Ultrasmall platinum nanoparticles enable deep tumor penetration and synergistic therapeutic abilities through free radical species-assisted catalysis to combat cancer multidrug resistance

Despite the significant advancements in the development of a wide-variety of nanocarriers-based delivery systems for cancer therapy, several predominant issues remain unaddressed such as active combat of cancer multidrug resistance (MDR) and the limited penetration efficacy of the delivery systems. To address these issues, herein, we demonstrate the fabrication of a versatile nanoformulation by conveniently wrapping the ultrasmall platinum (Pt) nanoparticles-dispersed chitosan (CS) over the zinc-doped mesoporous silica nanocarriers (Zn-MSNs) through a facile, yet efficient self-assembly approach. These versatile nanocomposites decorated with highly active, ultrasmall Pt nanoparticles potentially facilitate the advanced therapeutic abilities of deep tumor penetration and aphotic (dark) synergistic ablation of the MDR tumors effectively. In this framework, pericellular actin staining results confirmed the effect of decorated Pt species on the integrity of the adherens junctions between cells. Remarkably, the Zn species that are doped in the siliceous frameworks substantially enhanced the loading efficiency of doxorubicin (Dox) molecules without any additional functionalization and facilitated the augmented anticancer efficacy by delivering them precisely in the tumor's acidic microenvironment through specifically dismantling the established coordination interactions between the host and guest species. Further, the resultant free radical species from the delivered Dox species intracellularly enabled the catalytic conversion of the Pt nanoparticles to their corresponding divalent ionic species, which synergistically participated in the tumor ablation. These consequences of Pt species toward synergistic ablation of MDR cells happened to be favourable only in the presence of Dox species, a free radical generator. In vitro and in vivo investigations confirm augmented antiproliferation and synergistic inhibition effects of designed nanocomposites in the MDR tumors. These nanocomposites decorated with highly active Pt nanoparticles potentially allow for deep tumor penetration and synergistic ablation of the tumor by conveniently combating the MDR efficaciously.