The effect of surface modification of ultrasmall palladium nanoparticles (Pd NPs) with polyethylene glycol and glucose on cellular uptake and radiosensitizing potential - Comprehensive in vitro and molecular dynamics studies.

Glioblastoma multiforme (GBM) remains one of the most aggressive and radioresistant brain tumors, highlighting the urgent need for effective radiosensitizers compatible with proton radiotherapy (PRTH). Ultrasmall (< 5 nm) palladium nanoparticles (Pd NPs) were synthesized and subsequently surface-functionalized with thiolated polyethylene glycol (PEG-SH) and thiolated glucose (Glu-SH). The influence of surface chemistry on biological interactions and radiosensitizing performance was then investigated. Structural characterization confirmed the formation of highly crystalline, monodisperse Pd NPs, while FTIR spectroscopy and zeta potential analysis verified successful stepwise surface modification. In vitro studies on LN229 and U118 GBM cell lines showed that PEGylated Pd NPs (Pd NPs-PEG) markedly reduced nonspecific cytotoxicity, whereas subsequent Glu-SH functionalized Pd NPs-PEG (Pd NPs-PEG-Glu) preserved cytocompatibility while significantly enhancing proton-induced cell killing. Label-free holotomographic microscopy enabled real-time visualization and quantification of NPs-cells interactions, revealing distinct uptake dynamics driven by surface functionalization and cellular heterogeneity. Molecular dynamics simulations indicated strong association of Pd-based NPs with phospholipid headgroups without membrane penetration, while PEG chains partially screened NP-membrane interactions. Surface-engineered ultrasmall Pd-based NPs, particularly Pd NPs-PEG-Glu, were established as potential radiosensitizers for PRTH, and it was demonstrated that nanoscale surface chemistry dictates membrane interactions, cellular uptake and therapeutic efficacy in vitro.