title: Pharmaceutical nanocarrier association with chondrocytes and cartilage explants: influence of surface modification and extracellular matrix depletion.
abstract: OBJECTIVE
  To evaluate cartilage diffusion and isolated chondrocyte association of micelles and liposomes and to determine the effect of cell-penetrating peptide (CPP) surface functionalization and extracellular matrix depletion on chondrocyte association and cartilage diffusion, respectively.
  
  
  METHODS
  Rhodamine-labeled micelles and liposomes were incubated with bovine chondrocytes and cell-associated fluorescence was quantified using flow cytometry. Rhodamine-labeled CPP-modified micelles and liposomes were incubated with chondrocytes and cell-associated fluorescence was compared to unmodified nanocarriers. Rhodamine-labeled micelles and liposomes were incubated with bovine cartilage explants for 1, 2 and 4 h and cartilage-associated fluorescence was compared across groups. Cartilage explants were treated with interleukin-1 alpha (IL-1α) or with 0.25% trypsin. Rhodamine-labeled micelles and liposomes were incubated with control, IL-1 and trypsin-treated explants and cartilage-associated fluorescence was compared across groups.
  
  
  RESULTS
  Chondrocyte-associated fluorescence following treatment with micelles was significantly higher (P < 0.001) than fluorescence in the cells treated with liposomes while there was no difference between cell-associated fluorescence in the liposomes-treated and untreated controls. CPP-modified nanocarriers exhibited a significant increase in chondrocyte association compared to unmodified nanocarriers (P < 0.001). Micelles exhibited a time and concentration-dependent diffusion in cartilage explants while liposomes showed no diffusion. Following IL-1 and trypsin treatments, micelle diffusion in articular cartilage was significantly higher (P < 0.001) than their diffusion in untreated explants.
  
  
  CONCLUSIONS
  Micelles exhibit superior association with isolated chondrocytes compared to liposomes. Surface modification with a CPP enhances chondrocyte association of both nanocarriers. 15 nm diameter micelles are better than 138 nm diameter liposomes in penetrating articular cartilage and extracellular matrix depletion enhances micelle penetration.
authors.affiliation: Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA. khaled.elsaid@mcphs.edu
authors.forename: K A
authors.initials: KA
authors.lastname: Elsaid
authors.forename: L
authors.initials: L
authors.lastname: Ferreira
authors.forename: T
authors.initials: T
authors.lastname: Truong
authors.forename: A
authors.initials: A
authors.lastname: Liang
authors.forename: J
authors.initials: J
authors.lastname: Machan
authors.forename: G G
authors.initials: GG
authors.lastname: D'Souza
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology* / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects*; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005109:Extracellular Matrix / Q000187:drug effects*; D005456:Fluorescent Dyes; D007270:Injections, Intra-Articular; D008081:Liposomes; D008823:Micelles; D023421:Models, Animal; D012235:Rhodamines; D013997:Time Factors
chemical_list: D057846:Cell-Penetrating Peptides; D005456:Fluorescent Dyes; D008081:Liposomes; D008823:Micelles; D012235:Rhodamines