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Q&A: UTHSC's Mauro Ferrari on Developing a Multi-Stage siRNA Delivery System


Mauro Ferrari

Professor/chair, nanomedicine and biomedical engineering, University of Texas Health Science Center; Professor, experimental therapeutics, MD Anderson Cancer Center


• Professor, nanomedicine, University of Texas Health Science Center — 2006-2009
• Adjunct professor, biochemistry/molecular biology, University of Texas Medical Branch — 2006-2008
• Professor, biomedical engineering, Ohio State University — 1996-2006
• Professor, internal medicine, Ohio State University — 1999-2002
• Assistant professor, materials science/engineering, University of California, Berkeley — 1991-1996
• PhD, mechanical engineering, University of California, Berkeley — 1989
• MS, mechanical engineering, University of California, Berkeley — 1987

Earlier this month, researchers from the University of Texas Health Science Center's Department of Nanomedicine and Biomedical Engineering reported in Cancer Research on the development of a systemic siRNA delivery system that achieved sustained delivery of the RNAi payload in two orthotopic mouse models of ovarian cancer.

The system is specifically composed of mesoporous silicon particles loaded with neutral nanoliposomes that contained siRNAs targeting the oncoprotein EphA2. The researchers found that the system resulted in EphA2 gene silencing for at least three weeks in the mice after a single intravenous injection.

Additionally, treatment resulted in reduced tumor burden, angiogenesis, and cell proliferation with no significant changes in serum chemistries or in proinflammatory cytokines, according to the paper.

This week, RNAi News spoke with Mauro Ferrari, the study's senior author, about the findings and the delivery technology.

Let's start with on overview of your research.

We are fortunate that we have the first department in the nation, probably the world, in nanomedicine in a medical school. We have a large operation — about 100 people — working along four different research and development platforms. The one we're talking about [for this interview] is the platform that pertains to systemic delivery of small interfering RNAs.

The way we deliver those systemically is through [what] we call the multi-stage vector system. The whole notion of the multi-stage vector system has to do with the fact that, in general, for conventional drugs, for biotechnological drugs, for siRNAs, or for anything else … the trip from the point of systemic injection to the intended location of arrival, the target … is an extremely complicated one.

Of course, science has been focusing on the biological recognition, the specificity of delivery, if you will. However, the reality is that [this] is just a small part of the story. The dominant part of the story is what we call biological barriers, which are all the physiological and pathological defenses that the body puts up against invasion from foreign attackers, as drugs or nanoparticles or siRNAs are seen.

The list of these include enzymatic degradation; the [blood] vessel walls through which [molecules must pass] to get to a tumor; the tumor interstitium … the cell membrane … the vesicles that take up things from outside of the cell and bring them [inside]; and perhaps even the nuclear membrane.

There are many of those barriers that come one after the other, so the multi-stage systems we have are designed to address this sequence of biological barriers [in] multiple stages. [This approach is] pretty much along the lines of what NASA did to get the first man on the moon; the trip is very difficult and long, and has very distinct phases, so you're going to have a rocket that carries a second stage [with] a landing module. That is the nature of our multi-stage systems.

In [the Cancer Research paper], we have disclosed a system [comprising] a carrier that is made of fully degradable, completely harmless, nanoporous silicon that we make through processes that are well-known in the field of microelectronics — processes collectively known as [photolithography].

This first stage is designed to deploy and concentrate, until full degradation occurs, on the blood vessel walls that we are targeting, and other places in the body, so that they act as intravascular depots. This is the first example [of this approach]. … The depots that exist in the literature and the clinic are subcutaneous. People will inject pellets of biodegradable material under the skin or in the muscle, and as they degrade … the active [ingredient] gets released. But … it doesn't get released into the bloodstream … so especially for biological drugs … the trip from the muscle, [for example], into the blood vessels is impossible most of the time.

This created the need for a blood vessel wall depot, which is what we have accomplished.

[In addition to] the nanoporous silicon particles … the second stage [of the system involves] special families of nanoscale lipid vesicles — let's call them nanoliposomes. They are neutral, they are not pegylated so they fit into the nanoporous particle [of the first stage], and inside of them we have the siRNAs of interest.

In [the work described in Cancer Research], we have chosen an siRNA that targets EphA2, which is a kinase receptor that is over-expressed in many cancers, including ovarian cancer, and is involved in proliferation, dysregulation, and angiogenesis.

In the article, we have shown [for the first time the creation] of an intravascular depot, [as well as] that a single injection of these particles silence the [target] gene for a period as long as three weeks from the moment of injection, which is unthinkable. The third [achievement is that] for the three weeks, there is clear evidence of therapeutic efficacy in that we had tumor shrinkage and reduction in objective measures of both proliferation and angiogenesis.

Keep in mind that … we had tumor shrinkage without concurrent chemotherapy. Of course, nobody would ever dream in this day and age to [treat a patient] with siRNA alone; you always do siRNA [treatment] with concurrent chemotherapy. In this case, we did siRNA alone and we have tumor shrinkage. We think this is a major achievement.

In light of these encouraging data, what is the next step in developing the multi-stage system?

Along the ovarian [cancer] line, which is something we are very interested in, we are looking at taking this … to the clinic as quickly as possible. So we are moving that into larger animals … and we are doing that in conjunction with a company [I co-founded] called Leonardo Biosystems, [which is minority owned by Calando Pharmaceuticals parent firm Arrowhead Research].

With them and the funding the company has attracted, we are looking at moving that into the conventional chain of larger animals and non-human primates. At the same time, we are going to be looking at [adding the siRNA drug] to chemotherapeutic regimens to see if we can increase their therapeutic efficacy.

[And] we are going to be looking at the delivery of … different siRNAs … for different indications. When we published the article in Cancer Research, we received dozens of requests from many different laboratories worldwide asking for us to deliver their siRNAs. Many of these requests are very valuable and come from the world's best groups. We are certainly hoping to be able to field these requests.

But in order to be able to do that, we need to expand … [the system's] production platform. That's what we're getting ready to do … [so that we can] provide this delivery platform to anybody of quality that will ask. But I cannot do that with my current cadre of postdocs and technicians; I need to multiply them probably by ten.

Is that something that will be handled in the lab, or will Leonardo start providing that service?

As long as we are staying at the rodent level, as long as we need to do the fundamental exploratory tailoring and lab-level tinkering that is necessary to do proof-of-principle validation, the suitable place to do that will be at the university. Anytime things escalate to the level that you need to do FDA-caliber experiments, we cannot do that from a university lab and we will involve the company.

Is that arrangement already in place? Does Leonardo have commercial rights to the delivery platform?

Leonardo is not ready yet to provide multi-stage vectors to research groups worldwide — this will require the building of additional infrastructure. [The company] does have commercial rights to the delivery platform, having acquired them from the intellectual property owner, the University of Texas Health Science Center in Houston.

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