Poly(amidoamine) Dendrimer-Coordinated Copper(II) Complexes as a Theranostic Nanoplatform for the Radiotherapy-Enhanced Magnetic Resonance Imaging and Chemotherapy of Tumors and Tumor Metastasis.

Abstract

The development of a powerful nanoplatform to realize the simultaneous therapy and diagnosis of cancer using a similar element for theranostics remains a critical challenge. Herein, we report such a theranostic nanoplatform based on pyridine (Pyr)-functionalized generation 5 (G5) poly(amidoamine) dendrimers complexed with copper(II) (Cu(II)) for radiotherapy-enhanced T₁-weighted magnetic resonance (MR) imaging and the synergistic radio-chemotherapy of both tumors and tumor metastasis. In this study, amine-terminated G5 dendrimers were covalently linked with 2-pyridinecarboxylic acid, acetylated to neutralize their remaining terminal amines, and complexed with Cu(II) through both the internal tertiary amines and the surface Pyr groups to form the G5.NHAc-Pyr/Cu(II) complexes. We show that the complexes are able to inhibit the proliferation of different cancer cell lines with half-maximal inhibitory concentrations ranging from 4 to 10 μM and induce significant cancer cell apoptosis. Due to the presence of Cu(II), the G5.NHAc-Pyr/Cu(II) complexes display an r₁ relaxivity of 0.7024 mM^-1 s^-1, enabling effective in vivo MR imaging of tumor xenografts and lung metastatic nodules. Further, under radiotherapy (RT) conditions, the tumor MR imaging sensitivity can be significantly enhanced, and the G5.NHAc-Pyr/Cu(II) complexes enable the enhanced chemotherapy of both a xenografted tumor model and a blood-vessel metastasis model. With the demonstrated theranostic potential of the dendrimer-Cu(II) nanocomplexes without additional agents or elements for RT-enhanced MR imaging and chemotherapy of tumor and tumor metastasis, this novel Cu(II)-based nanohybrids may hold great promise for the theranostics of different cancer types and metastases.