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 Mn2+ 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.

Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

“…As an alternative, manganese oxide (MnO) NPs provide the advantage over iron oxide in that they can provide switchable, bright contrast on T 1 MRI due to the paramagnetic properties of the Mn 2+ ion. Our group and other studies have shown that intact MnO NPs are in an “OFF” state and create minimal T 1 MRI signal due to the Mn 2+ ions being tightly bound and inaccessible to the surrounding water molecules [ 5 – 10 ]. In acidic media, MnO dissolves to form Mn 2+ , which coordinates with water molecules to decrease T 1 and produce a positive MRI signal, thus turning “ON” MRI contrast [ 5 – 10 ].…”

3D Cell Culture—Can It Be As Popular as 2D Cell Culture?

“…The larger the pores, the larger the size of protein molecules that can pass through, and the faster the material metabolism. [ 169 ] A hydrogel itself can also be loaded with drugs, [ 170,171 ] biological factors, [ 172,173 ] and other substances [ 174 ] during the cultivation process, and they are slowly released into the cultivation system. During the synthesis of hydrogel materials, chemical bonds or covalent bonds are used to access drug groups or protein groups, which can better control the release of drugs.…”

Assessment of spin-lattice T1 and spin-spin T2 relaxation time measurements in breast cell cultures at 1.5 Tesla as a potential diagnostic tool in vitro

“…Cells from the bioreactor were transferred to tubes to increase their concentration in a small volume. There are many studies in the literature that discuss measuring the relaxation time of cell cultures [6][7][8][9][10]. To determine the T 1 time, the study was carried out in the T 1 FSE sequence.…”

“…If we assume that for calculations we will always take the same area in the image, and the result of the test will shift the examined structures, and the ROI will accidentally find adjacent tissues not covered by measurement in other sequences, this may lead to falsification of the IS value and thus increase the uncertainty of the relaxation time measurement result. Analysing the work of various authors, many solutions can be found to increase the speed of obtaining the T 1 times [7][8][9][11][12][13][14]. The vast majority of them, however, essentially use SR or IR methods.…”