Dendrimer nanoclusters loaded with gold nanoparticles for enhanced tumor CT imaging and chemotherapy via an amplified EPR effect

Abstract

The design of efficient multifunctional nanomedicines to overcome adverse side effects within biological systems and to achieve desirable computed tomography (CT) imaging and therapeutics of tumors remains challenging. Herein, we report the design of multifunctional nanoclusters (NCs) based on generation 3 (G3) poly(amidoamine) (PAMAM) dendrimers. In brief, G3 dendrimers were crosslinked with 4,4′-dithiodibutryic acid (DA) to generate disulfide-bond-containing dendrimer nanoclusters (DNCs), functionalized with 1,3-propane sultone (1,3-PS) to be zwitterionic, in situ loaded with gold nanoparticles (Au NPs), and finally encapsulated with the drug doxorubicin (DOX). The designed DOX/Au@DNCs-PS possess a favorable colloidal stability with a hydrodynamic size of 249.4 nm, a redox-responsive drug release profile, and enhanced cellular uptake in vitro. We show that DOX/Au@DNCs-PS have a greater DOX penetration and growth inhibition of three-dimensional (3D) tumor spheroids than the single dendrimer counterpart in vitro. Furthermore, the developed Au@DNCs-PS enable a better Au-mediated X-ray attenuation property than the single dendrimer counterpart material. Likely due to the amplified enhanced permeability and retention (EPR) effect, the created Au@DNCs-PS and DOX/Au@DNCs-PS enable better CT imaging and chemotherapeutic effect of a mouse breast tumor model, respectively, than the single dendrimer counterparts. With its proven biocompatibility, the constructed formulation may hold promising potential for development for different cancer nanomedicine applications.