Leveraging cystine transporters for kidney-targeted drug delivery

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Trustees of Princeton University $151,760 on January 9, 2027, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop kidney-targeted drug delivery using solute carrier transporters.

The research establishes proof-of-concept for exploiting cystine transporters SLC7A9 and SLC7A13, which are highly expressed in kidney tissue, to deliver drugs selectively to kidney cells. The recipient's laboratory has developed cystine transporter-aimed motifs (CTAMs)—inert cystine analogs that serve as substrates for these transporters. Drugs conjugated to CTAMs can be transported into kidney cells and released via cleavable linkers, a strategy termed SLC hijacking. Aim 1 identifies CTAM-drug conjugates that exploit these transporters for kidney-specific delivery by assessing uptake and activity in cell culture systems, conducting in vivo studies using wild-type and transporter knockout mice, and using MALDI-MS imaging to map intra-kidney localization. Aim 2 evaluates the therapeutic potential of CTAM-prednisolone conjugates in a chronic kidney disease mouse model, assessing efficacy in reducing renal inflammation and determining whether kidney-specific delivery mitigates systemic toxicity and adrenal insufficiency.

Work is performed in Princeton, New Jersey. The period of performance runs from January 9, 2027, through July 31, 2029.

Abstract

Targeted drug delivery can improve therapeutic efficacy and reduce systemic toxicity, yet kidney- specific delivery remains an unmet need. Current strategies using nanoparticles or macromolecules have shown limited success, highlighting the need for alternative approaches. Solute carrier (SLC) transporters, which mediate the uptake of metabolites and small-molecule drugs, offer a promising solution. Drugs often accumulate in tissues enriched for specific slcs, suggesting that these transporters can be exploited for tissue-selective delivery. This project aims to establish proof-of-concept for kidney-targeted drug delivery by hijacking cystine transporters SLC7A9 and SLC7A13. These transporters are highly expressed in the kidney, making them ideal candidates for selective targeting. Our lab has developed cystine transporter-aimed motifs (ctams), inert cystine analogs that serve as substrates for these transporters. Drugs conjugated to ctams can be transported into kidney cells and released via cleavable linkers, enabling precise delivery-a strategy termed SLC hijacking. Aim 1 will identify ctam-drug conjugates that exploit SLC7A9 and SLC7A13 for kidney-specific delivery. Uptake and activity will be assessed in cell culture systems, followed by in vivo studies using wild-type and transporter knockout mice. Maldi-MS imaging will map intra-kidney localization of conjugates. Aim 2 will evaluate the therapeutic potential of ctam-prednisolone conjugates in a chronic kidney disease mouse model. Studies will assess efficacy in reducing renal inflammation and determine whether kidney-specific delivery mitigates systemic toxicity and adrenal insufficiency. Successful completion of this work will establish SLC hijacking as a novel strategy for kidney- targeted drug delivery and provide a broadly applicable workflow for discovering SLC-based targeting motifs. This approach has the potential to transform precision therapeutics by improving drug localization and reducing off-target effects.