title: Vascular targeting to the SST2 receptor improves the therapeutic response to near-IR two-photon activated PDT for deep-tissue cancer treatment.
abstract: BACKGROUND
  Broader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo-activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment.
  
  
  METHODS
  Human tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting.
  
  
  RESULTS
  Tumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~120fs to ~3ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors.
  
  
  CONCLUSIONS
  The use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures.
authors.affiliation: Montana State University, Department of Microbiology, Bozeman, MT 59717, USA. jeanrstarkey@gmail.com
authors.forename: Jean R
authors.initials: JR
authors.lastname: Starkey
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Pascucci
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Drobizhev
authors.forename: Aleisha
authors.initials: A
authors.lastname: Elliott
authors.forename: Aleksander K
authors.initials: AK
authors.lastname: Rebane
mesh_terms: D001808:Blood Vessels / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010778:Photochemotherapy; D017785:Photons; D017481:Receptors, Somatostatin / Q000187:drug effects*; D019265:Spectroscopy, Near-Infrared
chemical_list: D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2
keywords: 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride; ATCC; American type culture collection; BAE; CMF; DMEM; Dulbecco's minimal essential medium; EDC; EDTA; EGF; Ethylenediaminetetraacetic acid; FITC; GE11 peptide; Laser pulse; NIR; PBS; PDT; Photodynamic therapy; SCID; SST2r; Somatostatin receptor 2; UCNP; VEGF; Vascular shutdown; YHWYGYTPQNVI; bovine aortic endothelial; calcium and magnesium free saline; epidermal growth factor; fluorescein isothiocyanate; near infrared; phosphate buffered saline; photodynamic therapy; severe combined immunodeficient; somatostatin type 2 receptor; upconversion nanoparticle; vascular endothelial growth factor