Apollo Biosciences, a five-year-old company developing a silica-based delivery system invented at the University of Vermont, has expanded its focus beyond traditional chemotherapeutic agents to siRNA.
Apollo is keeping its eye on the cancer market with its RNAi efforts, however, and is ramping up in vitro and in vivo studies examining whether its so-called Pharmefex technology can be used to deliver siRNA targeting pathways associated with malignant mesothelioma.
The Pharmefex technology is essentially acid-prepared mesoporous silica, or APMS, that has been modified with tetraethylene glycol to enhance cellular uptake, Chris Landry, Apollo’s co-founder, CSO, and UVM professor, told RNAi News this week.
“We have a prep that involves surfactants and other co-solvents, [which] create a material that is spherical and has a particle diameter of about 1 or 2 microns,” he said. “The really unique thing about this solid is that it is very porous — it has a huge internal pore volume and a lot of internal surface area.”
Landry said that initially he and Apollo co-founder James Hickey were exploring a number of possible applications for Pharmefex, including filtration.
“But based on some of the other research areas I was working on wearing my academic hat, we decided to start working on some drug- and molecular-delivery applications in biological systems,” he said.
”The idea is that if we pre-load [the APMS] particle with a chemotherapeutic [agent], because there is so much internal volume, we could be delivering a much more effective dose of the chemotherapeutic” while limiting unnecessary exposure to the drug before it gets into target tissue.
Apollo’s most developed programs involve using Pharmefex to deliver doxorubicin and dacarbazine. But work at UVM with single-stranded, double-stranded, and plasmid DNA led Landry and collaborators at UVM to consider the possible RNAi applications of the technology.
“We think we have methods where we can get DNA [into cells] and release it slowly over time [using this technology] to enhance the uptake and release,” Landry said. Discussions about these findings with Brooke Mossman, a UVM professor and Apollo consultant, eventually led to looking into whether the delivery technology could be used to deliver therapeutic siRNA.
Currently, Apollo is “on the front end” of its RNAi efforts, refining its siRNA constructs and examining different pore diameters and conditions required to load them into APMS, Landry said.
But the company’s efforts are accelerating following the receipt of a two-year, $200,000 grant from the National Cancer Institute.
According to the grant’s abstract, the funding will be used to develop siRNA and shRNA constructs targeting the ERK1/2 and ERK5 pathways, which are critical to malignant mesothelioma cell proliferation and chemoresistance.
“There is interest from [industry] but I think they probably want to see a little more [data] about the route of administration before they would go further.”
The grant project also includes optimizing APMS for uptake by human malignant mesothelioma cells, and then testing whether the RNAi constructs combined with the delivery agent can down-regulate the ERK1/2 and ERK5 pathways in vitro. Follow-on research is expected to involve in vivo work in a mouse xenograft model of malignant mesothelioma.
“Part of the funding from this grant will also be used to hire a technician and, on the UVM side, a grad student to start working on this project,” Landry added.
Landry also hopes that additional financing will become available through partnerships between Apollo and industry players interested in the Pharmefex technology, but he noted that it might be a while before any deals are signed.
“There is interest from [industry] but I think they probably want to see a little more [data] about the route of administration before they would go further,” he said. “With silica, people tend to back off [because of toxicity concerns] so we have to do [additional] studies even though we have some preliminary studies showing there is no immune response in vivo and so on.”
Earlier this year, Landry and Mossman published research showing that APMS could be delivered to lung epithelial and mesothelioma cells without triggering any adverse reactions.
According to that data, “when injected intrapleurally in mice, [tetraethylene glycol-modified APMS] were taken up by both CD45-positive and -negative cells of the diaphragm, lung, and spleen, whereas APMS administered by the intranasal route were predominantly in lung epithelial cells and alveolar macrophages. After intrapleural or intranasal administration, APMS were non-immunogenic and non-toxic as evaluated by differential cell counts and lactate dehydrogenase levels in bronchoalveolar and pleural lavage fluids.”
However, “we obviously need to do longer time courses and get some more convincing data before people dip their toes in the pool,” Landry said. ”But I think that’s not so far away; we could have that data in 6 to 12 months.”