Novel, nano-sized, liposome-encapsulated polyamidoamine dendrimer derivatives facilitate tumour targeting by overcoming the polyethylene glycol dilemma and integrin saturation obstacle

Drug delivery systems (DDSs) commonly employ arginine–glycine–aspartic acid (RGD) peptides with polyethylene glycol (PEG)-dependent enhanced permeability and retention (EPR) effect to optimise tumour-targeting. However, the PEG dilemma and integrin saturation obstacle are major challenges. To address these issues, we constructed a novel, nano-sized DDS by encapsulating doxorubicin (DOX)-loaded folic acid derivatives of polyamidoamine dendrimer (PAMAM G5.0) in cyclic RGD-tyrosine-lysine pentapeptide (c[RGDyK])-modified liposomes (RGD-SL[FND/DOX]), prepared using thin-film hydration, film-dispersion and hydration-sonication. The liposomes were PEGylated, sterically stabilised and pH-sensitive. In vitro, RGD-SL[FND/DOX] showed pH-sensitive holistic FND/DOX release, and pH-dependent uptake and cytotoxicity in human cancer KB cells. At pH 7.4, RGD-SL[FND/DOX] demonstrated greater cellular uptake and cytotoxicity than relevant control formulations (except FND/DOX) did, although this advantage disappeared at pH 6.5. In vivo, RGD-SL[FND/DOX] inhibited S180 sarcoma xenografted tumour growth in Kunming mice more effectively than FND/DOX did. These findings demonstrate the feasibility of constructing double-stage tumour-targeting nano-sized DDSs such as RGD-SL[FND/DOX]. c[RGDyK] and the EPR effect, facilitated by the particle size (about 110 nm) and PEGylation, helped to target the DDS to the tumour tissue, while the subsequent pH-dependent release of FND/DOX and folic acid-mediated endocytosis specifically targeted the tumour cells, thereby overcoming the PEG dilemma and integrin saturation obstacle.