title: Biomimetic delivery strategies at the urothelium: targeted cytoinvasion in bladder cancer cells via lectin bioconjugates.
abstract: OBJECTIVE
  Urothelial cells, including bladder cancer (BCa) cells, represent a highly valuable but challenging target for localized antineoplastic therapy. This study describes a novel, biomimetic approach to improve intravesical drug delivery, based on glycan-specific targeting. In direct analogy to the invasion mechanism used by uropathogenic bacteria, we evaluate the potential of lectin bioconjugates to facilitate binding and uptake of large payload molecules at this penetration-hostile barrier.
  
  
  METHODS
  Wheat germ agglutinin (WGA) served as a targeting ligand and was covalently coupled to fluorescein-labeled bovine serum albumin (fBSA), yielding multivalent protein bioconjugates. Cytoadhesion, uptake and intracellular processing were characterized on a panel of urothelial cell lines of non-malignant and malignant origin.
  
  
  RESULTS
  Conjugation to WGA rendered the fBSA payload protein strongly cytoadhesive, with a clear preference in binding to cancerous cells. The highly specific, lectin-mediated recognition process was followed by rapid internalization, and extensive but non-exclusive accumulation in acid and LAMP-2-positive compartments. Stage of malignancy and mechano-structural cell configuration were important determinants for the sorting between different processing pathways.
  
  
  CONCLUSIONS
  Lectin-bioconjugates allow for triggering endogenous uptake routes and influencing the intracellular distribution in BCa cells. They hold considerable promise for enhancing the delivery of small molecule drugs and complex biomolecules in intravesical therapy.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstr. 14, Vienna, 1090, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Neutsch
authors.forename: Britta
authors.initials: B
authors.lastname: Eggenreich
authors.forename: Ela
authors.initials: E
authors.lastname: Herwig
authors.forename: Martina
authors.initials: M
authors.lastname: Marchetti-Deschmann
authors.forename: Günter
authors.initials: G
authors.lastname: Allmaier
authors.forename: Franz
authors.initials: F
authors.lastname: Gabor
authors.forename: Michael
authors.initials: M
authors.lastname: Wirth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D032701:Biomimetics; D002417:Cattle; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019459:Urothelium / Q000378:metabolism*; D014909:Wheat Germ Agglutinins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014909:Wheat Germ Agglutinins; D012710:Serum Albumin, Bovine