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Engineering Polymer‐Binding Bispecific Antibodies for Enhanced Pretargeted Delivery of Nanoparticles to Mucus‐Covered Epithelium
Author(s) -
Huckaby Justin T.,
Parker Christina L.,
Jacobs Tim M.,
Schaefer Alison,
Wadsworth Daniel,
Nguyen Alexander,
Wang Anting,
Newby Jay,
Lai Samuel K.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201814665
Subject(s) - pretargeting , mucus , chemistry , drug delivery , pegylation , biophysics , drug carrier , conjugate , nanotechnology , polyethylene glycol , antibody , monoclonal antibody , materials science , immunology , biochemistry , radioimmunotherapy , biology , organic chemistry , ecology , mathematical analysis , mathematics
Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand‐conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two‐step “pretargeting” approach through engineering a bispecific antibody that binds both cell‐surface ICAM‐1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus‐coated Caco‐2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2‐fold or more compared to either non‐targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces.