Bypassing Endocytosis Size-Restrictions

M. Ansar1#, D. Serrano2#, I. Papademetriou3, T. Bhowmick1 and S. Muro1,3*

1Institute for Bioscience & Biotechnology Research, University of Maryland, College Park, MD 20742, USA; 2Biological Sciences Graduate Program, University of Maryland, College Park, MD 20742, USA; 3Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.

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Summary
Most endocytic receptors used for intracellular drug delivery mediate uptake via clathrin or caveolar pathways associated with ≤ 200-nm vesicles, greatly restricting design of drug carriers. Endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1) is an independent pathway that allows uptake of nano- and micro-carriers in cells and in vivo. This is due to recruitment of cellular sphingomyelinases, which leads to ceramide generation at carrier binding sites. Ceramide then enables engulfment of carriers within a wide size-range. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors different from ICAM-1 and associated with size-restricted pathways (e.g. the clathrin route). We coated sphingomyelinase on the surface of those carriers. This allowed ceramide generation and enhanced endocytosis independently from the receptor being targeted by the carrier. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size-restrictions of its associated endocytic route. This strategy holds considerable promise to enhance flexibility of design of drug carriers for intracellular delivery.

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