Design of a graphene oxide-BODIPY conjugate for glutathione depletion and photodynamic therapy

Abstract

Boron dipyrromethene derivates (BODIPYs) are promising photosensitisers (PSs) for cancer treatment using photodynamic therapy (PDT). This study investigates the functionalisation of graphene oxide (GO) with a BODIPY derivate for glutathione (GSH) depletion and PDT. The functionalisation of GO with a 3,5-dichloro-8-(4-boronophenyl) BODIPY via a diol derivatisation with the phenyl boronic acid moiety at the meso position of the BODIPY core, allowed to preserve the intrinsic properties of GO. We demonstrated that both chlorine atoms were substituted by GSH in the presence of glutathione transferase (GST), inducing a relevant bathochromic shift in the absorption/emission features and thus generating the active PS. Ex vitro assessment using cell lysates containing cytoplasmatic GST revealed the intracellular catalytic mechanism for the nucleophilic substitution of the GO-BODIPY adduct with GSH. Confocal microscopy studies showed important differences in the cellular uptake of free BODIPY and GO-BODIPY and revealed the coexistence of GO-BODIPY, GO-BODIPY-GS, and GO-BODIPY-GS2 species inside vesicles and in the cytoplasm of the cells after 24 h of incubation. In vitro biocompatibility and safety of GO and GO-BODIPY were evaluated in 2D and 3D models of prostate adenocarcinoma cells (PC-3), where no toxicity was observed up to 100 µg/mL of GO/GO-BODIPY in all treated groups 24 h post-treatment (cell viability > 90%). Only a slight decrease to 80% at 100 µg/mL was observed after 48 h of incubation. We demonstrated the efficacy of a GO adduct containing an α-chlorine-substituted BODIPY for the simultaneous depletion of intracellular GSH and the photogeneration of reactive oxygen species using a halogen white light source (5.4 mW/cm2) with a maximum in the range of 500-800 nm, which significantly reduced cell viability (< 50%) after irradiation. Our study provides a new vision on how to apply BODIPY derivates and potentiate the toxicity of PDT in prostate and other types of cancer.

Bonding of Neuropeptide Y on Graphene Oxide for Drug Delivery Applications to the Central Nervous System

“…Based on our previous results ,− , describing the impact of graphene materials on neuronal functions, we have selected a nanoscale GO obtained by Hummers’ oxidation of graphite for combination with the NPY peptide. The single layer of GO sheets possessed a size distribution centered at 430 nm . For the covalent functionalization, we first prepared GOTEG-N 3 via epoxide ring opening (Scheme ).…”

“…GO–NPY, GO, and the intermediate GOTEG-N 3 were characterized by TGA, XPS (Figure ), and FTIR (Figure S1). SEM of GO (Figure S2) allowed us to visualize the single layers and to calculate the size distribution, as already reported in a previous paper where we used the same starting material . TGA was used to compare the weight loss after each synthetic step.…”

“…The single layer of GO sheets possessed a size distribution centered at 430 nm. 31 For the covalent functionalization, we first prepared GOTEG-N 3 via epoxide ring opening ( Scheme 1 ). In particular, TEG-N 3 was chosen to introduce a spacer with a water soluble and flexible chain between the graphitic surface and the peptide ( Scheme 1 A).…”

“…SEM of GO ( Figure S2 ) allowed us to visualize the single layers and to calculate the size distribution, as already reported in a previous paper where we used the same starting material. 31 TGA was used to compare the weight loss after each synthetic step. The thermal profile was analyzed by derivative thermogravimetry (DTG; Figure 1 a,b).…”

Coupling BODIPY with nitrogen-doped graphene quantum dots to address the water solubility of photosensitizers

“…27,28 On the contrary, organic PDT photosensitizers non-covalently attached to graphene-related nanoconjugates and carbon-related dots have been introduced by various groups. [29][30][31][32] Recently, the synthesis of graphene oxide dots bearing covalently attached BODIPY PSs for PDT applications have been introduced. 33 These studies demonstrate the great potential of functionalized GQD-PSs for phototherapy.…”