MnO2-gated Nanoplatforms with Targeted Controlled Drug Release and Contrast-Enhanced MRI Properties: from 2D Cell Culture to 3D Biomimetic Hydrogels

Abstract

Multifunctional nanomaterials combining diagnosis and therapeutic properties have attracted a considerable attention in cancer research. Yet some important challenges are still to be faced, including an optimal coupling between these two types of properties that would be effective within complex biological tissues. To address these points, we have prepared novel nanoplatforms associating controlled drug delivery of doxorubicin and Magnetic Resonance Imaging (MRI) contrast-enhancement that exhibit high specificity towards cancer cells compared to normal cells and evaluated them both in 2D cultures and within 3D tissue-like biomimetic matrices. Methods: Nanoplatforms were prepared from hollow silica nanoparticles coated with MnO2 nanosheets and conjugated with the AS1411 aptamer as a targeting agent. They were fully characterized from a chemical and structural point of view as well as for drug release and MRI signal enhancement. Standard two-dimensional monolayer cultures were performed using HeLa and Normal Human Dermal Fibroblasts (NHDF) cells to testify targeting and cytotoxicity. Cellularized type I collagen-based hydrogels were also used to study nanoparticles behavior in 3D biomimetic environments. Results: The as-established nanoplatforms can enter HeLa cells, leading to the dissociation of the MnO2 nanosheets into Mn 2+ that enhanced T1 magnetic resonance signals and concomitantly release doxorubicin, both effects being markedly more significant than in the presence of NHDFs. Moreover, particles functionality and specificity were preserved when the cells were immobilized within type I collagen-based fibrillar hydrogels. Conclusion: The use of MnO2 nanosheets as glutathione-sensitive coatings of drug loaded nanoparticles together with surface conjugation with a targeting aptamer offers an effective strategy to obtain efficient and specific nanotheranostic systems for cancer research, both in 2D and 3D. The here-described tissue-like models should be easy to implement and could constitute an interesting intermediate validation step for newly-developed theranostic nanoparticles before in vivo evaluation.