title: Tunable physiologic interactions of adhesion molecules for inflamed cell-selective drug delivery.
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.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Kang
authors.forename: Taehyun
authors.initials: T
authors.lastname: Park
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Chen
authors.forename: Greg
authors.initials: G
authors.lastname: Dickens
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.forename: Kevin
authors.initials: K
authors.lastname: Lu
authors.forename: Nikolai
authors.initials: N
authors.lastname: Rakhilin
authors.forename: Susan
authors.initials: S
authors.lastname: Daniel
authors.forename: Moonsoo M
authors.initials: MM
authors.lastname: Jin
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016023:Integrins; D008081:Liposomes; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D018799:Intercellular Adhesion Molecule-1; C050414:celastrol