Harnessing Cystine Solute Carrier Transporters to Enable Targeted Renal Drug Delivery Using Transporter-Aimed Molecular Motifs

Abstract

Targeted drug delivery aims to enhance drug accumulation at sites of disease while minimizing systemic toxicity, yet most existing strategies are limited by inefficient tissue‑specific uptake. Solute carrier (SLC) transporters regulate the cellular transport of metabolites, nutrients, and many small‑molecule drugs. The observation that drugs can accumulate in tissues expressing specific SLCs suggests that endogenous transport pathways could be exploited for tissue‑selective delivery; however, this strategy remains largely unexplored, particularly for existing therapeutics. Here, we establish a generalizable approach to targeted drug delivery by designing small‑molecule motifs that selectively engage individual SLC transporters to direct therapeutic payloads to defined tissues. As a proof of concept, we focused on cystine transporters, including SLC7A11/xCT, commonly overexpressed in cancer, and SLC7A9 and SLC7A13, which are highly expressed in renal proximal tubule cells. We developed metabolite‑mimetic scaffolds termed cystine transporter‑aimed motifs (CTAMs) that are selectively transported by specific cystine transporters and can be conjugated to diverse drug payloads through cleavable linkers. Using high‑throughput in vitro uptake assays and mouse tissue distribution studies, we identified CTAMs that selectively engage SLC7A13. CTAM conjugated to diverse drug payloads showed robust, SLC7A13‑dependent kidney targeting in mice while substantially reducing drug exposure in non‑renal tissues compared to unconjugated parent drugs. Transporter dependence was confirmed using genetic loss‑of‑function models, and MALDI-MS imaging localized CTAM‑drug conjugates to SLC7A13‑expressing regions within the kidney. To explore translational potential, we focused on the glucocorticoid prednisolone. We identified kidney‑targeted CTAM‑prednisolone conjugates and are evaluating their efficacy in the adenine‑induced chronic kidney disease model. Together, these findings establish a broadly applicable platform for exploiting endogenous metabolite transport pathways to achieve tissue‑selective drug delivery and improve the therapeutic index of small‑molecule drugs.