Category Archives: medicine

A nanoparticle for a medical imaging machine that doesn’t exist yet

Researchers at the University of Buffalo (New York state) have created a nanoparticle that can be detected by six imaging devices according to a Jan. 20, 2015 news item on ScienceDaily,

It’s technology so advanced that the machine capable of using it doesn’t yet exist.

Using two biocompatible parts, University at Buffalo researchers and their colleagues have designed a nanoparticle that can be detected by six medical imaging techniques:

• computed tomography (CT) scanning;

• positron emission tomography (PET) scanning;

• photoacoustic imaging;

• fluorescence imaging;

• upconversion imaging; and

• Cerenkov luminescence imaging.

The advantages are obvious should somebody, somewhere create a hexamodal (aka, multimodal, aka hypmodal) sensing device capable of exploiting the advantages of this nanoparticle as the researchers hope.

A Jan. 20, 2015 University of Buffalo news release (also on EurekAlert) by Charlotte Hsu, which originated the news item, describes the ideas underlying the research,

This kind of “hypermodal” imaging — if it came to fruition — would give doctors a much clearer picture of patients’ organs and tissues than a single method alone could provide. It could help medical professionals diagnose disease and identify the boundaries of tumors.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” says researcher Jonathan Lovell, PhD, UB assistant professor of biomedical engineering. “Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

When Lovell and colleagues used the nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the deepest tissue penetration, while the photoacoustic imaging showed blood vessel details that the first two techniques missed.

Differences like these mean doctors can get a much clearer picture of what’s happening inside the body by merging the results of multiple modalities.

A machine capable of performing all six imaging techniques at once has not yet been invented, to Lovell’s knowledge, but he and his coauthors hope that discoveries like theirs will spur development of such technology.

The news release also offers a description of the nanoparticles,

The researchers designed the nanoparticles from two components: An “upconversion” core that glows blue when struck by near-infrared light, and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium and thulium. The ytterbium is dense in electrons — a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer also is adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these two biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful, new tool for medical imaging,” says Prasad, also a SUNY Distinguished Professor of chemistry, physics, medicine and electrical engineering at UB. “More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals such as cadmium that are known to pose potential risks and found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” Chen adds. “These broad, potential capabilities are due to a plurality of optical, photoacoustic and radionuclide imaging abilities that the agent possesses.”

Lovell says the next step in the research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end, Lovell says.

The researchers have provided two images,

This transmission electron microscopy image shows the nanoparticles, which consist of a core that glows blue when struck by near-infrared light, and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core. Credit: Jonathan Lovell

This transmission electron microscopy image shows the nanoparticles, which consist of a core that glows blue when struck by near-infrared light, and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.
Credit: Jonathan Lovell

University at Buffalo researchers and colleagues have designed a nanoparticle detectable by six medical imaging techniques. This illustration depicts the particles as they are struck by beams of energy and emit signals that can be detected by the six methods: CT and PET scanning, along with photoacoustic, fluorescence, upconversion and Cerenkov luminescence imaging. Credit: Jonathan Lovell

University at Buffalo researchers and colleagues have designed a nanoparticle detectable by six medical imaging techniques. This illustration depicts the particles as they are struck by beams of energy and emit signals that can be detected by the six methods: CT and PET scanning, along with photoacoustic, fluorescence, upconversion and Cerenkov luminescence imaging.
Credit: Jonathan Lovell

Here’s a link to and a citation for the paper,

Hexamodal Imaging with Porphyrin-Phospholipid-Coated Upconversion Nanoparticles by James Rieffel, Feng Chen, Jeesu Kim, Guanying Chen, Wei Shao, Shuai Shao, Upendra Chitgupi, Reinier Hernandez, Stephen A. Graves, Robert J. Nickles, Paras N. Prasad, Chulhong Kim, Weibo Cai, and Jonathan F. Lovell. Advanced Materials DOI: 10.1002/adma.201404739 Article first published online: 14 JAN 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This article is behind a paywall.

Multi-walled carbon nanotubes and blood clotting

There’s been a lot of interest in using carbon nanotubes (CNTs) for biomedical applications such as drug delivery. New research from Trinity College Dublin (TCD) suggests that multi-walled carbon nanotubes (MWCNTs) may have some limitations when applied to biomedical uses. From a Jan. 20, 2014 news item on Nanowerk (Note: A link has been removed),

Scientists in the School of Pharmacy and Pharmaceutical Sciences in Trinity College Dublin, have made an important discovery about the safety issues of using carbon nanotubes as biomaterials which come into contact with blood. The significance of their findings is reflected in their paper being published as the feature story and front page cover of the international, peer-reviewed journal Nanomedicine (“Blood biocompatibility of surface-bound multi-walled carbon nanotubes”).

A Jan. 19, 2015 TCD press release, which originated the news item, offers a good description of the issues around blood clotting and the research problem (nonfunctionalized CNTs and blood compartibility) the scientists were addressing (Note: Links have been removed),

When blood comes into contact with foreign surfaces the blood’s platelets are activated which in turn leads to blood clots being formed. This can be catastrophic in clinical settings where extracorporeal circulation technologies are used such as during heart-lung bypass, in which the blood is circulated in PVC tubing outside the body. More than one million cardiothoracic surgeries are performed each year and while new circulation surfaces that prevent platelet activation are urgently needed, effective technologies have remained elusive.

One hope has been that carbon nanotubes, which are enormously important as potentially useful biomedical materials, might provide a solution to this challenge and this led the scientists from the School of Pharmacy and Pharmaceutical Sciences in collaboration with Trinity’s School of Chemistry and with colleagues from UCD and the University of Michigan in Ann Arbour to test the blood biocompatibility of carbon nanotubes. They found that the carbon nanotubes did actually stimulate blood platelet activation, subsequently leading to serious and devastating blood clotting. The findings have implications for the design of medical devices which contain nanoparticles and which are used in conjunction with flowing blood.

Speaking about their findings, Professor Marek Radomski, Chair of Pharmacology, Trinity and the paper’s senior author said: “Our results bear significance for the design of blood-facing medical devices, surface-functionalised with nanoparticles or containing surface-shedding nanoparticles. We feel that the risk/benefit ratio with particular attention to blood compatibility should be carefully evaluated during the development of such devices. Furthermore, it is clear that non-functionalised carbon nanotubes both soluble and surface-bound are not blood-compatible”.

The press release also quotes a TCD graduate,

Speaking about the significance of these findings for Nanomedicine research, the paper’s first author Dr Alan Gaffney, a Trinity PhD graduate who is now Assistant Professor of Anaesthesiology in Columbia University Medical Centre, New York said: “When new and exciting technologies with enormous potential benefits for medicine are being studied, there is often a bias towards the publication of positive findings. [emphasis mine] The ultimate successful and safe application of nanotechnology in medicine requires a complete understanding of the negative as well as positive effects so that un-intended side effects can be prevented. Our study is an important contribution to the field of nanomedicine and nanotoxicology research and will help to ensure that nanomaterials that come in contact with blood are thoroughly tested for their interaction with blood platelets before they are used in patients.”

Point well taken Dr. Gaffney. Too often there’s an almost euphoric quality to the nanomedicine discussion where nanoscale treatments are described as if they are perfectly benign in advance of any real testing. For example, I wrote about surgical nanobots being used in a human clinical trial in a Jan. 7, 2015 post which features a video of the researcher ‘selling’ his idea. The enthusiasm is laudable and necessary (researchers work for years trying to develop new treatments) but as Gaffney notes there needs to be some counter-ballast and recognition of the ‘positive bias’ issue.

Getting back to the TCD research, here’s a link to and a citation for the paper (or counter-ballast),

Blood biocompatibility of surface-bound multi-walled carbon nanotubes by Alan M. Gaffney, MD, PhD, Maria J. Santos-Martinez, MD, Amro Satti, Terry C. Major, Kieran J. Wynne, Yurii K. Gun’ko, PhD, Gail M. Annich, Giuliano Elia, Marek W. Radomski, MD. January 2015 Volume 11, Issue 1, Pages 39–46 DOI: http://dx.doi.org/10.1016/j.nano.2014.07.005 Published Online: July 26, 2014

This paper is open access.

Biocompatible cellulose sheaths for implants

Strictly speaking this is not my usual scale which is nano but the topic is of some interest to me so here goes a micro scale story.

It’s well known the body rejects foreign objects no matter how helpful or necessary to our continued existence. A Jan. 19, 2015 news item on Nanowerk describes research into developing more biocompatible implants (Note: A link has been removed),

The human immune system distinguishes between endogenous and foreign bodies. This is highly useful when defending the body against pathogens, but can become a problem if a patient requires an artificial implant like a pacemaker or a heart assist device. In some cases the body responds with an inflammation, and it may even reject the device altogether. Researchers at ETH Zurich [Swiss Federal Institute of Technology] are now introducing a promising method to ameliorate this process –fabricating pre-structured cellulose materials that cover or coat devices with three-dimensional micro-structures and thus make them exceptionally biocompatible (“Surface-Structured Bacterial Cellulose with Guided Assembly-Based Biolithography (GAB)”).

A Jan. 19, 2015 ETH Zurich press written by Angelika Jacobs, which originated the news item, describes the research in more detail,

Researchers had already discovered that cells interact better with rough or structured surfaces than with smooth ones and can cling to them more effectively. However, until now it has not been possible to apply these surface structures to one of the most promising materials in the field of medicine: cellulose produced by bacteria. Bacterial cellulose has received major attention in research in recent years due to the fact that it is durable, adaptable and well tolerated by the human body. For example, practical tests are already being carried out on artificial blood vessels and cartilage made using bacterial cellulose. The versatile material is also an effective option for use as wound dressings.

A research team led by ETH Professor Dimos Poulikakos and Aldo Ferrari at the Laboratory of Thermodynamics in Emerging Technologies, has now succeeded in creating bacterial cellulose with a controlled surface structure. This is produced using a silicon mould with a three-dimensional, optimised geometry (such as a line grid) on a micrometre scale, which is then floated on the surface of a nutrient solution in which the cellulose-producing bacteria grow. The bacteria create a dense network of cellulose strands at the interface between liquid and air. The researchers observed that when the mould was present the bacteria conformed to it, producing a cellulose layer together with a negative replica of the line grid.

Surface structure conveys signals to cells

The line grid also enabled the bacteria to produce an increased number of cellulose strands in approximate alignment with the grid. “In principle, human cells have the ability to identify fibres, such as endogenous collagen, as part of the connective tissue,” explains Aldo Ferrari. The cellulose strands and the grid pattern provide cells with an orientation along predetermined paths that they can sense. “This is of major benefit to wound dressings. Skin cells could grow over a wound more effectively if they moved in accordance with structured cellulose.” The material also has a sort of memory: the structure is even retained when the cellulose is dried for storage purposes and moistened again just before use.

Poulikakos explains that in the production of cellulose surfaces, it is now possible to provide them with a message for the cells that will grow there in the future. “Think of it as a form of Braille.” This enables the right ‘message’ intended for later use to be written on the surface.

Less inflammation due to a structured surface

Such structures serve not only as means of orientation for cells, but also help to minimise the body’s rejection reaction to an artificial implant. In studies using mice, researchers compared smooth and structured cellulose and discovered that the mice with structured cellulose inserted under their skin showed significantly fewer signs of inflammation.

The researchers are now looking to follow up on these initial promising results by testing the material under more complex conditions. They could, for example, structure the cellulose surface of artificial blood vessels in a way that optimises the flow of blood, thereby ensuring that these vessels do not become blocked as easily.

As is often the case these days, there the researchers will be attempting to commercialize this work (from the news release; Note: A link has been removed),

In addition, researchers working with Poulikakos and Ferrari have founded the spin-off Hylomorph to make the method market-ready. “We are planning to apply the structured cellulose as part of the “Zurich Heart” project at the new Wyss Translational Center [founded jointly by ETH Zurich and the University of Zurich; it is not related to the Wyss Institute of Biologically Inspired Engineering at Harvard University],” reveals Poulikakos. The aim of this project is to develop artificial cardiac pump devices that help patients with serious heart problems in the period before a heart donor becomes available – they could even be used as a permanent alternative to a donor heart. Although cardiac pumps are already available, the options that they provide have been limited until now as they are not particularly durable and can cause complications. “Our aim is for artificial implants to be accepted by the patient’s body without inflammation or rejection,” explains Ferrari. As part of the Zurich Heart project, the researchers are, in effect, helping to design the packaging and internal coating for the optimised cardiac pumps. The aim is to minimise the number of complications in the future.

Here’s a link to and a citation for the paper,

Surface-Structured Bacterial Cellulose with Guided Assembly-Based Biolithography (GAB) by Simone Bottan, Francesco Robotti, Prageeth Jayathissa, Alicia Hegglin, Nicolas Bahamonde, José A. Heredia-Guerrero, Ilker S. Bayer, Alice Scarpellini, Hannes Merker, Nicole Lindenblatt, Dimos Poulikakos, and Aldo Ferrari. ACS Nano, Article ASAP DOI: 10.1021/nn5036125
Publication Date (Web): December 19, 2014

Copyright © 2014 American Chemical Society

The paper is behind a paywall.

I can’t find a Hylomorph website or one for the Wyss Translational Center (there is a Dec. 12, 2014 ETH media release announcing its existence).

Microplasm-generated gold nanoparticles and the heart

Scientists are hoping they’ve found a better way to detect early signs of a heart attack according to a Jan. 15, 2015 news item on Nanotechnology Now,

NYU [New York University] Polytechnic School of Engineering professors have been collaborating with researchers from Peking University on a new test strip that is demonstrating great potential for the early detection of certain heart attacks.

Kurt H. Becker, a professor in the Department of Applied Physics and the Department of Mechanical and Aerospace Engineering, and WeiDong Zhu, a research associate professor in the Department of Mechanical and Aerospace Engineering, are helping develop a new colloidal gold test strip for cardiac troponin I (cTn-I) detection. The new strip uses microplasma-generated gold nanoparticles (AuNPs) and shows much higher detection sensitivity than conventional test strips. The new cTn-I test is based on the specific immune-chemical reactions between antigen and antibody on immunochromatographic test strips using AuNPs.

A Jan. 14, 2015 NYU Polytechnic School of Engineering news release (also on EurekAlert but dated Jan. 15, 2015), which originated the news item, explains what makes these new test strips more sensitive (hint: microplasma-generated gold nanoparticles),

Compared to AuNPs produced by traditional chemical methods, the surfaces of the gold nanoparticles generated by the microplasma-induced liquid chemical process attract more antibodies, which results in significantly higher detection sensitivity.

cTn-I is a specific marker for myocardial infarction. The cTn-I level in patients experiencing cardiac infarction is several thousand times higher than in healthy people. The early detection of cTn-I is therefore a key factor of heart attack diagnosis and therapy.

The use of microplasmas to generate AuNP is yet another application of the microplasma technology developed by Becker and Zhu.  Microplasmas have been used successfully in dental applications (improved bonding, tooth whitening, root canal disinfection), biological decontamination (inactivation of microorganisms and biofilms), and disinfection and preservation of fresh fruits and vegetables.

The microplasma-assisted synthesis of AuNPs has great potential for other biomedical and therapeutic applications such as tumor detection, cancer imaging, drug delivery, and treatment of degenerative diseases such as Alzheimer’s.

The routine use of gold nanoparticles in therapy and disease detection in patients is still years away: longer for therapeutic applications and shorter for biosensors. The biggest hurdle to overcome is the fact that the synthesis of monodisperse, size-controlled gold nanoparticles, even using microplasmas, is still a costly, time-consuming, and labor-intensive process, which limits their use currently to small-scale clinical studies, Becker explained.

Here’s a link to and citation for the paper,

Microplasma-Assisted Synthesis of Colloidal Gold Nanoparticles and Their Use in the Detection of Cardiac Troponin I (cTn-I) by Ruixue Wang, Shasha Zuo, Dong Wu, Jue Zhang, Weidong Zhu, Kurt H. Becker, and Jing Fang. Plasma Processes and Polymers DOI: 10.1002/ppap.201400127 Article first published online: 11 DEC 2014

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This article is behind a paywall.

For anyone curious about the more common chemical methods of producing gold nanoparticles, there’s this video produced in Australia by TechNyou Education. There’s a specific technique described which I believe is one of the most commonly used and I think this can be generalized to other gold nanoparticle chemical production processes,

One more thing, this video runs over my 5 min. policy limit for videos. To do this, I battled my inclination to include something that I think is useful for understanding more about nanoparticles and my desire to make sure that my blog doesn’t get too bloated.

Tattoos that detect glucose levels

Temporary tattoos with a biomedical function are a popular topic and one of the latest detects glucose levels without subjecting a person with diabetes to pin pricks. From a Jan. 14, 2015 news item on ScienceDaily,

Scientists have developed the first ultra-thin, flexible device that sticks to skin like a rub-on tattoo and can detect a person’s glucose levels. The sensor, reported in a proof-of-concept study in the ACS [American Chemical Society] journal Analytical Chemistry, has the potential to eliminate finger-pricking for many people with diabetes.

A Jan. 14, 2015 ACS news release on EurekAlert, which originated the news item, describes the current approaches to testing glucose and the new painless technique,

Joseph Wang and colleagues in San Diego note that diabetes affects hundreds of millions of people worldwide. Many of these patients are instructed to monitor closely their blood glucose levels to manage the disease. But the standard way of checking glucose requires a prick to the finger to draw blood for testing. The pain associated with this technique can discourage people from keeping tabs on their glucose regularly. A glucose sensing wristband had been introduced to patients, but it caused skin irritation and was discontinued. Wang’s team wanted to find a better approach.

The researchers made a wearable, non-irritating platform that can detect glucose in the fluid just under the skin based on integrating glucose extraction and electrochemical biosensing. Preliminary testing on seven healthy volunteers showed it was able to accurately determine glucose levels. The researchers conclude that the device could potentially be used for diabetes management and for other conditions such as kidney disease.

There is a Jan. 14, 2015 University of California at San Diego news release (also on EurekAlert) describing the work in more detail,

Nanoengineers at the University of California, San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. …

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in Professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the Center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive—a few cents—and hence can be replaced without much financial burden on the patient.”

The Center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

This reminds me a little of the Google moonshot project concerning health diagnostics. Announced in Oct. 2014, that project involved swallowing a pill containing nanoparticles that would circulate through your body monitoring your health and recongregating at your wrist so a band worn there could display your health status (Oct. 30, 2014 article by Signe Brewster for GigaOm). Experts welcomed the funding while warning the expectations seemed unrealistic given the current state of research and technology. This temporary tattoo seems much better grounded in terms of the technology used and achievable results.

Here’s a link to and a citation for the paper,

Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study by Amay J. Bandodkar, Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez, and Joseph Wang. Anal. Chem., 2015, 87 (1), pp 394–398 DOI: 10.1021/ac504300n Publication Date (Web): December 12, 2014

Copyright © 2014 American Chemical Society

This appears to be an open access paper.

My latest posting posting on medical tattoos (prior to this) is an Aug. 13, 2014 post about a wearable biobattery.

Maybe nano drug delivery not so magical after all?

There’s a lot of talk about the potential for a better way to treat disease with more accurate delivery of nanoparticle-based medicines to specific areas that need the treatment. For example, current treatments which shrink and eliminate cancer tumours also destroy healthy tissue and often have deleterious side effects while a nanoparticle-based treatment could seek out and eliminate the tumour only with few or no side effects. However, new research suggests that tumours may be more complex than previously understood.

From a Jan. 14, 2015 news item on Azonano,

Nanoparticle drugs–tiny containers packed with medicine and with the potential to be shipped straight to tumors–were thought to be a possible silver bullet against cancer. However new cancer drugs based on nanoparticles have not improved overall survival rates for cancer patients very much. Scientists at the University of North Carolina at Chapel Hill now think that failure may have less to do with the drugs and tumors than it does the tumor’s immediate surroundings.

The work, published in Clinical Cancer Research, merges relatively old and new ideas in cancer treatment, on one hand underscoring the importance of personalized medicine and on the other, reinforcing a relatively new idea that the tumor microenvironment might affect the delivery of drugs to tumors – a factor that may alter drug delivery from person to person, from cancer to cancer and even from tumor to tumor.

A Jan. 13, 2015 University of North Carolina news release (also on EurekAlert), which originated the news item, provides more details about the research,

“Tumors create bad neighborhoods,” said William Zamboni, the study’s senior author and an associate professor at the UNC Eshelman School of Pharmacy. “They spawn leaky, jumbled blood vessels that are like broken streets, blind alleys and busted sewers. There are vacant lots densely overgrown with collagen fibers. Immune-system cells patrolling the streets might be good guys turned bad, actually working for the tumor. And we’re trying to get a large truckload of medicine through all of that.”

In their work, Zamboni and colleagues from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine joined forces to see how much of the standard small-molecule cancer drug doxorubicin and its nanoparticle version, Doxil, actually made it into two varieties of triple-negative breast-cancer tumor models created by UNC’s Chuck Perou, the May Goldman Shaw Distinguished Professor of Molecular Oncology at the UNC School of Medicine and a professor at UNC Lineberger. Triple-negative breast cancer accounts for 10 to 17 percent of cases and has a poorer prognosis than other types of breast cancer.

At first, what they saw was no surprise: significantly more of the nanodrug Doxil made it into both triple-negative breast-cancer tumors compared with the standard small-molecule doxorubicin. “That’s nothing new,” Zamboni said. “We’ve seen that for twenty years.” They also saw the same amount of doxorubin in both tumors.

What did surprise them was that significantly more of the nanodrug Doxil – twice as much – was delivered to the C3-TAg triple-negative breast cancer tumor than to the T11 triple-negative breast cancer tumor.

“These tumors are subtypes of a subtype of one kind of cancer and are relatively closely related,” said Zamboni. “If the differences in delivering nanoagents to these two tumors are so significant, we can only imagine what the differences might be between breast cancer and lung cancer.”

Zamboni and his team suggest that better profiling of tumors and their microenvironments would allow doctors not only to better identify patients who would most benefit from nanoparticle-based cancer therapy, but also that clinicians may need to learn more about a patient’s tumor before prescribing treatment with one of the newer nanoparticle drugs.

This work gives the Israeli project I wrote about in my Jan. 7, 2015 post regarding a human clinical trial of nanobot delivery of a drug treatment (the world’s first) a new perspective. As a medical writer friend of mine (Susan Baxter) notes, these things are always more complicated than we think they’ll be and she adds tumours change over time.

Given how often we’ve discovered the human body is a complex, interwoven set of ecosystems, it’s perplexing that so much of the discussion around treatment is still  reductionist, i.e., drug kill tumour.

Getting back to this current research, here’s a link to and a citation for the paper,

Effects of Tumor Microenvironment Heterogeneity on Nanoparticle Disposition and Efficacy in Breast Cancer Tumor Models by Gina Song, David B. Darr, Charlene M. Santos, Mark Ross, Alain Valdivia, Jamie L. Jordan, Bentley R. Midkiff, Stephanie Cohen, Nana Nikolaishvili-Feinberg, C. Ryan Miller, Teresa K. Tarrant, Arlin B. Rogers, Andrew C. Dudley, Charles M. Perou, and William C. Zamboni. CCR-14-0493 Clin Cancer Res December 1, 2014 20 6083 doi: 10.1158/1078-0432 Published Online First September 17, 2014

This paper is behind a paywall of sorts. I haven’t seen this particular designation before but in addition to purchasing a subscription or short term access, there’s an option called: “patientACCESS – Patients/Caregivers desiring access to articles.” I’m not sure if that’s fee-based or not.

A newish Tekmira results from a merger with OnCore Biopharma

A Jan. 12, 2015 news item on Azonano announces a new business entity, a combined Tekmira Pharmaceuticals (located in North Vancouver, Canada) and OnCore Biopharma (located in Pennsylvania, US),

Tekmira Pharmaceuticals Corporation, a leading developer of RNA interference (RNAi) therapeutics, and OnCore Biopharma, Inc., a biopharmaceutical company dedicated to discovering, developing and commercializing an all-oral cure for patients suffering from chronic hepatitis B virus (HBV) infection, announced today that they have agreed to merge to create a new leading global HBV company focused on developing a curative regimen for hepatitis B patients by combining multiple therapeutic approaches.

A Jan. 11, 2015 Tekmira news release, which originated the news item, provides details including how this merger will affect the work on the Tekmira ebola treatment,

This transaction is expected to bring together the companies’ broad expertise in antiviral drug development, Tekmira’s Phase 1-ready HBV RNAi therapeutic and OnCore’s multiple HBV programs, to build a robust portfolio of compounds aimed at eradicating HBV. The combined company’s most advanced products are expected to be TKM-HBV, an RNAi therapeutic designed to eliminate HBV surface antigen (HBsAg) expression, a key component of host immune suppression, which is on track to begin human clinical trials in the first quarter of 2015; and OCB-030, a second-generation cyclophilin inhibitor focused on the suppression of viral replication, as well as stimulation and reactivation of the body’s immune response, which is anticipated to enter human clinical trials in the second half of 2015. The combined company anticipates progressing additional programs toward the clinic to achieve the goal of expeditiously evaluating combination regimens.

The combined pipeline is expected to target the three pillars necessary to develop a curative regimen for HBV, including assets focused on suppressing HBV replication, reactivating and stimulating the host immune response directed at HBV and eliminating covalently closed circular DNA (cccDNA). The parties believe that, together, these three pillars are the foundation for achieving a curative regimen.

Dr. Mark J. Murray, Chief Executive Officer of Tekmira, said, “We believe that the merger between Tekmira and OnCore has the potential to transform the HBV treatment landscape by bringing together the technologies and science needed to eradicate the virus and develop a cure for this debilitating and deadly disease. Our new company has the potential to advance multiple, highly active, complementary agents into the clinic in rapid succession, and create an HBV therapeutics powerhouse, thereby potentially offering significant benefits to the global medical community working to improve the lives of HBV patients. Importantly, we also believe this transaction has the potential to create significant value for our shareholders.”

Patrick Higgins, Chief Executive Officer of OnCore, said, “Tekmira and OnCore share a vision that effective combination regimens will ultimately cure HBV, a goal now being realized for hepatitis C virus. This merger is expected to bring together the promise of TKM-HBV with our existing HBV portfolio and accelerate our timeline for combination clinical trials. It is expected to deliver both near-term catalysts and long-term value creation. We believe that the ability to rapidly and sequentially combine novel HBV therapeutics is extremely valuable. We intend to utilize our collective expertise in liver disease and a focused development program, as we did at Pharmasset, to expeditiously and efficiently meet our shared goals.”

An Industry-Leading, Multi-Functional HBV Portfolio

Through the combined portfolio, OnCore and Tekmira intend to advance a robust pipeline of assets that uniquely targets the three pillars for delivering a curative regimen for HBV, including suppressing HBV replication, reactivating and stimulating the host immune response directed at HBV and eliminating cccDNA, the stable source of HBV viral genomic material. Post-closing, the combined company’s HBV portfolio is expected to include  product assets, which can be viewed in a chart by clicking on the following  link: http://media.globenewswire.com/cache/14025/file/31117.pdf

“We intend to take a focused, iterative approach to identifying the most effective combination regimens, while applying what we learn at each stage to optimize future compounds and combinations,” said Dr. Michael Sofia, the combined company’s Chief Scientific Officer and an inventor of sofosbuvir (Sovaldi) for the treatment of hepatitis C. “We believe that the ability to combine multiple unique programs housed in the same company is a significant competitive advantage, and should provide considerable efficiency in terms of speed and ease of decision-making. Combining the OnCore and Tekmira HBV portfolios underpins our vision to accelerate the delivery of a curative HBV regimen.”

Non-HBV Programs Continuing to Move Forward

Tekmira is a global leader in the RNAi field, and has created a diverse pipeline of products in development to treat serious human diseases, such as cancer and viral infections, including Ebola. The company has also licensed its leading lipid nanoparticle (LNP) delivery technology to partners around the world.

The management teams and Boards of Directors of Tekmira and OnCore believe that there is significant value in Tekmira’s non-HBV assets and collaborations. TKM-PLK1 is currently in Phase 2 in multiple indications and TKM-Ebola is expected to enter Phase 2 in West Africa in early 2015. Tekmira also maintains an active RNAi research and development effort. The combined management team and Board of Directors plans to continue to move forward with these programs with the goal of maximizing their value.

The news release goes on to describe the deal,

Under the terms of the agreement, the transaction will be carried out by way of a merger pursuant to which OnCore will merge with a wholly-owned subsidiary of Tekmira and thereby become a wholly-owned subsidiary of Tekmira. Upon closing of the transaction the stockholders of OnCore will hold approximately fifty percent (50%) of the total number of outstanding shares of capital stock of Tekmira, calculated on a fully-diluted and as-converted basis using the treasury stock method. The terms and conditions of the transaction are more fully set forth in the Merger Agreement. The implied market value of the combined company, based on the closing price of Tekmira common shares on the NASDAQ Global Market on January 9, 2015, is approximately USD$750 million.

The merger is subject to approval of a majority of the shareholders of Tekmira present, in person or by proxy, at a special meeting of Tekmira shareholders. Completion of the transaction is also subject to customary closing conditions, including regulatory approvals.  The transaction is expected to close in the first half of 2015, shortly after completion of the Securities and Exchange Commission (SEC) review process and receipt of Tekmira shareholder approval. The Tekmira Board of Directors unanimously approved and recommends that Tekmira shareholders vote FOR the proposed transaction at a special meeting of shareholders.

Details regarding these and other terms of the transaction are set out in the Merger Agreement, which will be filed by Tekmira on the SEC website at www.sec.gov and on the Canadian securities administrator’s website at www.sedar.com.

The combined company plans to retain top executives and board members from Tekmira and OnCore. The new company’s management team will include Mark J. Murray, PhD, Chief Executive Officer; Patrick T. Higgins, President and Chief Operating Officer; Bruce Cousins, Chief Financial Officer; Michael J. Sofia, PhD, Chief Scientific Officer; Mark Kowalski, MD, PhD, Chief Medical Officer; Bryce Roberts, Chief Legal Officer; Michael J. McElhaugh, Chief Business Officer; and Michael J. Abrams, PhD, Chief Discovery Officer. William T. Symonds, PharmD, who led the clinical development of sofosbuvir for the treatment of HCV infection at Pharmasset and later Gilead Sciences, Inc., will be Chief Development Officer and lead the clinical development of the portfolio.

Vivek Ramaswamy will serve as Chairman of the combined company; Dr. Daniel Kisner MD will serve as its Vice-Chairman. The combined company will be headquartered in Vancouver, BC.

I don’t understand how a company, OnCore, which is becoming a subsidiary qualifies as an equal partner in a merger but I gather this is business speak. In any event, the truly curious can find the webcast for a conference call about the deal held on Jan. 12, 2015 at 5 am PT (8 am ET)  along with an accompanying presentation here. The webcast will be available only from January 12, 2015 at 9:00 am PT  / 12 noon ET to January 17, 2015 at 9:00 am PT  / 12 noon ET and, for access, you must register on the site.

I have written previously about Tekmira, in a Nov. 19, 2014 post regarding another of its business deals and in a Sept. 23, 2014 post about its ebola treatment.

Engineering a small intestine

Researchers at the Children’s Hospital Los Angeles (CHLA) have successfully engineered small intestines that appear to be functional when transplanted into mice according to a Jan. 8, 2015 news item on ScienceDaily,

A new study by researchers at Children’s Hospital Los Angeles has shown that tissue-engineered small intestine grown from human cells replicates key aspects of a functioning human intestine. The tissue-engineered small intestine they developed contains important elements of the mucosal lining and support structures, including the ability to absorb sugars, and even tiny or ultra-structural components like cellular connections.

A Jan. 8, 2015 Children’s Hospital Los Angeles news release (also on EurekAlert), which originated the news item, describes the problems the researchers were addressing,

Tissue-engineered small intestine (TESI) grows from stem cells contained in the intestine and offers a promising treatment for short bowel syndrome (SBS), a major cause of intestinal failure, particularly in premature babies and newborns with congenital intestinal anomalies.  TESI may one day offer a therapeutic alternative to the current standard treatment, which is intestinal transplantation, and could potentially solve its largest challenges – donor shortage and the need for lifelong immunosuppression.

Grikscheit [Tracy C. Grikscheit, MD, a principal investigator in The Saban Research Institute of CHLA and its Developmental Biology and Regenerative Medicine program]  aims to help her most vulnerable young patients, including babies who are born prematurely and develop a devastating disease called necrotizing enterocolitis (NEC), where life-threatening intestinal damage requires removal of large portions of the small intestine. Without enough intestinal length, the babies are dependent on intravenous feeding, which is costly and may cause liver damage.  NEC and other contributors to intestinal failure occur in 24.5 out of 100,000 live births, and the incidence of SBS is increasing.  Nearly a third of patients die within five years.

The news release goes on to describe precursor work from 2011 before describing the latest research,

CHLA scientists had previously shown that TESI could be generated from human small intestine donor tissue implanted into immunocompromised mice. However, in those initial studies – published in July 2011 in the biomedical journal Tissue Engineering, Part A – only basic components of the intestine were identified. For clinical relevance, it remained necessary to more fully investigate intact components of function such as the ability to form a healthy barrier while still absorbing nutrition or specific mechanisms of electrolyte exchange.

The new study determined that mouse TESI is highly similar to the TESI derived from human cells, and that both contain important building blocks such as the stem and progenitor cells that will continue to regenerate the intestine as a living tissue replacement. And these cells are found within the engineered tissue in specific locations and in close proximity to other specialized cells that are known to be necessary in healthy human intestine for a fully functioning organ.

“We have shown that we can grow tissue-engineered small intestine that is more complex than other stem cell or progenitor cell models that are currently used to study intestinal regeneration and disease, and proven it to be fully functional as it develops from human cells,” said Grikscheit. “Demonstrating the functional capacity of this tissue-engineered intestine is a necessary milestone on our path toward one day helping patients with intestinal failure.”

If I read this rightly, the researchers engineered more complex intestinal tissues, than those in the 2011 study, in two separate processes where they grew mouse and human small intestinal tissue and successfully implanted both types of tissue into mice. The results showed that these more complex tissue-engineered small intestines (TESIs), human or mouse, resembled each other functionally within the mice tested.

Here’s a link to and a citation for the paper,

Human and Mouse Tissue-Engineered Small Intestine Both Demonstrate Digestive And Absorptive Function by Christa Nicole Grant, Garcia Mojica Salvador, Frederic G Sala, Jeffrey Ryan Hill, Daniel E Levin, Allison L Speer, Erik R Barthel, Hiroyuki Shimada, Nicholas C. Zachos, and Tracy C. Grikscheit. American Journal of Physiology – Gastrointestinal and Liver Physiology Published 8 January 2015Vol. no. , DOI: 10.1152/ajpgi.00111.2014

This paper is behind a paywall.

Surgical nanobots to be tested in humans in 2015?

Thanks to James Lewis at the Foresight’s Institute blog and his Jan. 6, 2015 posting about an an announcement of human clinical trials for surgical nanobots (Note: Links have been removed),

… as structural DNA nanotechnology rapidly expanded the repertoire of atomically precise nanostructures that can be fabricated, it became possible to fabricate functional DNA nanostructures incorporating logic gates to deliver and release molecular cargo for medical applications, as we reported a couple years ago (DNA nanotechnology-based nanorobot delivers cell suicide message to cancer cells). More recently, DNA nanorobots have been coated with lipid to survive immune attack inside the body.

Lewis then notes this (Note: A link has been removed),

 … “Ido Bachelet announces 2015 human trial of DNA nanobots to fight cancer and soon to repair spinal cords“:

At the British Friends of Bar-Ilan University’s event in Otto Uomo October 2014 Professor Ido Bachelet announced the beginning of the human treatment with nanomedicine. He indicates DNA nanobots can currently identify cells in humans with 12 different types of cancer tumors.

A human patient with late stage leukemia will be given DNA nanobot treatment. Without the DNA nanobot treatment the patient would be expected to die in the summer of 2015. Based upon animal trials they expect to remove the cancer within one month.

The information was excerpted from Brian Wang’s Dec. 27, 2014 post on his Nextbigfuture blog,

One Trillion 50 nanometer nanobots in a syringe will be injected into people to perform cellular surgery.

The DNA nanobots have been tuned to not cause an immune response. They have been adjusted for different kinds of medical procedures. Procedures can be quick or ones that last many days.

Using DNA origami and molecular programming, they are reality. These nanobots can seek and kill cancer cells, mimic social insect behaviors, carry out logical operators like a computer in a living animal, and they can be controlled from an Xbox. Ido Bachelet from the bio-design lab at Bar Ilan University explains this technology and how it will change medicine in the near future.

I advise reading both Wang’s and Lewis’ posts in their entirety. To give you a sense of how their posts differ (Lewis is more technical), I solicited information from the websites hosting their blog postings.

Here’s more about Wang from the About page on the Nextbigfuture blog,

Brian L. Wang, M.B.A. is a long time futurist. A lecturer at the Singularity University and Nextbigfuture.com author. He worked on the most recent ten year plan for the Institute for the Future and at a two day Institute for the Future workshop with Universities and City planners in Hong Kong (advising the city of Hong Kong on their future plans). He had a TEDx lecture on Energy. Brian is available as a speaker for corporations and organizations that value accurate and detailed insight into the development of technology global trends.

Lewis provides a contrast (from the About page listing Lewis on the Foresight Institute website),

Jim received a B.A. in chemistry from the University of Pennsylvania in 1967, an M.A. in chemistry from Harvard University in 1968, and a Ph.D. in chemistry, from Harvard University in 1972. After doing postdoctoral research at the Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland, from 1971-1973, Jim did research in the molecular biology of tumor viruses at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, from 1973-1980, first as a postdoctoral researcher, and then as a Staff Investigator and Senior Staff Investigator. He continued his research as an Associate Member, Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, from 1980-1988, and then joined the Bristol-Myers Squibb Pharmaceutical Research Institute in Seattle, WA, as a Senior Research Investigator from 1988-1996. Since 1996 he has been working as a consultant on nanotechnology.

Getting back to Bachelet, his team’s work, a precursor for this latest initiative, has been featured here before in an April 11, 2014 post,

This latest cockroach item, which concerns new therapeutic approaches, comes from an April 8, 2014 article by Sarah Spickernell for New Scientist (Note: A link has been removed),

It’s a computer – inside a cockroach. Nano-sized entities made of DNA that are able to perform the same kind of logic operations as a silicon-based computer have been introduced into a living animal.

Ido Bachelet can be seen in this February 2014 video describing the proposed surgical nanobots,

Bar-Ilan University where Bachelet works is located in Israel. You can find more information about this work and more on the Research group for Bio-Design website.

Gummy bears and an antiparticle story

Gummy bear on the experimental set-up – To avoid influences of the colour, the scientists only examined red gummy bears using positrons. Photo: Wenzel Schürmann / TUM

Gummy bear on the experimental set-up – To avoid influences of the colour, the scientists only examined red gummy bears using positrons. Photo: Wenzel Schürmann / TUM

Gelatin is commonly used as a delivery system for drugs. It’s particularly effective for timed release of medications, in part, due to tiny pores. According to a Dec. 29, 2014 news item on Nanowerk, researchers at the Technische Universität München (TUM) have found a way to measure these pores using gummy bears in a bid to improve gelatin’s effectiveness as a delivery system (Note: A link has been removed),

Gelatin is used in the pharmaceutical industry to encapsulate active agents. It protects against oxidation and overly quick release. Nanopores in the material have a significant influence on this, yet they are difficult to investigate. In experiments on gummy bears, researchers at Technische Universität München (TUM) have now transferred a methodology to determine the free volume of gelatin preparations (“The Free Volume in Dried and H2O-Loaded Biopolymers Studied by Positron Lifetime Measurements”).

A Dec. ??, 2014 TUM press release, which originated the news item, describes the research in more detail,

Custom-tailored gelatin preparations are widely used in the pharmaceutical industry. Medications that do not taste good can be packed into gelatin capsules, making them easier to swallow. Gelatin also protects sensitive active agents from oxidation. Often the goal is to release the medication gradually. In these cases slowly dissolving gelatin is used.

Nanopores in the material play a significant role in all of these applications. “The larger the free volume, the easier it is for oxygen to penetrate it and harm the medication, but also the less brittle the gelatin,” says PD Dr. Christoph Hugenschmidt, a physicist at TU München.

However, characterizing the size and distribution of these free spaces in the unordered biopolymer is difficult. A methodology adapted by the Garching physicists Christoph Hugenschmidt and Hubert Ceeh provides relief. “Using positrons as highly mobile probes, the volume of the nanopores can be determined, especially also in unordered systems like netted gelatins,” says Christoph Hugenschmidt.

Positrons are the antiparticles corresponding to electrons. They can be produced in the laboratory in small quantities, as in this experiment, or in large volumes at the Heinz Maier Leibnitz Research Neutron Source (FRM II) of the TU München. If a positron encounters an electron they briefly form an exotic particle, the so-called positronium. Shortly after it annihilates to a flash of light.

To model gelatin capsules that slowly dissolve in the stomach, the scientists bombarded red gummy bears in various drying stages with positrons. Their measurements showed, that in dry gummy bears the positroniums survive only 1.2 nanoseconds on average while in soaked gummy bears it takes 1.9 nanoseconds before they are annihilated. From the lifetime of the positroniums the scientists can deduce the number and size of nanopores in the material.

Here’s a link to and a citation for the paper,

The Free Volume in Dried and H2O-Loaded Biopolymers Studied by Positron Lifetime Measurements by Christoph Hugenschmidt and Hubert Ceeh. J. Phys. Chem. B, 2014, 118 (31), pp 9356–9360 DOI: 10.1021/jp504504p Publication Date (Web): July 21, 2014
Copyright © 2014 American Chemical Society

This paper is behind a paywall but there is another, freely available, undated paper on the topic (Note: the July 2014 published paper is cited there).

Drying Gummi Bears Reduce Anti-Matter Lifetime by Christoph Hugenschmidt und Hubert Ceeh.

Enjoy!