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Shooting drugs to an infection site with a slingshot

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It seems as if I’ve been writing up nanomedicine research a lot lately, so I would have avoided this piece. However, since I do try to cover Canadian nanotechnology regardless of the topic and this work features researchers from l’Université de Montréal (Québec, Canada), here’s one of the latest innovations in the field of nanomedicine. (I have some additional comments about the nano scene in Canada and one major issue concerning nanomedicine at the end of this posting.) From a May 8, 2017 news item on ScienceDaily,

An international team of researchers from the University of Rome Tor Vergata and the University of Montreal has reported, in a paper published this week in Nature Communications, the design and synthesis of a nanoscale molecular slingshot made of DNA that is 20,000 times smaller than a human hair. This molecular slingshot could “shoot” and deliver drugs at precise locations in the human body once triggered by specific disease markers.

A May 8, 2017 University of Montreal news release (also on EurekAlert), which originated the news item, delves further into the research (Note: A link has been removed),

The molecular slingshot is only a few nanometres long and is composed of a synthetic DNA strand that can load a drug and then effectively act as the rubber band of the slingshot. The two ends of this DNA “rubber band” contain two anchoring moieties that can specifically stick to a target antibody, a Y-shaped protein expressed by the body in response to different pathogens such as bacteria and viruses. When the anchoring moieties of the slingshot recognize and bind to the arms of the target antibody the DNA “rubber band” is stretched and the loaded drug is released.

“One impressive feature about this molecular slingshot,” says Francesco Ricci, Associate Professor of Chemistry at the University of Rome Tor Vergata, “is that it can only be triggered by the specific antibody recognizing the anchoring tags of the DNA ‘rubber band’. By simply changing these tags, one can thus program the slingshot to release a drug in response to a variety of specific antibodies. Since different antibodies are markers of different diseases, this could become a very specific weapon in the clinician’s hands.”

“Another great property of our slingshot,” adds Alexis Vallée-Bélisle, Assistant Professor in the Department of Chemistry at the University of Montreal, “is its high versatility. For example, until now we have demonstrated the working principle of the slingshot using three different trigger antibodies, including an HIV antibody, and employing nucleic acids as model drugs. But thanks to the high programmability of DNA chemistry, one can now design the DNA slingshot to ‘shoot’ a wide range of threrapeutic molecules.”

“Designing this molecular slingshot was a great challenge,” says Simona Ranallo, a postdoctoral researcher in Ricci’s team and principal author of the new study. “It required a long series of experiments to find the optimal design, which keeps the drug loaded in ‘rubber band’ in the absence of the antibody, without affecting too much its shooting efficiency once the antibody triggers the slingshot.”

The group of researchers is now eager to adapt the slingshot for the delivery of clinically relevant drugs, and to demonstrate its clinical efficiency. [emphasis mine] “We envision that similar molecular slingshots may be used in the near future to deliver drugs to specific locations in the body. This would drastically improve the efficiency of drugs as well as decrease their toxic secondary effects,” concludes Ricci.

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

Antibody-powered nucleic acid release using a DNA-based nanomachine by Simona Ranallo, Carl Prévost-Tremblay, Andrea Idili, Alexis Vallée-Bélisle, & Francesco Ricci. Nature Communications 8, Article number: 15150 (2017) doi:10.1038/ncomms15150 Published online: 08 May 2017

This is an open access paper.

A couple of comments

The Canadian nanotechnology scene is pretty much centered in Alberta and Québec. The two provinces have invested a fair amount of money in their efforts. Despite the fact that the province of Alberta also hosts the federal government’s National Institute of Nanotechnology, it seems that the province of Québec is the one making the most progress in its various ‘nano’ fields of endeavour. Another province that should be mentioned with regard to its ‘nano’ efforts is Ontario. As far as I can tell, nanotechnology there doesn’t enjoy the same level of provincial funding support as the other two but there is some important work coming out of Ontario.

My other comment has to do with nanomedicine. While it is an exciting field, there is a tendency toward a certain hyperbole. For anyone who got excited about the ‘slingshot’, don’t forget this hasn’t been tested on any conditions close to the conditions found in a human body nor have they even used, “... clinically relevant drugs,  … .”  It’s also useful to know that less than 1% of the drugs used in nanoparticle-delivery systems make their way to the affected site (from an April 27, 2016 posting about research investigating the effectiveness of nanoparticle-based drug delivery systems). By the way, it was a researcher at the University of Toronto (Ontario, Canada) who first noted this phenomenon after a meta-analysis of the research,

…

More generally, the authors argue that, in order to increase nanoparticle delivery efficiency, a systematic and coordinated long-term strategy is necessary. To build a strong foundation for the field of cancer nanomedicine, researchers will need to understand a lot more about the interactions between nanoparticles and the body’s various organs than they do today. …

It’s not clear from the news release, the paper, or the May 8, 2017 article by Sherry Noik for the Canadian Broadcasting Corporation’s News Online website, how this proposed solution would be administered but presumably the same factors which affect other nano-based drug deliveries could affect this new one,

Scientists have for many years been working on improving therapies like chemo and radiation on that score, but most efforts have focused on modifying the chemistry rather than altering the delivery of the drug.

“It’s all about tuning the concentration of the drug optimally in the body: high concentration where you want it to be active, and low concentration where you don’t want to affect other healthy parts,” says Prof. Alexis Vallée-Bélisle of the University of Montreal, co-author of the report published this week in Nature Communications.

“If you can increase the concentration of that drug at the specific location, that drug will be more efficient,” he told CBC News in an interview.

‘Like a weapon’

Restricting the movement of the drug also reduces potentially harmful secondary effects on other parts of the body — for instance, the hair loss that can result from toxic cancer treatments, or the loss of so-called good bacteria due to antibiotic use.

The idea of the slingshot is to home in on the target cells at a molecular level.

…

The two ends of the strand anchor themselves to the antibody, stretching the strand taut and catapulting the drug to its target.

“Imagine our slingshot like a weapon, and this weapon is being used by our own antibody,” said Vallée-Bélisle, who heads the Laboratory of Biosensors & Nanomachines at U of M. “We design a specific weapon targeting, for example, HIV. We provide the weapon in the body with the bullet — the drug. If the right solider is there, the soldier can use the weapon and shoot the problem.”

Equally important: if the wrong soldier is present, the weapon won’t be deployed.

So rather than delay treatment for an unidentified infection that could be either viral or bacterial, a patient could receive the medication for both and their body would only use the one it needed.

Getting back to my commentary, how does the drug get to its target? Through the bloodstream?  Does it get passed through various organs? How do we increase the amount of medication (in nano-based drug delivery systems) reaching affected areas from less than 1%?

The researchers deserve to be congratulated for this work and given much encouragement and thanks as they grapple with the questions I’ve posed and with all of the questions I don’t know how to ask.

Dirty medicine: a paper and a call for citizen scientists

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A May 19, 2014 news item on phys.org features the role microbes and dirt may play in the future of medicine,

Microbes are not only a rich source of disease, but also a rich source of medicines, and experts think many life-saving compounds produced by as-yet-unnamed bacteria are awaiting discovery. But they don’t always give up their secrets easily. Researchers must know where to look to find promising bacteria, and how to get them to grow in the lab, the traditional route to identifying potentially valuable molecules they produce.

Researchers in Sean Brady’s Laboratory of Genetically Encoded Small Molecules [Rockefeller University] are working on a way around these roadblocks. By using genomic sequencing technology, they can investigate the organisms that live in habitats like soil without having to grow the microbes in the lab. They are using this information to map out the location of gene clusters they believe may encode novel antibiotics, and, with help from citizen scientists around the country, they are hoping to process soil samples from areas they would never be able to visit on their own.

A May 16, 2014 Rockefeller University news release, which originated the news item, offers more details about the work,

n a preliminary effort, Brady’s lab has surveyed nearly 100 soil samples from two U.S. regions, looking for genetic sequences that encode certain molecule-making abilities. “We hope to expand to other regions of the country and the world, to incorporate many more samples in order to create maps of the biosynthetic diversity of soil microbes,” says Zachary Charlop-Powers, a postdoc in the lab. “These maps could help guide drug discovery by identifying variants on known bacterial genes that might be part of a gene cluster encoding a new antibiotic.”

Medicine already owes a major debt to microbes, particularly bacteria. These tiny organisms have produced or inspired many antibiotics, from tetracycline to vancomycin, as well as cancer-fighting drugs and immune system-suppressing therapies used for organ transplants. These bacterial natural products are part of the organisms’ chemical defense system and these molecules have historically been isolated from the broth of bacteria grown in the laboratory.

“However, genetic evidence hints there are many, many more bacteria out there that we may not be able to grow,” Brady says. “And they should be an equally rich source of useful natural products. We have been developing genetic tools to help us look for new chemistry by looking at the genes used to synthesize these natural products.”

For the past five years, Brady’s lab has been sequencing and shifting through DNA obtained directly from soil to identify potentially useful genes, which the researchers then transplant into more-laboratory friendly bugs.

Charlop-Powers, Brady and colleagues recently published the first geographical survey intended to speed this discovery process in the Proceedings of the National Academy of Sciences. For this study, they focused on genes responsible for producing two important families of biologically active molecules: nonribosomal peptides and polyketides. These families include most of the therapeutic molecules isolated from cultured bacteria, but in spite of this diversity, the underlying genetic architecture remains constant. In these families, repetitive genetic domains generate molecules in an assembly line-like fashion that evolution has frequently retooled.

In DNA from 96 soil samples collected for the survey, the researchers looked at two of these domains to get a sense for the diversity and richness of microbes capable of producing compounds these families. They found a link between the type of soil and the sorts of molecules its resident microbes had the capacity to produce. “For reasons we don’t understand, arid soils turned out to harbor microbes capable of producing a greater diversity of compounds,” Charlop-Powers says. For this preliminary survey, Brady called on his family to send in samples from Arizona and New Mexico; another postdoc in his lab, Jeremy Owen, collected soil in New England.

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

Chemical-biogeographic survey of secondary metabolism in soil by Zachary Charlop-Powers, Jeremy G. Owen, Boojala Vijay B. Reddy, Melinda A. Ternei, and Sean F. Brady. Proceedings of the National Academy of Sciences 111, 3757–3762. doi: 10.1073/pnas.1318021111. Epub 2014 Feb 18.

This paper is behind a paywall.

Given the magnitude of the project, the Rockefeller University news release includes a call for citizen scientists,

The Brady Lab would like to extend this study and hopes to encourage citizen scientists to contribute to the effort. The lab has set up a website: www.drugsfromdirt.org and after signing up, citizen scientists will receive information about how to collect and ship samples. The process is simple, says Brady: “Take a sandwich bag, a spoon or a trowel, and dump a couple of spoonfuls in the bag and ship it to us.”

That is a simple process! I notice a focus on recruiting children and youth on the Drugs For Dirt homepage,

We are particularly interested in working with school groups and science classes.

It’s a good idea that could be extended to other age groups and other types of groups. My suggestions, what about seniors groups and gardening groups?

Cientifica’s white paper on nanotechnology in drug delivery (NDD)

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The white paper, not to be confused with the full market report which will set you back 3000 GBP (or 5000 USD), offers an 18 pp. overview of  nanotechnology in drug delivery (NDD). Excerpted from the NDD white paper,

The advantages over current treatment modalities include lower drug toxicities, improved bioavailability, reduced economic costs of treatment, and increased patient adherence to treatment. The medical management of malignancies has already been greatly impacted by nanotechnology, but soon other medical specialties will utilize these novel forms of drug delivery to achieve optimal treatment success. Additionally, innovative research and development of more therapeutically effective carriers will continue including improved forms of polymer– drug conjugates, liposomes, dendrimers, micelles, polymeric vesicles and nanocapsules. Finally, implantable drug delivery systems will open up many more opportunities for nanotechnology utilization. (p. 6 PDF)

The promise of lower toxicities and better performance is compelling both from a potential user’s (patient) perspective and a healer’s perspective. As for investors, opening up new therapies can be a lucrative business as Cientifica notes in its white paper,

Forecasts indicate the nanotechnology market will reach close to a trillion dollars by 2015, presenting investors with a unique opportunity. However, the market for applications of nanotechnology is complex to understand, multi disciplinary and highly segmented. It is therefore vital for any would-be investor to gain an understanding of which market sectors nanotechnology is likely to impact most profoundly in the near term.

Since we now know most (if not all) biological processes occur at the nanoscale, the application of life science principles – studying the causes of biological phenomena at the molecular level – means that medical and biomedical research is increasingly using a bottom-up (rather than the topdown) approach. The low bioavailability resulting from traditional oral and intravenous drug delivery methods and the market forces at work in the pharmaceutical industry, where patents expire after a relatively short period of time unless a novel form of drug delivery is developed that will extend the patent, are two major forces that will fuel the growth of the nanotech drug delivery market. The third factor at play is a combination of improved global health and a correspondingly dramatic increase in the size of the global aging population. [emphases mine] (p. 4 PDF)

I’m a little more conservative than the folks at Cientifica; I’m not yet ready to say that we ‘know’ most biological processes occur at the nanoscale since we are not yet able to test the hypothesis at smaller scales. I am convinced by the ‘low bioavailability’ and ‘global health/aging’ trends and I’m happy to see the shorter patent period mentioned.

Brief overview: Patents are a problematic area as there are arguments that current patent regimes are stifling innovation (Do Patents Encourage or Hinder Innovation? The Case of the Steam Engine; Patent Law Is Highly Controversial) while others suggest longer patent periods are needed (Drug Patents Stifling Innovation by Financially Straining Pharmaceutical Companies).

I don’t entirely buy the argument that pharmaceutical companies pour all of their profits into research and struggle financially as a consequence. (Are there any large pharmaceutical companies in serious financial trouble? Please let me know as I’ve not heard of any.) In fact, this shorter patent period seems to be stimulating the current interest and research into nanotechnology-enabled therapies. This is exactly what the patent system was designed to do in the first place, stimulate innovation.

In general, I found the white paper quite useful in that it helped me to better understand some of the material I scan on a daily basis. I particularly appreciated this breakdown,

The report has discovered that there are three areas of medicine where nanotechnology shows the greatest promise:

i. Nanotechnology in drug delivery;

ii. Nanotechnology in medical and biomedical diagnostics;

iii. Nanotechnology in regenerative medicine and tissue engineering (p. 5 PDF)

I am surprised that Cientifica considers nanotechnology in drug delivery as the most promising area for investors as it seems to me that the diagnostics area has more products close to commercialization but my view is limited, there are other factors at play and, also, investing is not my area of expertise.

From a marketing perspective, my hat’s off to the folks at Cientifica for writing a white paper that provides a good overview and acts as a teaser for the full report.

Any other quibbles I have with this material are philosophical and addressed to the industry sector. I wish there was less military-influenced language used. For example (excerpted from the white paper),

The “magic bullet” concept, first theorized by Paul Ehrlich in 1891, represents the first early description of the drug-targeting paradigm. The aim of drug targeting is to deliver drugs to the right place, at the right concentration, for the right period of time. As drug characteristics differ substantially in chemical composition, molecular size, hydrophilicity, and protein binding, the essential characteristics that identify efficacy are highly complex. All of these factors are investigated to bring a new compound to market although only a fraction reaches active clinical use. (p. 13 PDF)

The ‘magic bullet’ and drug-targeting concept is from the 19th century (or possibly earlier). Can’t we find a language that is more reflective of our own age and our current understanding of biology and technology? That challenge is for writers, artists, scholars and others who help to define our understanding of the world and our place in it.