Tunable physiologic interactions of adhesion molecules for inflamed cell-selective drug delivery.

TitleTunable physiologic interactions of adhesion molecules for inflamed cell-selective drug delivery.
Publication TypeJournal Article
Year of Publication2011
AuthorsKang S, Park T, Chen X, Dickens G, Lee B, Lu K, Rakhilin N, Daniel S, Jin MM
JournalBiomaterials
Volume32
Issue13
Pagination3487-98
Date Published2011 May
ISSN1878-5905
KeywordsCell Adhesion, Cell Adhesion Molecules, Cell Line, Drug Delivery Systems, Endothelium, Flow Cytometry, Humans, Inflammation, Integrins, Intercellular Adhesion Molecule-1, Liposomes, Monocytes, Pentacyclic Triterpenes, Reverse Transcriptase Polymerase Chain Reaction, Triterpenes
Abstract

Dysregulated inflammation contributes to the pathogenesis of various diseases. Therapeutic efficacy of anti-inflammatory agents, however, falls short against resilient inflammatory responses, whereas long-term and high-dose systemic administration can cause adverse side effects. Site-directed drug delivery systems would thus render more effective and safer treatments by increasing local dosage and minimizing toxicity. Nonetheless, achieving clinically effective targeted delivery to inflammatory sites has been difficult due to diverse cellular players involved in immunity and endogenous targets being expressed at basal levels. Here we exploit a physiological molecular interaction between intercellular adhesion molecule (ICAM)-1 and lymphocyte function associated antigen (LFA)-1 to deliver a potent anti-inflammatory drug, celastrol, specifically and comprehensively to inflamed cells. We found that affinity and avidity adjusted inserted (I) domain, the major binding site of LFA-1, on liposome surface enhanced the specificity toward lipopolysaccharides (LPS)-treated or inflamed endothelial cells (HMEC-1) and monocytes (THP-1) via ICAM-1 overexpression, reflecting inherent affinity and avidity modulation of these molecules in physiology. Targeted delivery of celastrol protected cells from recurring LPS challenges, suppressing pro-inflammatory responses and inflammation-induced cell proliferation. Targeted delivery also blocked THP-1 adhesion to inflamed HMEC-1, forming barriers to immune cell accumulation and to aggravating inflammatory signals. Our results demonstrate affinity and avidity of targeting moieties on nanoparticles as important design parameters to ensure specificity and avoid toxicities. We anticipate that such tunable physiologic interactions could be used for designing effective drug carriers for in vivo applications and contribute to treating a range of immune and inflammatory diseases.

DOI10.1016/j.biomaterials.2011.01.046
Alternate JournalBiomaterials
PubMed ID21306773
Related Institute: 
Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
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