Design, Synthesis, and Biological Evaluation of Dexamethasone–Salvianolic Acid B Conjugates and Nanodrug Delivery against Cisplatin-Induced Hearing Loss

Cisplatin
(CDDP) is an extensively used chemotherapeutic agent
but has a high incidence of severe ototoxicity. Although a few molecules
have entered clinical trials, none have been approved to prevent or
treat CDDP-induced hearing loss by the Food and Drug Administration.
In this study, an amphiphilic drug–drug conjugate was synthesized
by covalently linking dexamethasone (DEX) and salvianolic acid B (SAL)
through an ester or amide bond. The conjugates could self-assemble
into nanoparticles (NPs) with ultrahigh drug loading capacity and
favorable stability. Compared with DEX, SAL, or their physical mixture
at the same concentrations, both conjugates and NPs showed enhanced
otoprotection in vitro and in vivo. More importantly, the conjugates
and NPs almost completely restored hearing in a guinea pig model with
good biocompatibility. Immunohistochemical analyses suggested that
conjugates and NPs activated the glucocorticoid receptor, which may
work as one of the major mechanisms for their protective effects.