Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.
Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolae-mediated pathways, allows uptake of nano- and microcarriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and microcarriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems.
Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742, United States.
Maria
M
Ansar
Daniel
D
Serrano
Iason
I
Papademetriou
Tridib Kumar
TK
Bhowmick
Silvia
S
Muro
D000199:Actins / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D021941:Caveolae / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002518:Ceramides / Q000737:chemistry; D002966:Clathrin / Q000737:chemistry; D004337:Drug Carriers; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011137:Polystyrenes / Q000737:chemistry; D017527:Receptor, IGF Type 2 / Q000737:chemistry*; D011990:Receptors, Transferrin / Q000737:chemistry*; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry
D000199:Actins; D002518:Ceramides; D002966:Clathrin; D004337:Drug Carriers; C573420:ICAM1 protein, human; D011137:Polystyrenes; D017527:Receptor, IGF Type 2; D011990:Receptors, Transferrin; D018799:Intercellular Adhesion Molecule-1; D013108:Sphingomyelin Phosphodiesterase