Self-assembled nanoparticles of glycosylated AABB-type phthalocyanines for selective photodynamic therapy

Photodynamic therapy (PDT) is still hindered by limitations such as poor bioavailability and insufficient selectivity towards tumor cells. To overcome these drawbacks, nanostructured delivery systems have emerged as promising platforms due to their ability to enhance bioavailability and achieve efficient tumor targeting. In this context, nanoparticles (NPs) formed by the self-assembly of highly amphiphilic photosensitizers (PS) in aqueous media are particularly attractive. Among the various PS available, phthalocyanines (Pcs) are especially suitable for constructing nanoassemblies for PDT owing to their outstanding optical and photophysical properties, as well as their ability to form stable nanoaggregates in water through a combination of π-π stacking and hydrophobic interactions. In this work, we describe the design, synthesis, and evaluation of two amphiphilic, glucose-functionalized zinc(II) phthalocyanines (Zn(II)Pcs) as self-assembled PS for PDT. These derivatives are obtained from binaphthyloxy-linked AABB-type Zn(II)Pc synthons previously reported by our group, which are functionalized at the binaphthol ring with glucose units via Sonogashira coupling or copper-catalyzed click reaction. The resulting amphiphiles, GluPc-1 and GluPc-2, spontaneously self-assemble into stable NPs (15-30 nm) that undergo partial disassembly inside cells, which restores the photophysical properties required for efficient PDT. Notably, the glucose moieties exposed on the NP surface enhance selective uptake by tumor cells overexpressing glucose transporters (GLUT-1). Biological studies in cancerous (A549 and HT29) and non-cancerous (HEK293) cell lines confirmed preferential uptake in GLUT1-positive cells, while cytotoxicity assays demonstrated negligible dark toxicity and potent light-induced phototoxic effects.