Aiming to improve upon existing bone-growth agents, a team from Louisiana State University is developing a light-activated nanoparticle for the targeted delivery of microRNA mimics involved in bone and blood vessel growth.
Supporting the work is a five-year National Science Foundation grant worth $400,000 in its first year.
In clinical settings, bone morphogenetic proteins are used to trigger bone growth for a variety of applications such as spinal fusion surgery or the treatment of fractures. However, they carry certain risks including the possibility of heterotopic ossification, a condition where bone forms in unintended, non-skeletal areas, according to Dan Hayes, an LSU nanomaterials researcher who is leading the NSF project.
To address this, Hayes and his colleagues are developing a nanoparticle system for delivering bone-forming miRNAs that is only active in areas exposed to certain light so that the drug would have no effect in areas of the body where bone growth is not wanted.
A first-generation version of the system consists of silver nanoparticles decorated with thiol-terminated photolabile antisense oligonucleotides. As reported last month in ACS Nano, the nanoparticles are taken up into cells via endocytosis and, when a specific wavelength of ultraviolet light is applied to them, photocleavable linkers binding the oligos to the particle are broken and the payload is released into the cytosol.
Using antisense oligos against intracellular adhesion molecule-1 as a proof of concept, Hayes and his team showed that the approach could be used to knock down target gene expression in vitro.
Encouraged by the findings, Hayes lab is now aiming to swap out the antisense molecules for mimics of osteogenic and angiogenic miRNAs in order to develop a compound that can be used for the same applications as bone morphogenetic proteins — growing bone and vascularizing it — but give a clinician more control over when and where the agent is active.
“It would only be active where we turned it on [with light], so it wouldn’t matter if it floated away” to non-targeted regions of the body, Hayes said.
Specifically, the team is looking a mimics of miR-148b, which has been shown to induce osteogenesis in mesenchymal stem cells, as well as miR-126, -132, and -92a, all of which are implicated in blood vessel formation.
According to Hayes, he and his team have already shown that a synthetic version of miR-148b, when joined to the nanoparticle, can promote progenitor cells to form bone. With the help of the NSF grant, they are now advancing that work into animal models, and are beginning to test the angiogenic nanoparticles in vitro.
Notably, the investigators do not use the mimic of the full miRNAs, he said, instead opting for a truncated version that maintains gene-silencing activity. By using a smaller mimic, a greater number of active molecules can be joined to the nanoparticle compared with full-length miRNAs.
“The shortest active region we can use allows us to pack more [payload] onto the particle,” Hayes said. “We get more bang for our buck.”
In addition to the planned animal and cell culture experiments, the NSF grant will support the further optimization of the nanoparticle system, he said.
A key concern is that, in its current form, the nanoparticle requires exposure to UV light in order to release the payload, which carries potential health risks. “We want to move that further into the visible range, further away from the blue,” he said.
Additionally, the funding will help in the development of cost-effective fabrication processes for the delivery system.
To date, “we’ve made substantial strides in making this a more robust manufacturing-friendly process,” he said. “The particle can be made at very high densities in a stable form.
“We’ll continue to make more with the money that’s been provided by the NSF.”
The grant runs from March 15 until Feb. 28, 2018.