Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing l-Thyroxine-Derived Prodrugs
Arun Kumar Tonduru1, Seyed Hamed Maljaei1, Santosh Kumar Adla1
1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Abstract:
OATP1C1 (organic anion-transporting polypeptide 1C1) transports thyroid hormones, particularly thyroxine (T4), into human astrocytes. In this study, we investigated the potential of utilizing OATP1C1 to improve the delivery of anti-inflammatory drugs into glial cells. We designed and synthesized eight novel prodrugs by incorporating T4 and 3,5-diiodo-l-tyrosine (DIT) as promoieties to selected anti-inflammatory drugs. The prodrug uptake in OATP1C1-expressing human U-87MG glioma cells demonstrated higher accumulation with T4 promoiety compared to those with DIT promoiety or the parent drugs themselves. In silico models of OATP1C1 suggested dynamic binding for the prodrugs, wherein the pose changed from vertical to horizontal. The predicted binding energies correlated with the transport profiles, with T4 derivatives exhibiting higher binding energies when compared to prodrugs with a DIT promoiety. Interestingly, the prodrugs also showed utilization of oatp1a4/1a5/1a6 in mouse primary astrocytes, which was further supported by docking studies and a great potential for improved brain drug delivery.
Insights
Researchers developed novel prodrugs using thyroid hormone thyroxine (T4) to enhance anti-inflammatory drug delivery into brain glial cells via OATP1C1 transporter. T4-based prodrugs showed superior uptake and binding, indicating potential for improved brain drug delivery.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Organic anion-transporting polypeptide 1C1 (OATP1C1) facilitates thyroid hormone transport into astrocytes.
- Targeting glial cells is crucial for treating central nervous system disorders.
Purpose of the Study:
- To investigate OATP1C1-mediated delivery of anti-inflammatory drugs into glial cells.
- To design and synthesize novel prodrugs for enhanced brain drug delivery.
Main Methods:
- Synthesis of eight novel prodrugs incorporating thyroxine (T4) or 3,5-diiodo-l-tyrosine (DIT) promoieties.
- Assessment of prodrug uptake in OATP1C1-expressing human U-87MG glioma cells.
- In silico modeling and docking studies of OATP1C1-prodrug interactions.
- Evaluation of prodrug transport in mouse primary astrocytes.
Main Results:
- Prodrugs with T4 promoieties exhibited significantly higher uptake in OATP1C1-expressing cells compared to DIT prodrugs or parent drugs.
- In silico models revealed dynamic binding of prodrugs to OATP1C1, with T4 derivatives showing stronger predicted binding energies.
- Prodrugs were also transported by oatp1a4/1a5/1a6 in mouse astrocytes, suggesting broader transporter interaction.
Conclusions:
- Thyroxine-based prodrugs effectively utilize OATP1C1 for enhanced uptake into glial cells.
- The developed prodrug strategy holds significant potential for improving brain drug delivery.
- Further research may leverage OATP1C1 for targeted delivery of therapeutics to the brain.
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