Journal article
Conjugation Chemistry Markedly Impacts Toxicity and Biodistribution of Targeted Nanoparticles, Mediated by Complement Activation
Advanced materials (Weinheim), v 37(5), e2409945
01 Feb 2025
PMID: 39663706
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Conjugation chemistries are a major enabling technology for the development of drug delivery systems, from antibody-drug conjugates to antibody-targeted lipid nanoparticles inspired by the success of the COVID-19 vaccine. However, here it is shown that for antibody-targeted nanoparticles, the most popular conjugation chemistries directly participate in the activation of the complement cascade of plasma proteins. Their activation of complement leads to large changes in the biodistribution of nanoparticles (up to 140-fold increased uptake into phagocytes of the lungs) and multiple toxicities, including a 50% drop in platelet count. It is founded that the mechanism of complement activation varies dramatically between different conjugation chemistries. Dibenzocyclooctyne, a commonly used click-chemistry, caused aggregation of conjugated antibodies, but only on the surface of nanoparticles (not in bulk solution). By contrast, thiol-maleimide chemistry do not activate complement via its effects on antibodies, but rather because free maleimide bonded to albumin in plasma, and clustered albumin is then attacked by complement. Using these mechanistic insights, solutions are engineered that reduced the activation of complement for each class of conjugation chemistry. These results highlight that while conjugation chemistry is essential for the future of nanomedicine, it is not innocuous and must be designed with opsonins like complement in mind.
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Details
- Title
- Conjugation Chemistry Markedly Impacts Toxicity and Biodistribution of Targeted Nanoparticles, Mediated by Complement Activation
- Creators
- Michael H Zaleski - University of PennsylvaniaLiam S Chase - University of PennsylvaniaElizabeth D Hood - University of PennsylvaniaZhicheng Wang - University of PennsylvaniaJia Nong - University of PennsylvaniaCarolann L Espy - University of PennsylvaniaMarco E Zamora - Drexel University, School of Biomedical Engineering, Science, and Health SystemsJichuan Wu - University of PennsylvaniaLianne J Morrell - University of PennsylvaniaVladimir R Muzykantov - University of PennsylvaniaJacob W Myerson - University of PennsylvaniaJacob S Brenner (Corresponding Author) - University of Pennsylvania
- Publication Details
- Advanced materials (Weinheim), v 37(5), e2409945
- Publisher
- Wiley
- Grant note
- 5R21AI166778 / Foundation for the National Institutes of Health 1R01HL164594 / Foundation for the National Institutes of Health 5R01HL160694 / Foundation for the National Institutes of Health 5R01HL157189 / Foundation for the National Institutes of Health 5R01HL155106 / Foundation for the National Institutes of Health R01 HL164594 / NHLBI NIH HHS R01 HL153510 / NHLBI NIH HHS R01 HL155106 / NHLBI NIH HHS R01 HL160694 / NHLBI NIH HHS Pennsylvania Department of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001374672200001
- Scopus ID
- 2-s2.0-85211485817
- Other Identifier
- 991022004950204721
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Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Multidisciplinary
- Chemistry, Physical
- Materials Science, Multidisciplinary
- Nanoscience & Nanotechnology
- Physics, Applied
- Physics, Condensed Matter