Modular design of multifunctional core-shell tecto dendrimers complexed with copper(II) for MR imaging-guided chemodynamic therapy of orthotopic glioma

Abstract

The development of a novel multifunctional nanoplatform to overcome the blood-brain barrier (BBB), increase diagnostic sensitivity, and improve the therapeutic effects of glioma for precision theranostics remains a serious challenge. Herein, through supramolecular assembly based on the host-guest recognition between β-cyclodextrin (CD) and adamantane (Ad), we developed a modular design approach to generate multifunctional core-shell tecto dendrimers with acetyl termini (M-CSTD.NHAc) for theranostics of orthotopic glioma. In our design, the CSTDs composed of CD-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers as cores and Ad-functionalized G3 PAMAM dendrimers (G3. NH2-Ad) as shells were constructed, in which the G3.NH2-Ad dendrimers acted as standalone modules to be modified with pyridine for copper (Cu(II)) complexation, dermorphin for BBB crossing and arginine-glycine-aspartic acid peptide for glioma targeting, respectively. We show that the formed M-CSTD.NHAc exhibit the good ability to resist protein adsorption, to penetrate BBB and to target glioma cells in vitro, and the created M-CSTD.NHAc/Cu(II) complexes can react with self-supplying hydrogen peroxide inside the glioma cells to produce hydroxyl radicals through Fenton-like reaction to cause lipid peroxidation and cell death. With the displayed r1 relaxivity of 0.7331 mM−1s−1, the developed M-CSTD.NHAc/Cu(II) complexes are able to act as an intelligent platform to cross the BBB and target orthotopic glioma for MR imaging and chemodynamic therapy of glioma after intravenous injection. The developed modular design strategy to produce multifunctional CSTDs may be extended to prepare other nanoplatforms for various precision medicine applications.