title: Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging.
abstract: Matrix metalloproteinase enzymes, overexpressed in HT-1080 human fibrocarcinoma tumors, were used to guide the accumulation and retention of an enzyme-responsive nanoparticle in a xenograft mouse model. The nanoparticles were prepared as micelles from amphiphilic block copolymers bearing a simple hydrophobic block and a hydrophilic peptide brush. The polymers were end-labeled with Alexa Fluor 647 dyes leading to the formation of labeled micelles upon dialysis of the polymers from DMSO/DMF to aqueous buffer. This dye-labeling strategy allowed the presence of the retained material to be visualized via whole animal imaging in vivo and in ex vivo organ analysis following intratumoral injection into HT-1080 xenograft tumors. We propose that the material is retained by virtue of an enzyme-induced accumulation process whereby particles change morphology from 20 nm spherical micelles to micrometer-scale aggregates, kinetically trapping them within the tumor. This hypothesis is tested here via an unprecedented super-resolution fluorescence analysis of ex vivo tissue slices confirming a particle size increase occurs concomitantly with extended retention of responsive particles compared to unresponsive controls.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Radiology, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Miao-Ping
authors.initials: MP
authors.lastname: Chien
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Carlini
authors.forename: Dehong
authors.initials: D
authors.lastname: Hu
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Barback
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.forename: David J
authors.initials: DJ
authors.lastname: Hall
authors.forename: Galya
authors.initials: G
authors.lastname: Orr
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gianneschi
mesh_terms: D000818:Animals; D002460:Cell Line; D004798:Enzymes / Q000737:chemistry*; D064593:Heterografts; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods*; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism*
chemical_list: D004798:Enzymes