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Abstract
Background: New approaches are required to improve the efficacy of drugs capable of enhancing ablative radioiodide (RAI) uptake, especially in RAI-refractory disease. Our recent experiments revealed that valosin-containing protein inhibitors (VCPi) such as clotrimazole and disulfiram markedly increase sodium iodide symporter (NIS) activity in vitro. However, novel drug design strategies may be needed to overcome the poor solubility and rapid metabolism of VCPi which diminish their thyroidal impact in vivo.
Aim: To determine whether rational drug design and reformulation strategies improve the efficacy of VCPi on NIS function in vitro and in vivo.
Methods: Computational iterative drug design was accompanied by de novo drug synthesis. RAI (125I) uptake assays were used to monitor NIS function in vitro. Technetium-99m pertechnetate (99mTc) uptake after intravenous administration was used to evaluate NIS function in wild-type BALB/c mice.
Results: Based on 3D modelling and iterative drug construction, we designed 21 novel analogues of clotrimazole and the allosteric VCPi UPDC30425, all with improved predicted bioavailability (LogP), and synthesised 4 additional compounds based on CryoEM high-resolution features of the VCPi NMS873 docking to VCP. In parallel, we prepared albumin nano-encapsulated copper-diethyldithiocarbamate [Cu(DDC)2-alb] - a stabilised reformulation of a disulfiram metabolite. While several clotrimazole analogues specifically increased RAI uptake, the greatest impact was observed with Cu(DDC)2-alb treatment in thyroidal TPC-1-NIS (2.8-fold; P < 0.01) and 8505C-NIS cells (3.0-fold; P < 0.01). Importantly, intraperitoneal administration of Cu(DDC)2-alb significantly induced thyroidal 99mTc-uptake in BALB/c mice (~40%; n = 11;3mg/kg dose; P < 0.001), as well as increasing thyroidal NIS (1.9-fold; P < 0.01) and thyroid peroxidase mRNA (1.8-fold;P<0.001) expression. A significant positive correlation was apparent between thyroidal 99mTc-uptake and NIS mRNA (rs=0.4477; P = 0.0169) in Cu(DDC)2-alb treated mice, uniting systemic drug effects on NIS expression and function.
Conclusions: Our study demonstrates a promising drug strategy utilising a disulfiram metabolite to enhance NIS function in vivo, with clinical potential to improve treatment in RAI-refractory thyroid cancer.
Aim: To determine whether rational drug design and reformulation strategies improve the efficacy of VCPi on NIS function in vitro and in vivo.
Methods: Computational iterative drug design was accompanied by de novo drug synthesis. RAI (125I) uptake assays were used to monitor NIS function in vitro. Technetium-99m pertechnetate (99mTc) uptake after intravenous administration was used to evaluate NIS function in wild-type BALB/c mice.
Results: Based on 3D modelling and iterative drug construction, we designed 21 novel analogues of clotrimazole and the allosteric VCPi UPDC30425, all with improved predicted bioavailability (LogP), and synthesised 4 additional compounds based on CryoEM high-resolution features of the VCPi NMS873 docking to VCP. In parallel, we prepared albumin nano-encapsulated copper-diethyldithiocarbamate [Cu(DDC)2-alb] - a stabilised reformulation of a disulfiram metabolite. While several clotrimazole analogues specifically increased RAI uptake, the greatest impact was observed with Cu(DDC)2-alb treatment in thyroidal TPC-1-NIS (2.8-fold; P < 0.01) and 8505C-NIS cells (3.0-fold; P < 0.01). Importantly, intraperitoneal administration of Cu(DDC)2-alb significantly induced thyroidal 99mTc-uptake in BALB/c mice (~40%; n = 11;3mg/kg dose; P < 0.001), as well as increasing thyroidal NIS (1.9-fold; P < 0.01) and thyroid peroxidase mRNA (1.8-fold;P<0.001) expression. A significant positive correlation was apparent between thyroidal 99mTc-uptake and NIS mRNA (rs=0.4477; P = 0.0169) in Cu(DDC)2-alb treated mice, uniting systemic drug effects on NIS expression and function.
Conclusions: Our study demonstrates a promising drug strategy utilising a disulfiram metabolite to enhance NIS function in vivo, with clinical potential to improve treatment in RAI-refractory thyroid cancer.
| Original language | English |
|---|---|
| Article number | OR3 |
| Pages (from-to) | 4-4 |
| Number of pages | 1 |
| Journal | Thyroid Research |
| Volume | 16 |
| Issue number | S1 |
| DOIs | |
| Publication status | Published - 11 Jul 2023 |
| Event | 71st Annual Meeting of the British Thyroid Association - Royal College of Pathologists, London, United Kingdom Duration: 9 Jun 2023 → 9 Jun 2023 Conference number: 71 |
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