Phototoxic effects of pheophorbide-a nanoconjugates on melanoma tumor spheroids.

Abstract

Melanoma is the deadliest form of skin cancer, with a rapidly rising incidence and a poor prognosis for patients diagnosed at advanced stages. Photodynamic therapy (PDT) represents a promising, minimally invasive treatment for melanoma. However, its clinical use is often limited by poor tumour selectivity and suboptimal intracellular accumulation of conventional photosensitizers (PSs). To address these challenges, an active targeted photosensitizer nanoparticle that uses pheophorbide-a (Ppa) conjugated with gold nanoparticles (AuNPs) and folic acid (FA) was fabricated. AuNPs serve as nanocarriers with their unique features of high biocompatibility, good photophysical properties, and high load capacity that help in the effective delivery of PSs. The Ppa-AuNP-FA nanobioconjugate was synthesized and characterized for morphology, stability, and photodynamic performance. The phototoxic efficacy of the nanophotosensitiser was tested on three-dimensional (3D) melanoma multicellular tumour spheroids (MCTS). Optimization studies of free Ppa yielded an IC50 concentration of 9.3 μM, which was used throughout the study. A high concentration of Ppa significantly ruptured spheroids, indicating the need to modify this PS to reduce dose dependency and prevent unwanted side effects in patients. Upon laser irradiation (10 J/cm2), Ppa- AuNP-FA caused significant disruption of the spheroid outer membrane, increased intracellular reactive oxygen species (ROS) production, and induced severe cell death compared to free Ppa and non-targeted controls. Our findings demonstrate that the coupling of Ppa with AuNPs and FA improves PS delivery, phototoxicity, and cellular uptake. The Ppa-AuNP-FA complex may become an excellent approach in the active targeting nanotechnology platform for improving PDT in malignant melanoma.

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