title: Somatostatin analogues for receptor targeted photodynamic therapy.
abstract: Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.
authors.affiliation: Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Slávka
authors.initials: S
authors.lastname: Kaščáková
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.affiliation: Department of Otolaryngology and Head & Neck Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Henriette S
authors.initials: HS
authors.lastname: De Bruijn
authors.affiliation: Department of Radiology, School of Medicine, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Radiology, School of Medicine, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Katy
authors.initials: K
authors.lastname: van der Wansem
authors.affiliation: Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Angelique
authors.initials: A
authors.lastname: van der Ploeg-van den Heuvel
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brugts
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Aart-Jan
authors.initials: AJ
authors.lastname: van der Lelij
authors.affiliation: Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Henricus J C M
authors.initials: HJ
authors.lastname: Sterenborg
authors.affiliation: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.affiliation: Department of Otolaryngology and Head & Neck Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Robinson
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Martin P
authors.initials: MP
authors.lastname: van Hagen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D020014:K562 Cells; D058990:Molecular Targeted Therapy / Q000379:methods*; D010778:Photochemotherapy / Q000379:methods*; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D017481:Receptors, Somatostatin; D013004:Somatostatin
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