Tag Archives: nanotherapeutics

Magical nanobots at University of Florida kill (almost) 100% of Hepatitis C virus—in the lab

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I’ve always preferred the term nanobots but the folks at the University of Florida are calling them nanorobots, from the July 16, 2012 news item on phys.org,

University of Florida researchers have moved a step closer to treating diseases on a cellular level by creating a tiny particle that can be programmed to shut down the genetic production line that cranks out disease-related proteins.

In laboratory tests, these newly created “nanorobots” all but eradicated hepatitis C virus infection. The programmable nature of the particle makes it potentially useful against diseases such as cancer and other viral infections.

The research effort, led by Y. Charles Cao, a UF associate professor of chemistry, and Dr. Chen Liu, a professor of pathology and endowed chair in gastrointestinal and liver research in the UF College of Medicine, is described online this week in the Proceedings of the National Academy of Sciences.

The news item originated with a July 16, 2012 news release from the University of Florida which goes on to explain how the researchers succeeded,

The Holy Grail of nanotherapy is an agent so exquisitely selective that it enters only diseased cells, targets only the specified disease process within those cells and leaves healthy cells unharmed.

To demonstrate how this can work, Cao and colleagues, with funding from the National Institutes of Health, the Office of Naval Research and the UF [University of Florida] Research Opportunity Seed Fund, created and tested a particle that targets hepatitis C virus in the liver and prevents the virus from making copies of itself.

Hepatitis C infection causes liver inflammation, which can eventually lead to scarring and cirrhosis. The disease is transmitted via contact with infected blood, most commonly through injection drug use, needlestick injuries in medical settings, and birth to an infected mother. More than 3 million people in the United States are infected and about 17,000 new cases are diagnosed each year, according to the Centers for Disease Control and Prevention. Patients can go many years without symptoms, which can include nausea, fatigue and abdominal discomfort.

Current hepatitis C treatments involve the use of drugs that attack the replication machinery of the virus. But the therapies are only partially effective, on average helping less than 50 percent of patients, according to studies published in The New England Journal of Medicine and other journals. Side effects vary widely from one medication to another, and can include flu-like symptoms, anemia and anxiety.

Cao and colleagues, including graduate student Soon Hye Yang and postdoctoral associates Zhongliang Wang, Hongyan Liu and Tie Wang, wanted to improve on the concept of interfering with the viral genetic material in a way that boosted therapy effectiveness and reduced side effects.

The particle they created can be tailored to match the genetic material of the desired target of attack, and to sneak into cells unnoticed by the body’s innate defense mechanisms.

Recognition of genetic material from potentially harmful sources is the basis of important treatments for a number of diseases, including cancer, that are linked to the production of detrimental proteins. It also has potential for use in detecting and destroying viruses used as bioweapons.

The new virus-destroyer, called a nanozyme, has a backbone of tiny gold particles and a surface with two main biological components. The first biological portion is a type of protein called an enzyme that can destroy the genetic recipe-carrier, called mRNA, for making the disease-related protein in question. The other component is a large molecule called a DNA oligonucleotide that recognizes the genetic material of the target to be destroyed and instructs its neighbor, the enzyme, to carry out the deed. By itself, the enzyme does not selectively attack hepatitis C, but the combo does the trick.

“They completely change their properties,” Cao said.

In laboratory tests, the treatment led to almost a 100 percent decrease in hepatitis C virus levels. In addition, it did not trigger the body’s defense mechanism, and that reduced the chance of side effects. Still, additional testing is needed to determine the safety of the approach. [emphases mine]

This treatment builds on some previous research,

The UF nanoparticle design takes inspiration from the Nobel prize-winning discovery of a process in the body in which one part of a two-component complex destroys the genetic instructions for manufacturing protein, and the other part serves to hold off the body’s immune system attacks. This complex controls many naturally occurring processes in the body, so drugs that imitate it have the potential to hijack the production of proteins needed for normal function. The UF-developed therapy tricks the body into accepting it as part of the normal processes, but does not interfere with those processes.

Since there’s no mention of human clinical trials, I’m guessing that we are at least 10 years from seeing this therapeutic agent on the market.

After drafting this post yesterday (July 17, 2012) and while waiting to post it today, I found Dexter Johnson’s July 17 2012 posting where he makes some important points about this research (Note: I have removed a link),

Of course, this is a long way from becoming a treatment anytime soon. A major caveat is that the use of nanotreatments for the targeting and destroying of abnormal cells like cancer cells is always problematic since those cells are “still us” as George Whitesides noted some time back.  It’s always a bit of a tricky business to make sure that nanoparticles are targeting those biological processes within us that we want stopped and not the ones we want to keep.

Dexter goes on to comment about using the terms ‘nanobots’ or ‘nano robots’; he’s less sanguine about it than I am.

Nanodiagnostics: a roundtable at Kavli and new report from Cientifica

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The Kavli Foundation, based in California, held a roundtable discussion on ‘Fighting Cancer with Nanotechnology‘ which focused largely on diagnostics and drug delivery. According to a March 14, 2012 news item on Nanowerk, the four participants were:

  • Anna Barker – Former Deputy Director of the National Cancer Institute (NCI) and current Director of Arizona State University’s Transformative Healthcare Networks;
  • Mark E. Davis – Professor of Chemical Engineering at the California Institute of Technology (Caltech), and a member of the Experimental Therapeutics Program of the Comprehensive Cancer Center at the City of Hope;
  • James Heath – Professor of Chemistry at Caltech and a founding Board member of Caltech’s Kavli Nanoscience Institute;
  • Michael Phelps – Norton Simon Professor, and Chair of Molecular and Medical Pharmacology at the University of California Los Angeles.

The researchers discussed how nanotechnology holds the promise of revolutionizing the way medicine wages war against cancer, from providing new ways to combine drugs to delivering gene-silencing therapeutics for cancer cells. [emphasis mine]

Yet again, war has been used as a metaphor for healing. I particularly appreciate the way ‘revolution’, which resonates with US audiences in a very particular way, has been introduced.

The discussion features diagnostics,

JAMES HEATH: That is certainly an important application. A typical diagnostic test measures only a single protein. But the nature of cancer—even a single cancer type—is that it can vary significantly from patient to patient. The implication is that there is probably not a single protein biomarker that can distinguish between such patient variations. Even to confidently address a single diagnostic question may take measuring several protein biomarkers. Discovering the right biomarkers is extremely challenging—you might have 300 candidate biomarkers from which you want to choose just six, but you will likely have to test all 300 on a very large patient pool to determine the best six. That’s tough to do with existing technologies because each protein measurement requires a large sample of blood or tumor tissue, and each measurement is time-consuming, labor intensive and expensive. With some of the emerging nanotechnologies, a large panel of candidate protein biomarkers can be rapidly measured from just a pinprick of blood, or a tissue sample as small as a single cell. This allows one to accelerate the development of conventional diagnostic tests, but it also opens up the possibilities for fundamentally new diagnostic approaches. These are opportunities that nanotech is bringing into play that simply weren’t there before.

Here’s one of my favourite comments,

MICHAEL PHELPS: Yes. All of us developing therapeutics want to have a transparent patient—to see where the drug goes throughout all tissues of the body, whether it hits the disease target in a sufficient dose to induce the desired therapeutic effect on the target, and where else the drug goes in the body regarding side effects. [emphasis mine] PET [positron emission tomography ‘scan’] can reveal all this. For this reason almost all drug companies now use PET in their discovery and development processes.

I suspect Phelps was a bit over enthused and spoke without thinking. I’m sure most doctors and researchers would agree that what they want is to heal without harm and not transparent patients. That’s why they’re so excited about nanotechnology and therapeutics, they’re trying to eliminate or, at least, lessen harm in the healing process. It would be nice though if they get past the ‘war’ metaphors and dreams of transparent patients.

I found the comments about the US FDA (Food and Drug Administration), pharmaceutical companies and biotech startups quite interesting,

ANNA BARKER: These challenges are mostly related to perception and having the tools to demonstrate that the agent does what you say it does. It’s more difficult for nanotherapeutics than for other drugs because they employ a new set of technologies that the FDA is more guarded about approving. The FDA is responsible for the health of the American public, so they are very careful about putting anything new into the population. So the challenges have to do with showing you can deliver what you said you were going to deliver to the target, and that the toxicity and distribution of the agent in the body is what you predicted. You have to have different measures than what is included in the classic toxicology testing packages we use for potential drugs.

…

MARK DAVIS: There’s so much cool science that people want to do, but you’re limited in what you can do in patients for a number of reasons. One is financial. This area is not being pushed forward by big Pharma, but by biotech companies, and they have limited resources. Secondly, the FDA is still learning about these innovations, they can limit what you are allowed to do in a clinical trial. For example, when we did the first clinical trial with a nanoparticle that had a targeting agent enabling it to latch onto a specific receptor on cancer cells and a gene silencing payload, we realized it would be important to know if patients have this receptor and the gene target of the payload to begin with. Prebiopsies from patients before testing the nanotherapeutic on them to see if the tumor cells had this receptor and gene target in abundance would have been helpful. However, in this first-in-man trial, the FDA did not allow required biopsies, and they were performed on a volunteer-basis only.

It is a fascinating discussion as it provides insight into the field of nanotherapeutics and into the some of the researchers.

On the topic of nanodiagnostics but this time focusing on the business end of things, a new report has been released by Cientifica. From the March 13, 2012 press release,

Nanodiagnostics will be a $50-billion market by 2021; Cientifica’s “Nanotechnology for Medical Diagnostics” looks at emerging nanoscale technologies

…

Following on from Cientifica’s Nanotechnology for Drug Delivery report series, “Nanotechnology for Medical Diagnostics,” a 237-page report, takes a comprehensive look at current and emerging nanoscale technologies used for medical diagnostics.

Areas examined include quantum dots, gold nanoparticles, exosomes, nanoporous silica, nanowires, micro- and nanocantilever arrays, carbon nanotubes, ion channel switch nanobiosensors, and many more.

Cientifica estimates medical imaging is the sector showing the highest growth and impact of nanomaterials. Already a $1.7-billion market, with gold nanoparticle applications accounting for $959 million, imaging will continue to be the largest nanodiagnostics sector, with gold nanoparticles, quantum dots and nanobiosensors all easily exceeding $10 billion.

“Getting onboard with the right technology at the right time is crucial,” said Harper [Tim Harper, Cientifica’s Chief Executive Officer]. “The use of exosomes in diagnosis, for instance, a relatively new technique and a tiny market, is set to reach close to half a billion dollars by 2021.”

You can find out more and/or purchase the report here.

I have written about Cientifica’s  Nanotechnology for Drug Delivery (NDD) white paper here and have published an interview with Tim Harper about global nanotechnology funding and economic impacts here.

DARPA, innovation, passwords, people, and nanotherapeutics

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There have been a few articles recently about (US) DARPA (Defense Advance Research Projects Agency) that have roused my interest in how they view innovation and business. The first piece I’m mentioning is a request for a proposal (RFP) on nanotherapeutics in a Nov. 22, 2011 news item on Nanowerk,

Through the U.S. Department of Defense’s Small Business Innovation Research (SBIR) program, DARPA is currently soliciting research proposals to develop a platform capable of rapidly synthesizing therapeutic nanoparticles targeted against evolving and engineered pathogens (SB121-003: Rapidly Adaptable Nanotherapeutics pdf).

Here’s part of the problem they’re trying to solve,

Acquired resistance compromises our ability to fight emergent bacterial threats in injured warfighters and our military treatment facilities. For burn patients in particular, multidrug-resistant Acinetobacter calcoaceticus-baumannii complex (ABC) is a common cause of nosocomial infection, causing severe morbidity as well as longer hospital stays. Typically, antimicrobial resistant infections require a hospital stay three times as long and are in excess of four times as expensive. Therefore, new and innovative methods to control bacterial infection in the military health system are of critical importance.

Here’s what they want,

Recent advances in nanomaterials, genome sequencing, nucleotide synthesis, and bioinformatics could converge in nanotherapeutics with tailored sequence, specificity, and function that can overcome earlier challenges. Collectively, these core technologies could permit the development of an innovative pharmaceutical platform composed of nanoparticles with tethered small interfering RNA (siRNA) oligonucelotides whose sequence and objective can be reprogrammed “on-the-fly” to inhibit multiple targets within multiple classes of pathogens.

This topic is focused on the development of a revolutionary rapidly adaptable nanotherapeutic platform effective against evolving and engineered pathogens. The biocompatible materials used to fabricate the nanoparticle should optimize cellular targeting, intracellular concentration, target sequence affinity, resistance to nuclease, and knockdown of target genes. The platform should leverage state-of-the-art genomic sequencing and oligonucleotide synthesis technologies to permit rapid programmability against evolving biologic threats.

I have taken a look at the RFP and, predictably, there’s a militaristic element to the introduction,

DARPA’s mission is to prevent technological surprise for the United States and to create technological surprise for its adversaries. The DARPA SBIR [Small Business Innovation Research] and STTR [Small Business Technology Transfer] Programs are designed to provide small, high-tech businesses and academic institutions the opportunity to propose radical, innovative, high-risk approaches to address existing and emerging national security threats; thereby supporting DARPA’s overall strategy to bridge the gap between fundamental discoveries and the provision of new military capabilities. (p. 1)

In short, we should never be caught with our pants down but we would like to catch our enemies in that position.

I was surprised to find that the responders are expected to create a business plan that includes information about markets, customers, and sales (from the RFP),

5. Market/Customer Sets/Value Proposition – Describe the market and customer sets you propose to target, their size, and their key reasons they would consider procuring the technology.

• What is the current size of the broad market you plan to enter and the “niche” market opportunity you are addressing?

• What are the growth trends for the market and the key trends in the industry that you are planning to target?

• What features of your technology will allow you to provide a compelling value proposition?

DARPA – 3

• Have you validated the significance of these features and if not, how do you plan to validate?

6. Competition Assessment – Describe the competition in these markets/customer sets and your anticipated advantage (e.g., function, performance, price, quality, etc.)

7. Funding Requirements – List your targeted funding sources (e.g., federal, state and local, private (internal, loan, angel, venture capital, etc.) and your proposed plan and schedule to secure this funding.

Provide anticipated funding requirements both during and after Phase II required to:

• mature the technology

• as required, mature the manufacturing processes

• test and evaluate the technology

• receive required certifications

• secure patents, or other protections of intellectual property

• manufacture the technology to bring the technology to market for use in operational environments

• market/sell technology to targeted customers

8. Sales Projections – Provide a schedule that outlines your anticipated sales projections and indicate when you anticipate breaking even. (pp. 2-3)

I do understand that the US has a military-industrial complex which fuels much of the country’s economic growth; I just hadn’t expected that the military would care as much as they do (as per this RFP) about  their suppliers’ business plans and financial health. It makes sense. After all, you want your suppliers to stay in business as it’s expensive and time-consuming to find new ones.

I don’t know if this is a new philosophy for the agency but it does seem to fit nicely with the current director’s Regina Dugan’s approach. From a Q & A between Dugan and Adam L. Penenberg for an Oct. 19, 2011 article in Fast Company,

That seems a key part of your mission since you got here–that it’s not enough to be doing cutting-edge research.
When deputy director Kaigham Gabriel and I got here, we understood that DARPA is one of the gems of the nation. We had been asked to take good care of her. For me, part of that meant really understanding why DARPA has this half-century of success in innovation. And the first element in DARPA’s success is the power that lies at the intersection of basic science and application, in the so-called Pasteur’s Quadrant. Do you know Stokes’s theory of innovation?

Absolutely not.
Donald E. Stokes wrote a theory of innovation in the late 1990s. Till then, most people thought of innovation as a linear process. You do basic science; then you do more advanced science; then you do the application work; then you commercialize it. What Stokes suggested is that it doesn’t happen that way at all. He preferred to think of it in a quadrant fashion, defining one row as very deep science and the other as light science; the two columns were a low-application drive and a high-application drive. Pasteur’s Quadrant happens at the deep-science-, high-application-drive quadrant. That’s DARPA’s absolute power lane. It’s called Pasteur’s Quadrant because serious concerns about food safety drove his research.

A very recent example of how it works for us is the blast-gauge work that we do. Here’s a big problem: TBI, traumatic brain injuries. So the way we approach it at DARPA is to say, “Okay, let’s understand the basic science, the phenomenology. How is it that an encounter with a blast injures the brain? What levels of blasts cause what levels of injury? Is it the overpressure? Is it the acceleration? What is it?” A medical person from DARPA researched this and discovered it was the overpressure. And the DARPA physicist says, “We know how to measure that.” Together, they devise this little blast gauge that’s the size of a couple stacks of quarters [the gauge helps doctors measure a soldier’s blast-exposure level, enabling better assessment of injuries]. They develop it in one year, going through four iterations of the electronics. That’s fast.

All of this leads back to the idea of shipping products. The defense world is like a mini-society. It has to deploy to anyplace in the world on a moment’s notice, and it has to work in a life-or-death situation. That kind of focus, that kind of drive to ship an application, really does inspire greater genius. And the constancy of funding that comes with that–in good times or bad, whether this party or that party is in power–also helps inspire innovation.

Dugan later goes on to describe her first weeks at DARPA (she was sworn in July 2009) where she and the deputy director made it their mission to meet every single person on staff, all 217 of them.

Still on the theme of innovation and DARPA, there’s a Nov. 16, 2011 article, DARPA Is After Your Password, by Neal Ungerleider in Fast Company which has to be of huge interest to anyone who has passwords,

According to DARPA press materials, the agency is focusing on creating cutting-edge biometric identification products that can identify an individual user through their individual typing style. In the future, DARPA hopes smart computers will be able to verify account-holders’ identities through their typing speed, finger motions and quirks of movement.

…

Materials published by DARPA seem to indicate that researchers at the agency believe most contemporary account passwords–at least those adhering to best practices–are clunky, hard to remember, and ultimately insecure. According to program manager Richard Guidorizzi, “My house key will get you into my house, but the dog in my living room knows you’re not me. No amount of holding up my key and saying you’re me is going to convince my dog you’re who you say you are. My dog knows you don’t look like me, smell like me or act like me. What we want out of this program is to find those things that are unique to you, and not some single aspect of computer security that an adversary can use to compromise your system.”

…

Nobody likes entering passwords. Nobody likes remembering passwords. Nobody likes forgetting passwords. Creating a painless, easy, and secure password-replacement system will be a major cash cow for any firm that can effectively bring it to market. [emphasis mine]

My enthusiasm for a world without passwords aside, I do note the interest in having the technology come to market. I wonder if DARPA will accrue some financial benefit, i.e. a licensing agreement. I did quickly skim the RFP but was unable to confirm or disprove this notion.