Tailored Trojan horse nanocarriers for enhanced redox-responsive drug delivery

Redox-responsive anti-tumor nanomedicine is appealing in improving the therapeutic efficacy and patient compliance. However, the thiol-disulfide exchange reaction is reversible and kinetically very slow, resulting in poor drug release and delayed onset of drug action. To address this issue, a tailored Trojan horse nanocarrier is designed with pH-labile zeolitic imidazolate framework-8 (ZIF-8) as the core and disulfide-linked amphiphilic polymer-drug conjugate as the steric shell. A potent reductant, tris(3-hydroxypropyl)phosphine (THPP) is loaded in ZIF-8 and capped by myristyl alcohol. At low pH (e.g. endosome and lysosome), the collapse of ZIF-8 can induce the liberation of THPP that further cleaves the disulfide bond and release the drug post self-immolation. As the reaction between THPP and disulfide is both thermodynamically and kinetically favored, the drug release rate can be boosted. The proof-of-concept is demonstrated both in 4T1 murine mammary carcinoma cells and 4T1 tumor-bearing mice with curcumin as the model drug. Compared to the control nanosystem without THPP, the tailored nanocarrier can significantly enhance the drug release and hence therapeutic efficacy, which is demonstrated by the assays of cell viability, tumor growth inhibition, and histological staining. Such strategy can extend to a plethora of thiol-free cargos for controlled intracellular delivery.