Speaker
Description
"Introduction:
The ongoing search for novel drug delivery to a target site has led to increased interest in using bioorthogonal organometallic (BOOM) chemistry for localised prodrug activation. Anticancer prodrugs containing a palladium (Pd)-cleavable propargyl protecting group have been developed, necessitating a suitable method to deliver the palladium nanoparticle (PdNP) catalyst to a desired location. PdNP-immobilisation within a non-degradable, biocompatible polymer matrix enables implantation of the catalyst, e.g. intratumourally. Systemic administration of a harmless Pd-sensitive prodrug results in the localised generation of therapeutic concentrations of drug.
PdNP-functionalised poly(ethylene glycol) (PEG) microbeads were prepared, and immobilised within a poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel matrix. Catalytic activity of the materials was examined using a Pd-labile fluorogenic prodye. Absorption and release of the dye Resorufin (Res) by pHEMA was also investigated.
Methodology:
ChemMatrix® aminomethyl-PEG microbeads were functionalised with PdNPs by reduction of coordinated palladium(II) acetate with hydrazine monohydrate. PdNPs were physically entrapped at the surface by coupling surface amino groups to glutaric acid
Cross-linking of HEMA and ethylene glycol dimethacrylate (EGDMA), containing sheared gellan gum (GG) ± PdPEG microbeads, was initiated with ammonium persulfate/tetramethylethylenediamine (APS/TEMED). Hydrogel films of varying thicknesses were cut to discs with a biopsy punch, yielding a cross-linked pHEMA±PdPEG disc.
Catalytic efficiency of free PdPEG and pHEMA-PdPEG were evaluated by incubation with Pd-sensitive probe, propargylated Resorufin (Pro-Res), and measuring the increase in fluorescence intensity.
Diffusion and absorption were measured by monitoring the decrease in fluorescence of a solution of Res containing a pHEMA disc over time, until equilibrium is achieved.
Results:
PdPEG-loaded pHEMA was prepared by polymerisation of monomer and bead mixture in the presence of gellan gum. Inclusion of gellan gum within the mixture aids suspension of the beads during the cross-linking process, facilitating homogeneous dispersion of PdPEG microbeads throughout the network. Microbead immobilisation was successful with no leaching of beads occurring after several months.
The catalytic ability of PdNP-functionalised PEG microbeads (PdPEG), in solution or immobilised in a pHEMA matrix, was demonstrated by the fluorogenic depropargylation of Pro-Res. PdPEG beads achieved >75% conversion after 24 hours in biologically relevant conditions. The pHEMA immobilised-PdPEG achieved similar conversions, under the same conditions, after 72 hours due to the rate limiting diffusion step.
Decrease in fluorescence intensity, proportional to concentration, of a solution of Res containing a pHEMA disc quantified dye uptake. The dye exhibited a preference for pHEMA over the aqueous solution of more than two orders of magnitude. Further understanding and exploitation of this “depot effect” will aid design of a hydrogel implant which activates prodrugs and captures drug molecules to control their release.
Conclusions:
Entrapment of PdNPs within polymers, with retention of catalytic ability, was exhibited. Synthesised materials depropargylated fluorogenic Pro-Res, a model compound for Pd-sensitive prodrugs.
Immobilisation of PdPEG beads within pHEMA slowed prodye conversion, due to the rate-limitation of diffusion. Res exhibited preference for the pHEMA matrix over aqueous solution, likely due to hydrophobicity. Future work seeks to understand this behaviour, and modulate hydrogel implant properties to control this diffusion in/out of pHEMA."
20941859208
