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Biological Functionalization of Drug Delivery Carriers To Bypass Size Restrictions of Receptor-Mediated Endocytosis Independently from Receptor Targeting

Significance Statement

Numerous types of drug carriers have been designed to improve the solubility, pharmacokinetics and release of therapeutic agents. Many of these platforms are additionally functionalized to achieve targeting of endocytic receptors located on cells in need of intervention, so that the therapeutic cargoes can be transported intracellularly. Selecting appropriate receptors to be targeted by a drug carrier is key in order to achieve both selectivity toward the cell to intervene upon and to successfully access within its interior. However, not always the receptors expressed on the target cells are amenable for gaining access into cells. For instance, most drug delivery vehicles exploit clathrin- or caveolae-mediated endocytosis because numerous receptors are known which mediate transport through these means and many of these receptors are overexpressed in diseased cells. However, a limitation of these pathways is that they are not efficient in transporting objects that exceed the size limits of the transporting compartment with which they associate (generally between 50-150 nm in diameter). This greatly limits the design and application of drug delivery strategies because these transport pathways are invariably linked to the receptors being targeted. If the only available receptors to allow distinction between healthy and disease cells are linked to said pathways, then any option for intracellular delivery requires design of carriers below these size limits. Yet, this is not always possible or ideal; numerous formulations which exceed the nanometer size range at least in one dimension (elongated and filamentous carriers) have great potential to improve circulation and targeting specificity. Finding means to decouple target receptors from their subjacent entry pathways while enabling them to operate within a wider spectrum of carrier geometries would offer an invaluable opportunity to improve drug delivery. This article shows that this can be done by functionalizing drug carriers to mimic endocytosis via intercellular adhesion molecule 1 (ICAM-1) without the need of targeting this receptor. ICAM-1 mediates endocytosis of objects within a wide range of sizes thanks to its built-on ability to modify the lipid composition of the plasma membrane, which occurs via ICAM-1-mediated recruitment of cellular sphingomyelinases to the cell surface. Therefore, when drug carriers are functionalized with sphingomyelinases they can elicit a similar remodeling of the cell membrane composition even if the carrier targets a receptor different from ICAM-1, thereby enhancing internalization within the cell. This strategy offers for the first time the opportunity to enhance intracellular transport of drug carriers regardless of the receptors and pathways being targeted.

 

Figure key: Red actin filaments and green ceramide at areas of carrier binding on cells (ring-like structures), induced by sphingomyelin functionalization of the carrier surface.

Biological Functionalization of Drug Delivery Carriers To Bypass Size Restrictions of Receptor-Mediated Endocytosis Independently from Receptor Targeting

Journal Reference

Ansar M, Serrano D, Papademetriou I, Bhowmick TK, Muro S.

ACS Nano. 2013 Dec 23;7(12):10597-611.

Institute for Bioscience and Biotechnology Research, University of Maryland , College Park, Maryland 20742, United States.

 

Abstract

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.

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