Platelet membrane-camouflaged nanovesicle targeted delivery of MLN4924 for antitumor therapy

Abstract

Inhibition of the protein neddylation pathway has emerged as an attractive anticancer strategy in pre-clinical studies. MLN4924, as a small molecule inhibitor of neddylation, has been found to effectively inhibit the growth of a variety of cancer cells. However, its clinical application still faces some major challenges in terms of poor water solubility, biological stability, poor targeting, and rapid clearance from the body. Herein, we developed a biomimetic nanovesicle platform (named P-PAM/MLN) by ultrasonically storing the MLN4924-loaded polyamidoamine (PAMAM) dendrimer inside platelet membrane vesicles (PMVs) for tumor therapy. Benefiting from PMV-based camouflage, P-PAM/MLN exhibited enhanced tumor affinity, avoiding the off-target toxicity of MLN4924. Moreover, P-PAM/MLN could selectively release MLN4924 in response to the acidic microenvironment of lysosomal compartments via the “proton sponge” effect. Consequently, the biomimetic nanovesicles could remarkably inhibit tumor progression with negligible toxicity. In terms of significance, the nanovesicles provide a precisely targeted delivery platform for delivering small molecule drugs to the tumor tissue as well as an effective reference for the combined application of nanocarriers and clinical drugs.