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Somatostatin analogues for receptor targeted photodynamic therapy.

Kaščáková S, Hofland LJ, De Bruijn HS, Ye Y, Achilefu S, van der Wansem K, van der Ploeg-van den Heuvel A, van Koetsveld PM, Brugts MP, van der Lelij AJ, Sterenborg HJ, Ten Hagen TL, Robinson DJ, van Hagen MP - PLoS ONE (2014)

Bottom Line: When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower.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.These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.

View Article: PubMed Central - PubMed

Affiliation: Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.

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.

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Related in: MedlinePlus

Structures of Ce6 and its two [Tyr3]-octreotate conjugates.(A) Ce6; (B) [Tyr3]-octreotate motif; (C) Ce6-K3-[Tyr3]-octreotate (conjugate 1) and (D) Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (conjugate 2). A tri-lysine linker (K3) was used between Ce6 and [Tyr3]-octreotate motifs to improve the hydrophilicity of the monomeric conjugate 1. A similar linker was also inserted between the two [Tyr3]-octreotate motifs in the dimeric analog, conjugate 2.
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pone-0104448-g001: Structures of Ce6 and its two [Tyr3]-octreotate conjugates.(A) Ce6; (B) [Tyr3]-octreotate motif; (C) Ce6-K3-[Tyr3]-octreotate (conjugate 1) and (D) Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (conjugate 2). A tri-lysine linker (K3) was used between Ce6 and [Tyr3]-octreotate motifs to improve the hydrophilicity of the monomeric conjugate 1. A similar linker was also inserted between the two [Tyr3]-octreotate motifs in the dimeric analog, conjugate 2.

Mentions: The structures of Ce6 and 2 somatostatin analogue conjugates of Ce6, used in the present study are shown in Figure 1.


Somatostatin analogues for receptor targeted photodynamic therapy.

Kaščáková S, Hofland LJ, De Bruijn HS, Ye Y, Achilefu S, van der Wansem K, van der Ploeg-van den Heuvel A, van Koetsveld PM, Brugts MP, van der Lelij AJ, Sterenborg HJ, Ten Hagen TL, Robinson DJ, van Hagen MP - PLoS ONE (2014)

Structures of Ce6 and its two [Tyr3]-octreotate conjugates.(A) Ce6; (B) [Tyr3]-octreotate motif; (C) Ce6-K3-[Tyr3]-octreotate (conjugate 1) and (D) Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (conjugate 2). A tri-lysine linker (K3) was used between Ce6 and [Tyr3]-octreotate motifs to improve the hydrophilicity of the monomeric conjugate 1. A similar linker was also inserted between the two [Tyr3]-octreotate motifs in the dimeric analog, conjugate 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4128677&req=5

pone-0104448-g001: Structures of Ce6 and its two [Tyr3]-octreotate conjugates.(A) Ce6; (B) [Tyr3]-octreotate motif; (C) Ce6-K3-[Tyr3]-octreotate (conjugate 1) and (D) Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (conjugate 2). A tri-lysine linker (K3) was used between Ce6 and [Tyr3]-octreotate motifs to improve the hydrophilicity of the monomeric conjugate 1. A similar linker was also inserted between the two [Tyr3]-octreotate motifs in the dimeric analog, conjugate 2.
Mentions: The structures of Ce6 and 2 somatostatin analogue conjugates of Ce6, used in the present study are shown in Figure 1.

Bottom Line: When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower.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.These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.

View Article: PubMed Central - PubMed

Affiliation: Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus