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Somatostatin analogues for receptor targeted photodynamic therapy
Slávka Kaščáková1, Leo J Hofland2, Henriette S De Bruijn3
1Center 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.
Insights
This study developed a novel dual-targeted photodynamic therapy (PDT) using a somatostatin analogue conjugate (Ce6-K3-[Tyr3]-octreotate) that targets sst2 receptors on tumor and vascular cells. The conjugate showed enhanced uptake and specific targeting in vitro and in vivo, indicating potential for improved cancer treatment.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Photodynamic therapy (PDT) is an established anticancer treatment requiring photosensitizer targeting for efficacy.
- Improved photosensitizer delivery is crucial for treating pathologies in specific anatomical sites and minimizing healthy tissue damage.
Purpose of the Study:
- To develop and evaluate a novel dual-targeted PDT approach using conjugates that target both tumor cells and neovascular-endothelial cells via somatostatin receptor 2 (sst2).
- To synthesize and characterize two Chlorin e6 (Ce6) conjugates with a somatostatin analogue, [Tyr3]-octreotate.
Main Methods:
- Synthesis of two Ce6 conjugates: Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2).
- In vitro assessment of cellular uptake and photodynamic activity in sst2-expressing K562 cells.
- In vivo pharmacokinetic studies using fluorescence imaging in a rat skin-fold chamber model with sst2+ AR42J tumors.
Main Results:
- Conjugate 1 demonstrated enhanced sst2-mediated cellular uptake (2-fold increase) in vitro compared to wild-type cells, with phototoxicity abrogated by excess Octreotide.
- Conjugate 2 exhibited high hydrophobicity, leading to no receptor-mediated effects.
- In vivo studies showed conjugate 1 had distinct uptake profiles in tumor and neo-vasculature, significantly reduced by Octreotide co-treatment (4-fold reduction in tumor uptake).
- Conjugate 1 displayed lower phototoxicity than unconjugated Ce6 but higher photostability.
Conclusions:
- The sst2-targeting conjugate (Ce6-K3-[Tyr3]-octreotate) shows potential for dual vascular and cellular targeting in photodynamic therapy.
- Specific receptor-mediated uptake and reduced off-target accumulation suggest promise for improved therapeutic outcomes in sst2-expressing tumors.
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