pH-responsive endosomolytic pseudo-peptides for drug delivery to multicellular spheroids tumour models

Endosomolytic polymers can aid in the endosomal release of therapeutics to improve intracellular drug delivery. pH-responsive biomimetic pseudo-peptides were synthesised by grafting L-phenylalanine onto the pendant carboxylic acids of a polyamide, poly(L-lysine isophthalamide). PP-75 (stoichiometric L-phenylalanine grafting of 75 mol%) was determined to have the best endosomolytic property. The mean hydrodynamic size of PP-75 decreased with lower pH as the polymers adopted a more compact conformation due to protonation of acidic groups and increase in hydrophobicity. PP-75 was demonstrated to deliver model drugs effectively in three dimensional (3D) magnetic HeLa multicellular spheroids used as in vitro tumour models. These spheroids can be isolated easily and quickly by magnetic separation. Due to its relatively small size. PP-75 was able to penetrate from the exterior to the interior of these spheroids and was internalised by the cells in the spheroids. It could retain its pH-mediated membrane-lytic capability in 3D drug delivery by releasing internalised calcein from intracellular endosomes in the tumour models. Furthermore, cell viability results suggest that PP-75 showed no significant cytotoxicity towards cells in the spheroids. The pH-responsive PP-75 can potentially enhance the extracellular and intracellular delivery of therapeutics in tumours. (C) 2011 Elsevier Ltd. All rights reserved.