentially effective in the treatment of oral cancers.