Polyethylene Glycol-Encapsulated Histone Deacetylase Inhibitor Drug-Composite Nanoparticles for Combination Therapy with Artesunate

Abstract

Combination drug therapy has become an effective clinical practice for cancer treatment because of low cytotoxicity by the synergistic effect of each medicine. Luminescent Au nanoclusters (Au NCs) were formulated into spherical polyethylene glycol (PEG)–Au NC-encapsulated drug–sodium butyrate (NaB) composite nanoparticles (PEG–Au NC–NaB-NPs) in the presence of PEG and NaB. Their effect on cancer cells was investigated using bio imaging, unravelling the mechanism of the endocytosis pathway and combination therapeutic interventions with a plant-based antimalarial drug artesunate (ART). PEG–Au NC–NaB-NPs showed bright red luminescence in the lysosomal compartment of the cells upon uptake predominantly through a caveolae-mediated pathway. Combination of PEG–Au NC–NaB-NPs with ART displayed enhanced therapeutic activity at a reduced dose compared to its individual doses and revealed heightened synergistic activity as identified from the combination index. The mechanism of synergism revealed elevated generation of reactive oxygen species with both NaB and ART, which disrupts mitochondrial membrane potential as evident from JC-1 staining. Remarkably, the histone deacetylase (HDAC) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling assay enlightened the role of NaB and ART in HDAC inhibition and DNA fragmentation, respectively. Thus, induction of apoptosis with the synergistic effect of both NaB and ART with its meticulous mechanism makes it a promising tool for combinational cancer therapy. In vivo activity of the NPs was evaluated on Daltons lymphoma ascites bearing mice, which exhibited significant reduction of tumor volume and viable tumor cells with a prolonged life span.