In the field of the synthesis and functionalization of inorganic nano-objects for biomedical applications, most future researches aim at developing multifunctional theranostic NPs (i.e.) that include simultaneously therapeutic and diagnostic/imaging functions allowing to envision image-guided therapy.
The design of NPs for nanomedecine aims at leveraging various challenges in this domain :
- targeting, imaging and treating cancer cells which are addressed by the design of theranostic dendronized IO NPs
- developing drug delivery approaches combined to these imaging and treatment approaches which can be solved by the design of functional mesoporous silica
- extending the potential of such approaches towards other medical issues (renal failure through peritoneal dialysis, etc..)
1. Theranostic dendronized iron oxide nanoparticles
For biomedical applications, a key point is the design of an organic coating at ferrite NPs surface which is also challenging. Additionally to imaging, cell-targeting or drug release functions, there must be also functions preventing NPs from agglomeration in a physiological environment and favoring their biodistribution and bioelimination. The organic coating and its anchoring at the surface of NPs has to be tailored to prevent NPs’ opsonisation (the non-specific fouling of plasma protein) once entering the blood circulation and subsequent uptake by the reticuloendothelial system (RES). The final average hydrodynamic sizes of functionalized NPs has to be in the range of 10–100 nm for favoring high blood-circulation time necessary for in vivo delivery. Many synthetic and natural polymers have been used to cover the surface of iron oxide NPs however they shown various limitations (lacks of robustness, diminished impact of the core superparamagnetic properties).
2. Drug delivery, imaging and hyperthermia using functional mesoporous silica platforms
This part presents potential applications of silica engineered nanoplatforms for drug delivery, hyperthermia and imaging for cancer treatment but also their use as components of scaffolds for tissue engineering.
Different strategies were developed these last years :
- Drug delivery through fully degradable protein nanocarriers
- In vivo bio-imaging from functional mesoporous silica
- Magnetic hyperthermia, MRI and drug delivery from magnetic core-shells
- Photothermia and drug delivery from carbon@MS materials
A. Protein nanoparticles for drug delivery to cancer cells
The approach using MS as sacrificial templates, is a key strategy to form drug-loaded nanocapsules. The challenge was to move from the usual micron-scale to the sub-micron-scale. Here, we achieved the formation of homogenous HSA nanocapsules (30-60 nm size) loaded with and antitumor drug, doxorubicine (DOX) having a high drug payload (close 80% wt./protein NPs). The drug delivery from such nanocapsules was evaluated in multicellular tumor spheroid (MCTS) models made from Huh-7 (hepatocarcinoma) cells in coll. with Prof. F. Meyer (INSERM U1121). Data shown that such MCTS mimicking metastasis, exhibited a strong inhibition that can be related to a massive cancer cell death due to the antitumor drug release.
Templated protein capsules as drug delivery systems and evaluation in hepatocarcinoma spheroid cancer cell models. BBA – Gen. Subj. 2019, 1863, 332-341.
B . Fluorescent stellate silica probes for invivo bioimaging
In this work, we reported on an original strategy for the hierarchical assembly of novel well-dispersible and biocompatible luminescent nanoplatforms. They consist in stellate large pore MS encapsulating InP/ZnS QDs with a very high efficiency, which are then protected by performing two different methods based either on an additional inorganic coating of small pore MS shell, or a tight polymer capping.
These luminescent nanoplatforms were investigated in vitro and in vivo in biological studies in coll. with Dr S. Harlepp and Dr J. Goetz (INSERM U1109). As visualized by in vivo confocal macroscopy imaging within zebrafish (ZF) translucent embryos, these nanoplatforms are shown to rapidly extravasate from blood circulation to settle in neighboring tissues, ensuring a remanent fluorescent labelling of ZF tissues in vivo. Finally, such fluorescent and hybrid STMS composites are envisioned as novel luminescent nanoplatforms for in vivo fluorescence tracking applications and offer a versatile degree of additional functionalities (drug delivery, incorporation of magnetic/plasmonic core).
C. Theranostic magnetic core-mesoporous silica shell
In this part, we developed magnetic core-MS shell having various core size or pore morphology (small SPMS vs large STMS pores) for investigating possibilities to combine MRI, magnetic hyperthermia and drug delivery in cancer cells.
In a first work, Doxorubicin-loaded IO@SPMS and capped with serum albumin were shown to achieve drug release to hepatocarcinoma (Huh-7) spheroid cells (coll. with Prof. F. Meyer INSERM U1121) and T2-weighted MRI.
In a second work, using a bigger core suitable for magnetic hyperthermia applications covered with larger pore silica shell, we grafted QDs to the large pore and we capped the surface with proteins. This resulted in a multifunctional magnetic core-shell nanocomposite (100 nm size) displaying bimodal imaging (MRI and fluorescence) coupled with magnetic hyperthermia. The NPs under AMF allowed to kill Hela cancer cells in combination of free antitumor drugs using only a low amount of NPs. (Coll. Dr M. Tasso, CONICET, Univ La Plata, Argentina)
Fluorescent and Magnetic Stellate Mesoporous Silica for Bimodal Imaging and Magneic Hyperthermia. Appl. Mater. Today, 2019,16, 301-314
D. Carbon@silica based- materials for photothermia and drug delivery
In this work, the design of a new class of drug releasing carbon-based materials based on carbon nanotubes (CNTs) and few layer graphene (FLGs) was achieved for drug delivery or tissue engineering applications. MS coatings strategies were applied around two C-based materials with a great control over the shell thickness. Drug loading onto these C@MS materials was investigated with varying parameters (drug concentration, surface modification) and showed a great capacity of drug payload (≥ 100%wt). Regarding drug release, we showed that a fraction of drugs could be released with different local or remote stimuli applied on such composites: under low acidic conditions (pH ca. 4), or by applications of a NIR light. At least, such drug loaded C@MS NPs were loaded in an hydrogel and were evaluated in contact to D2A1 cell line (mouse breast carcinoma tumor). Results indicate that such NPs are able to kill cancer cells by photothermic effect under NIR light and ensure drug release activated by photothermal effect.