• Porter, Christopher J. H.
• Pathak, Rashmi
• Kelly, Brian D.
• Mehta, Dharmini
• Mcleod, Victoria M.
• Kaminskas, Lisa
• Leong, Nathania

Abstract

PEGylation typically improves the systemic exposure and tumour biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumour biodistribution, drug release kinetics and anti-cancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumour uptake were limited. The largest G5 PEG1100 dendrimer showed good tumour uptake and retention, but restricted drug liberation and therefore limited anti-cancer activity. Superior anti-cancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumour uptake and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.

Topics

• impedance spectroscopy
• molecular weight
• dendrimer