Multifunctional Low-Generation Dendrimer Nanogels as an Emerging Probe for Tumor-Specific CT/MR Dual-Modal Imaging

The development of nanoprobes that have amplified enhanced permeability and retention (EPR) effect is crucial for their precise cancer diagnosis performance. Here, we present the development of functional dendrimer-based nanogels (DNGs) with the generation three primary amine-terminated poly(amidoamine) (PAMAM) dendrimers (G3·NH₂) cross-linked by N,N'-bis(acryloyl) cystamine (BAC). The DNGs were prepared through a Michael addition reaction between G3·NH₂ dendrimers and BAC via an inverse microemulsion method and entrapped with gold nanoparticles (Au NPs) to form Au-DNGs. The Au-DNGs were sequentially modified with diethylenetriamine penta-acetic acid (DTPA)-gadolinium (Gd) complex, poly(ethylene glycol) (PEG)-linked arginine-glycine-aspartic (RGD) peptide, and 1,3-propanesultone (1,3-PS). The formed multifunctional RGD-Gd@Au-DNGs-PS (R-G@ADP) possessing an average diameter of 122 nm are colloidally stable and display a high X-ray attenuation coefficient, excellent r₁ relaxivity (9.13 mM^-1 s^-1), desired protein resistance rendered by the zwitterionic modification, and cytocompatibility. With the targeting specificity mediated by RGD and the much better tumor penetration capability than the counterpart material of single dendrimer-entrapped Au NPs, the developed multifunctional R-G@ADP enable targeted and enhanced computed tomography (CT)/magnetic resonance (MR) dual-modal imaging of a pancreatic tumor model in vivo. The current work demonstrates a unique design of targeted and zwitterionic DNGs with prolonged blood circulation time as an emerging nanoprobe for specific tumor CT/MR imaging through amplified passive EPR effect.