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.