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Inorganic therapeutic nanoparticles for osteoporosis

Periodic Reporting for period 1 - INTO (Inorganic therapeutic nanoparticles for osteoporosis)

Reporting period: 2016-06-01 to 2018-05-31

Osteoporosis is an area of unmet need, clinically and commercially. It is a progressive condition associated with pain and increases in fractures. The EU Mediterranean Osteoporosis Study (MEDOS) and European Vertebral Osteoporosis Study (EVOS) indicated a considerable demand for resources just from fractures caused by osteoporosis. Most drugs inhibit the cells responsible for resorption, but none of them show any effect on osteoblast (OBs) activity in promoting bone formation. Oral administrations of antiresorptive agents have side effects.
The aim here was to benefit 27.5 million people affected by osteoporosis in the European Union (EU) through development of a new nanodrug that will reduce side effects, stimulate new bone growth and neutralise of reactive oxygen species (ROS), which are one of the key triggers of osteoporosis. We demonstrated these therapeutic benefits in porous silica-ceria (MSNs-CeO2) nanoparticles in cell culture.
The interdisciplinary project objectives were to engineer and test novel mesoporous silica nanoparticles (MSNs) containing active inorganic ions, such as iron, zinc, calcium and strontium. The particles will also contain CeO2 nanoparticles (NPs) scavenger radicals that are produced in the osteoporotic process. Each dissolution ion has a therapeutic benefit but our main objective was to select the best composition that will have a direct and rapid impact in osteoporosis treatment. The cargo is not a conventional drug but a sustained delivery of a combination of active inorganic cations and rare earth nanoparticles. The cations take part in cell signaling and the rare earth nanoparticles act as antioxidants. A first step was to develop an accurate sol-gel synthesis route that produces spherical, monodispersed, large surface area, large pore volume MSNs with tuneable composition. Materials characterization (composition, size, shape, porosity) and the dose dependent effect of the nanoparticles on cell response was investigated.
During the first 10 months, the synthesis method for producing MSNs with controlled size and composition (80-250 nm) was developed by modifying the sol-gel Stöber method. A reproducible method was developed and 80.24 ± 11.80 nm spherical MSNs with high surface area (725 m2/g) were used to incorporate therapeutic ions such as cerium, calcium, strontium, zinc and iron and to provide their sustained and controlled release. The process was followed by material characterization (composition, size, shape, amorphous nature and magnetic properties).

From the 8th to the 13th month work focused on the optimisation of the MSNs for cell studies and for understanding how cells take up the particles and what is likely to happen when they do so. Biodegradation and ion release was evaluated in physiological conditions (pH=7.4) and acidic conditions (pH=5.85) which mimicks the environment inside the cells.

From the 12th to 20th month the interaction of the NPs with cells, such as bone growing cells (osteoblasts, OBs) and bone remodeling cells (osteoclasts, OCs) was investigated, including toxicity and internalization (and fate) of the nanoparticles into the cells, which was monitored by TEM and by confocal microscopy on fluorescent labelled NPs. A dose-dependant effect of concentration of NPs on toxicity was identified.
The most promising ceria containing NPs were chosen to test their antioxidant capability in bone growing (MC3T3-E1) cells when the cells were treated with the oxidizing agent t-butyl hydroperoxide (TBHP). They reduced the number of ROS present. Co-cultures of OBs and OSC (RAW264.7) showed that OBs produced new bone matrix while the OSC activity decreased.

The last part of the project (from the 19th to 24th month) included design of the NP delivery system not only for osteoporosis treatment but also for neurodegenerative disease and cancer treatment. The MSNs were found to be a promising carrier for different kind of ions.

To enable technology transfer of the NPs, the Fellow is applying for Faculty positions at prestigious universitiess such as Imperial College London, University College London, King's College London. EPSRC Early Career and Imperial College Research Fellowships are in preparation.
Osteoporosis is a worldwide concern, causing more than 8.9 million fractures per year with a reduced quality of life and disability. The economic burden on health care systems is predicted to increase due to the higher osteoporotic fractures resulting in higher request of medical visits, hospitalizations, and nursing home placements.
A satisfactory treatment for osteoporosis does not exist yet. The unique aspect of the NP system developed in this project is that the cargo delivered by the NPs is not a conventional drug but a combination of active inorganic cations and rare earth nanoparticles that give a combination of bone growth stimulation, bone resorption inhibition and reduction in reactive oxidative species. No side effects are expected and doses can be kept low because the NPs can be delivered locally. The preliminary results obtained during these 2 years will give a future prospective in terms of translation of the inorganic drug into the market for the treatment of osteoporosis. The cost of osteoporosis in the EU, which are predicted to double from €37 billion by 2050, can be decreased and quality of life improved.
The NPs have showed potential for neurodegenerative disease and cancer treatment. These obtained preliminary results are very promising and they can be exploiting for animal studies in order to translate the product in the market.
Confocal image of MC3T3-E1 cells incubated with MSNs-CeO2.