title: Tumor suppression via paclitaxel-loaded drug carriers that target inflammation marker upregulated in tumor vasculature and macrophages.
abstract: Clinically approved chemotherapeutic nanoparticles may provide advantages over free drugs by achieving slower clearance and preferential accumulation in tumors. However, the lack of leaky vasculatures can create barriers to the permeation of ~100 nm-sized nanoparticles in solid tumors. We hypothesized that nanoparticles designed to target both tumor and tumor stroma would penetrate deeper into the tumors. To construct such comprehensive drug carriers, we utilized cross-linked amphiphilic polymer nanoparticles and functionalized them to target ICAM-1, a biomarker prevalent in various tumors and inflamed tumor stroma. The targeting moiety was derived from the modular domain present in α(L) integrin, which was engineered for high affinity and cross-reactivity with human and murine ICAM-1. ICAM-1-selective delivery of paclitaxel produced potent tumor suppression of not only ICAM-1-positive cervical cancer cells but also ICAM-1-negative tumors, presumably by causing cytotoxicity in tumor-associated endothelium (CD31(+)) and macrophages (CD68(+)) over-expressing ICAM-1. Contrary to the strategies of targeting only the tumor or specific tumor stromal constituents, we present a strategy in delivering therapeutics to the major cellular components of solid tumors. Drug carriers against inflammation-biomarkers may be effective against many different types of tumors, while being less susceptible to the highly mutable nature of tumor markers.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Park
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Kang
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Chen
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Kim
authors.forename: Jeeyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Nahae
authors.initials: N
authors.lastname: Kim
authors.forename: Juyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Moonsoo M
authors.initials: MM
authors.lastname: Jin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D016169:Lymphocyte Function-Associated Antigen-1; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D017239:Paclitaxel