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Q&A: MD Anderson's Anil Sood on HDL Cholesterol for siRNA Delivery

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Sood_Anil.jpgName:
Anil Sood

Position:
Professor, gynecologic oncology/cancer biology, University of Texas MD Anderson Cancer Center

Background:
• Fellow, gynecologic oncology, University of Iowa Hospitals and Clinics — 1995-1998
• Residency, obstetrics/gynecology, University of Florida —1991-1995
• MD, University of North Carolina, Chapel Hill — 1991
• BS, pre-medicine, Davidson College — 1986

Reseachers from MD Anderson Cancer Center this month published a report in Neoplasia showing that high-density lipoprotein — the so-called good cholesterol — could be formulated as a delivery vehicle for therapeutic siRNAs in cancer models.

In the paper, reconstituted HDL nanoparticles were loaded with siRNAs against two key cancer genes and administered intravenously into orthotopic mouse models of cancer, and were able to effectively silence the expression of their targets.

This week, Gene Silencing News spoke with the study's senior author Anil Sood about the findings.

You were using HDL to deliver siRNA. What led led you to look at it for this application?

There have been a lot of nanoparticle systems that investigators have focused on that, at the end of the day, you just can't develop for therapeutic applications because they end up being quite toxic. We are interested in using systems that are not only biocompatible and efficient, but are safe … and have potential for human use. This particular carrier met those criteria on all accounts. As we worked with it, we [also] uncovered a unique mechanism by which it can deliver quite selectively, so we pursued it.

And this mechanism makes it particularly amenable for siRNA delivery to cancer cells?

Exactly. HDL is something that is present in our bodies — it's the good cholesterol. It gets taken up by a receptor called SR-B1, [or scavenger receptor type B1]. We were really quite intrigued that, for whatever reason, most cancer cells have high levels of this receptor. We haven't had a chance to look into what that means functionally, but for delivery purposes, [this characteristic] serves us rather well.

How did you develop the vehicles? You had to tweak the HDL a bit, right?

Absolutely. HDL absorbs things and gets bigger, becoming unstable. So we came up with a formulation that allows it to remain stable in the body so that we could use it for delivering drugs or, in this instance, siRNA.

Once the particles were developed, how did you go about testing them?

We [first] looked for SR-B1 expression in a variety of cancer cells, including ovarian cancer cells, colorectal, breast, pancreatic, and so on. Once we optimized the formulation, the next steps were to assess whether or not this delivery method could allow a high level of efficiency in terms of siRNA delivery. We tested that using a fluorescent dye and found that, indeed, we could get very good delivery into tumors.

Following that, we selected a couple of targets [associated with cancer growth and metastasis] that we view as important because there are really no other ways of targeting these genes. [Specifically,] we went after [signal transducer and activator of transcription 3], as well as focal adhesion kinase.

We carried out a number of experiments to assess [the approach's] therapeutic value.

And those were done in mouse models of ovarian and colorectal cancer?

Exactly.

What sort of inhibition were you seeing?

We could achieve greater than 80 percent knockdown in the tumor following delivery of siRNA.

Did you observe any kind of therapeutic benefit?

Yes. With STAT3 siRNAs, we saw a reduction in both ovarian cancer growth and really remarkable results with colon cancer models that are metastatic to the liver. … For many [cancer] targets, I feel that they would be better [addressed with siRNAs] in combination with a cytotoxic [agent]. So we also assessed combinations with chemotherapy, and that worked very well.

Was there any issue with delivery to non-tumor cells?

This receptor is expressed in the liver, so we know we're going to see uptake there. Apart from that, we looked at several other organs and really didn't see much in terms of uptake.

So what are the next steps?

The next steps are to characterize a formulation we can move forward with in terms of clinical development. We're going to work with the [National Cancer Institute's] nanotechnology characterization lab because we feel this is a very important platform to develop further. We're going to be working with them to assess all of the kinds of studies that would be required to bring [this delivery technology] into a clinical study.

Do you anticipate this would require a commercial partner?

Some type of partnership with industry would be highly valuable to us because in academia, we just don't have the kind of money required to scale this up and to carry out a phase I clinical trial. Our preference would be to see if we could partner up, but [in the meantime] we're going to continue to develop this technology toward the clinical arena.

When we spoke last (GSN 8/17/2006), you had just published data on a liposomal delivery of siRNA against focal adhesion kinase in ovarian cancer. What's the status of that work?

The DOPC technology itself is in clinical trials for an oligonucleotide in leukemia patients. For the siRNA [application], we have completed all of the safety studies. We are in a position to find funding to bring that to a phase I trial.

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