Valproic acid-based self-assembling nanoparticle prodrugs prevent skeletal muscle loss in cancer cachexia

Cancer cachexia is a multifactorial syndrome characterized by persistent skeletal muscle loss, affecting 80 % of patients with advanced cancer and accounting for 20 % of cancer-related deaths. Despite its prevalence, effective treatment options remain limited due to the side effects and poor pharmacokinetic (PK) profiles of existing therapeutics, including valproic acid (VPA). To overcome these limitations, we developed self-assembling VPA-based nanoparticle prodrugs (abbreviated as Nano^VPA), consisting of amphiphilic block copolymers, in which VPA is covalently conjugated via ester linkages. Nano^VPA significantly improved the PK profile of VPA by suppressing initial rapid plasma concentration spikes and achieving sustained VPA release, maintaining circulation for up to 48 h and enhancing skeletal muscle accumulation within 10 h post-administration. In vivo, twice-weekly administration of Nano^VPA significantly attenuated skeletal muscle loss in a cancer cachexia model by downregulating the expression of atrogin-1, a key muscle-specific ubiquitin ligase involved in proteolysis. These findings highlight the potential of Nano^VPA as a novel therapeutic strategy for cancer cachexia, offering improved efficacy and reduced dosing frequency with minimized side effects.