The Two Directions of Nanomedicine in the Treatment of Cancer


direction of cancer download

The cancer nanomedicine field is heading in two directions — debating whether the clinical translation of nanomaterials should be accelerated or whether some of the long-standing drug delivery paradigms have to be challenged first.

At the International Conference on Nanomedicine and Nanobiotechnology that was held in Munich, 16–18 October, the most striking talk was not given by a scientist, nor a clinician, but by Lora Kelly — a six-year pancreatic cancer survivor.

By telling her story of how it actually feels to receive chemotherapy, immunotherapy and radiation, she reminded everyone about the urgent need to improve cancer treatment regimes. The main goal remains to kill the cancer; however, it has become more evident how equally important it is to improve the quality of life of patients during treatment, that is, to reduce the often devastating side effects.

This is where nanomedicine comes in. Nanomaterials have the potential to direct drugs to specific tissues and to improve drug activity, as well as its transport in blood. Indeed, nanoparticles could ensure that therapeutic treatments act locally and not systemically, and thus improve anti-cancer efficacy while reducing damage to healthy tissues.

However, recent setbacks, including the bankruptcy of a prominent nanomedicine company1 and the less than 1% delivery efficiency claim2 (quoted at every cancer nanomedicine conference on at least one slide) have stirred discussions about the usefulness of nanomedicines for cancer treatment.

Some argue that the field is stuck in preclinical animal models owing to a lack of insight into the basics of nanomaterial–tissue interactions in the human body, from traversing biological barriers to clearance.

 

While less than 1% delivery efficiency might not be much, pharmacological parameters, such as peak drug concentration, clearance rate and elimination half-life, are often not as bad3, and these should be considered with equal importance.

Moreover, there are also clinical success stories of nanomedicines. Onpattro, a lipid nanoparticle-based short interfering RNA (siRNA) drug for the treatment of polyneuropathies, was approved by the US Food and Drug Administration in 2018, marking the first approved nanoparticle for nucleic acid delivery.

In a Comment in this issue, Akinc et al. report the endeavour of developing this nanomedicine, from the idea to preclinical and clinical testing4, to the final approval. There are further many opportunities for nanomaterials complementary to drug delivery, including bioimaging, modulation of the immune system and the tumour microenvironment, and, of course, local administration.

 

From an Editorial perspective, the ongoing discussion is reflected in the many manuscripts we receive, which often include both basic investigations and claims of clinical application. Naturally, this can lead to mixed peer-review reports echoing the disconnection between clinical vision and fundamental science.

Reviewers with a background in materials science or biomedical engineering often point out the gaps in the basic understanding of how a nanomaterial interacts with the biological environment, and clinicians would like to see more preclinical animal work. Indeed, a thorough fundamental study does not always need the claim of a specific application, as it might be exactly such overstatements that have precluded the field to deliver on the promise of revolutionizing drug delivery.

Along the same line, studies of nanoparticle transport through specific cells or nanomaterial–cell interactions at a molecular scale, do not necessarily require complex in vivo models; by contrast, applied studies claiming a therapeutic benefit need a robust in vivo validation in a relevant animal model — preferably with an intact immune system.

 

Going back to the goal of improving a patient’s life, possible side effects and impact on tissues other than tumours should also be reported. However, this data is often found, at best, somewhere in the supplementary information.

Regardless of the mouse model, the discussion rarely goes beyond the weight loss and the histology of organs. If the idea is to improve therapies, side effects need to be thoroughly investigated — even at an early preclinical stage. Similarly, we will make sure that studies claiming superiority of a therapeutic treatment compared to state-of-the-art treatment regimes are reviewed by clinical experts to ensure that clinical translation is — at least — possible and feasible.

Also, keeping regulatory requirements in mind, the more complex the new nanoparticle or nanoscale delivery agent, the more difficult it will be to get approval; and this is a valid criticism.

 

At Nature Nanotechnology, we consider both clinically relevant manuscripts and fundamental studies investigating the various barriers nanoparticles face on their journey through the body. We endeavour to assess the manuscripts we receive as fairly and consistently as possible, with the ongoing discussion in mind. We look forward to learning about possible alternative mechanisms and the heterogeneity of the enhanced permeability and retention (EPR) effect, nanoparticle interactions in the liver, spleen and kidneys during clearance, migration of nanomaterials through the tumour microenvironment, and nanoparticle uptake, lysosomal escape (or not) and transport in different cell types.

Such studies will shine a light on nanomaterial–tissue interactions, and also greatly contribute to the development of improved nanomedicines. Equally important, detailed investigations of nanoparticles in preclinical animal models as well as relevant organoid cultures will allow the optimization of treatment strategies and the reduction of side effects. Regardless of the aim, we urge authors to calibrate their claims in accordance with their data and scope of the investigation to preserve trust in cancer nanomedicine as a whole.

Monitoring Cancer at the Nano-Level – University of Waterloo


Waterloo QC Cancer 5c7d5fb4c0cfd

Tapered nanowire array device design. Credit: Nature Nanotechnology (2019). DOI: 10.1038/s41565-019-0393-2

How a new quantum sensor could improve cancer treatment

The development of medical imaging and monitoring methods has profoundly impacted the diagnosis and treatment of cancer. These non-invasive techniques allow health care practitioners to look for cancer in the body and determine if treatment is working.

But current techniques have limitations; namely, tumours need to be a specific size to be visible. Being able to detect cancer cells, even before there are enough to form a tumour, is a challenge that researchers around the world are looking to solve.

The solution may lie in nanotechnology

Researchers at the University of Waterloo’s Institute for Quantum Computing (IQC) have developed a quantum sensor that is promising to outperform existing technologies in monitoring the success of cancer treatments.

Sensor image

 Artist’s rendering of the interaction of incident single photon pulses and a tapered semiconductor nanowire array photodetector.

 

“A sensor needs to be very efficient at detecting light,” explains principal investigator Michael Reimer, an IQC faculty member and professor in the Faculty of Engineering. “What’s unique about our sensor is that the light can be absorbed all the way, from UV to infrared. No commercially available device exists that can do that now.”

 

Current sensors reflect some of the light, and depending on the material, this reflection can add up to 30 percent of the light not being absorbed.

This next-generation quantum sensor designed in Reimer’s lab is very efficient and can detect light at the fundamental limit — a single photon — and refresh for the next one within nanoseconds. Researchers created an array of tapered nanowires that turn incoming photons into electric current that can be amplified and detected.

When applied to dose monitoring in cancer treatment, this enhanced ability to detect every photon means that a health practitioner could monitor the dose being given with incredible precision — ensuring enough is administered to kill the cancer cells, but not too much that it also kills healthy cells.

Moving quantum technology beyond the lab

Reimer published his findings in Nature Nanotechnology in March and is now working on a prototype to begin testing outside of his lab. Reimer’s goal is to commercialize the sensor in the next three to five years.

“I enjoy the fundamental research, but I’m also interested in bringing my research out of the lab and into the real world and making an impact to society,” says Reimer.

He is no stranger to bringing quantum technology to the marketplace. While completing his post doctorate at the Delft University of Technology in The Netherlands, Reimer was an integral part of the startup, Single Quantum, developing highly efficient single-photon detectors based on superconducting nanowires.

Reimer’s latest sensor has a wide range of applications beyond dose monitoring for cancer treatments. The technology also has the ability to significantly improve high-speed imaging from space and long-range, high-resolution 3D images.

“A broad range of industries and research fields will benefit from a quantum sensor with these capabilities,” said Reimer. “It impacts quantum communication to quantum lidar to biological applications. Anywhere you have photon-starved situations, you would want an efficient sensor.”

He is exploring all industries and opportunities to put this technology to use.

Breakthroughs come in unexpected places

After earning his undergraduate degree in physics at the University of Waterloo, Reimer moved to Germany to play professional hockey. While taking graduate courses at the Technical University of Munich, he met a professor of nanotechnology who sparked his interest in the field.

“I played hockey and science was my hobby,” says Reimer. “Science is still my hobby, and it’s amazing that it is now my job.” Reimer went on to complete his PhD at the University of Ottawa/National Research Council of Canada, and turned his attention to quantum light sources. Reimer is an internationally renowned expert in quantum light sources and sensors. The idea for the quantum sensor came from his initial research in quantum light sources.

“To get the light out from the quantum light source, we had to come up with a way that you don’t have reflections, so we made this tapered shape. We realized that if we can get the light out that way we could also do the reverse — that’s where the idea for the sensor came from.”

Reimer will be at the Waterloo Innovation Summit on October 1, to present his latest breakthrough and its potential impact on the health care sector. And while he works to bring the sensor to market, Reimer’s lab continues to push the boundaries of quantum photonics.

From discovering the path to perfect photon entanglement to developing novel solid-state quantum devices, Reimer’s research is advancing technologies that could disrupt a multitude of industries and research fields.

Nanoparticles used to Transport Anti-Cancer Agent to Cells – University of Cambridge


Cancer transport 14-nanoparticle
Cells with MOFs carrying siRNA. Credit: University of Cambridge

Scientists from the University of Cambridge have developed a platform that uses nanoparticles known as metal-organic frameworks to deliver a promising anti-cancer agent to cells.

Research led by Dr. David Fairen-Jimenez, from the Cambridge Department of Chemical Engineering and Biotechnology, indicates  (MOFs) could present a viable platform for delivering a potent anti-cancer agent, known as siRNA, to .

Small interfering ribonucleic acid (siRNA), has the potential to inhibit overexpressed cancer-causing genes, and has become an increasing focus for scientists on the hunt for new cancer treatments.

Fairen-Jimenez’s group used computational simulations to find a MOF with the perfect pore size to carry an siRNA molecule, and that would breakdown once inside a cell, releasing the siRNA to its target. Their results were published today in Cell Press journal, Chem.

Some cancers can occur when  inside cells cause over-production of particular proteins. One way to tackle this is to block the gene expression pathway, limiting the production of these proteins.

SiRNA molecules can do just that—binding to specific gene messenger molecules and destroying them before they can tell the cell to produce a particular protein. This process is known as ‘gene knockdown’. Scientists have begun to focus more on siRNAs as potential cancer therapies in the last decade, as they offer a versatile solution to disease treatment—all you need to know is the sequence of the gene you want to inhibit and you can make the corresponding siRNA that will break it down. Instead of designing, synthesising and testing new drugs—an incredibly costly and lengthy process—you can make a few simple changes to the siRNA molecule and treat an entirely different disease.

One of the problems with using siRNAs to treat disease is that the molecules are very unstable and are often broken down by the cell’s natural defence mechanisms before they can reach their targets. SiRNA molecules can be modified to make them more stable, but this compromises their ability to knock down the target genes. It’s also difficult to get the molecules into cells—they need to be transported by another vehicle acting as a delivery agent.

Nanoparticles used to transport anti-cancer agent to cells
Crystalline metal-organic framework. Credit: David Fairen-Jimenez

The Cambridge researchers have used a special nanoparticle to protect and deliver siRNA to cells, where they show its ability to inhibit a specific target gene.

Fairen-Jimenez leads research into advanced materials, with a particular focus on MOFs: self-assembling 3-D compounds made of metallic and organic building blocks connected together.

There are thousands of different types of MOFs that researchers can make—there are currently more than 84,000 MOF structures in the Cambridge Structural Database with 1000 new structures published each month—and their properties can be tuned for specific purposes. By changing different components of the MOF structure, researchers can create MOFs with different pore sizes, stabilities and toxicities, enabling them to design structures that can carry molecules such as siRNAs into cells without harmful side effects.

“With traditional cancer therapy if you’re designing new drugs to treat the system, these can have different behaviours, geometries, sizes, and so you’d need a MOF that is optimal for each of these individual drugs,” says Fairen-Jimenez. “But for siRNA, once you develop one MOF that is useful, you can in principle use this for a range of different siRNA sequences, treating different diseases.”

“People that have done this before have used MOFs that don’t have a porosity that’s big enough to encapsulate the siRNA, so a lot of it is likely just stuck on the outside,” says Michelle Teplensky, former Ph.D. student in Fairen-Jimenez’s group, who carried out the research. “We used a MOF that could encapsulate the siRNA and when it’s encapsulated you offer more protection. The MOF we chose is made of a zirconium based metal node and we’ve done a lot of studies that show zirconium is quite inert and it doesn’t cause any toxicity issues.”

Using a biodegradable MOF for siRNA delivery is important to avoid unwanted build-up of the structures once they’ve done their job. The MOF that Teplensky and team selected breaks down into harmless components that are easily recycled by the cell without harmful side effects. The large pore size also means the team can load a significant amount of siRNA into a single MOF molecule, keeping the dosage needed to knock down the genes very low.

“One of the benefits of using a MOF with such large pores is that we can get a much more localised, higher dose than other systems would require,” says Teplensky. “SiRNA is very powerful, you don’t need a huge amount of it to get good functionality. The dose needed is less than 5% of the porosity of the MOF.”Structure-and-mechanism-of-siRNA-A-Structure-of-siRNA-B-Action-of-RNAi

MOFs or other vehicles to carry small molecules into cells is that they are often stopped by the cells on the way to their target. This process is known as endosomal entrapment and is essentially a defence mechanism against unwanted components entering the cell. Fairen-Jimenez’s team added extra components to their MOF to stop them being trapped on their way into the cell, and with this, could ensure the siRNA reached its target.

The team used their system to knock down a gene that produces fluorescent proteins in the cell, so they were able to use microscopy imaging methods to measure how the fluorescence emitted by the proteins compared between cells not treated with the MOF and those that were. The group made use of in-house expertise, collaborating with super-resolution microscopy specialists Professors Clemens Kaminski and Gabi Kaminski-Schierle, who also lead research in the Department of Chemical Engineering and Biotechnology.

Using the MOF platform, the team were consistently able to prevent gene expression by 27%, a level that shows promise for using the technique to knock down cancer genes.

Fairen-Jimenez believes they will be able to increase the efficacy of the system and the next steps will be to apply the platform to genes involved in causing so-called hard-to-treat cancers.

“One of the questions we get asked a lot is ‘why do you want to use a metal-organic framework for healthcare?’, because there are metals involved that might sound harmful to the body,” says Fairen-Jimenez. “But we focus on difficult diseases such as hard-to-treat cancers for which there has been no improvement in treatment in the last 20 years. We need to have something that can offer a solution; just extra years of life will be very welcome.”

The versatility of the system will enable the team to use the same adapted MOF to deliver different siRNA sequences and target different . Because of its large pore size, the MOF also has the potential to deliver multiple drugs at once, opening up the option of combination therapy.


Explore further

High-tech gel aids delivery of drugs

Precious Metal Flecks Could be Catalyst for Better Cancer Therapies


Precious Metal Flecks Cancer shutterstock_716719006

 

Researchers have found a way to dispatch minute fragments of palladium—a key component in motor manufacture, electronics and the oil industry—inside cancerous cells.

Tiny extracts of a precious metal used widely in industry could play a vital role in new cancer therapies.

Scientists have long known that the metal, used in catalytic converters to detoxify exhaust, could be used to aid cancer treatment but, until now, have been unable to deliver it to affected areas.

A molecular shuttle system that targets specific cancer cells has been created by a team at the University of Edinburgh and the Universidad de Zaragoza in Spain.

The new method, which exploits palladium’s ability to accelerate—or catalyse—chemical reactions, mimics the process some viruses use to cross cell membranes and spread infection.

The team has used bubble-like pouches that resemble the biological carriers known as exosomes, which can transport essential proteins and genetic material between cells. These exosomes exit and enter cells, dump their content, and influence how the cells behave.

This targeted transport system, which is also exploited by some viruses to spread infection to other cells and tissues, inspired the team to investigate their use as shuttles of therapeutics.

The researchers have now shown that this complex communication network can be hijacked. The team created exosomes derived from lung cancer cells and cells associated with glioma—a tumour that occurs in the brain and spinal cord—and loaded them with palladium catalysts.

These artificial exosomes act as Trojan horses, taking the catalysts—which work in tandem with an existing cancer drug- straight to primary tumours and metastatic cells.

Having proved the concept in laboratory tests, the researchers have now been granted a patent that gives them exclusive rights to trial palladium-based therapies in medicine.

The study was funded by the Engineering and Physical Sciences Research Council and the European Research Council. It has been published in the journal, Nature Catalysis.

Professor Asier Unciti-Broceta, from the University of Edinburgh’s CRUK Edinburgh Centre, said: “We have tricked exosomes naturally released by cancer cells into taking up a metal that will activate chemotherapy drugs just inside the cancer cells, which could leave healthy cells untouched.”

Professor Jesús Santamaría, of the Universidad de Zaragoza, said: “This has the potential to be a very exciting technology. It could allow us to target the main tumour and metastatic cells, thus reducing the side effects of chemotherapy without compromising the treatment.”

Story Source:

Materials provided by University of Edinburgh. Note: Content may be edited for style and length.

Scientists develop novel nano-vaccine for melanoma


Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0

Researchers at Tel Aviv University have developed a novel nano-vaccine for melanoma, the most aggressive type of skin cancer. Their innovative approach has so far proven effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

The focus of the research is on a nanoparticle that serves as the basis for the new vaccine. The study was led by Prof. Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology and head of the Laboratory for Cancer Research and Nanomedicine at TAU’s Sackler Faculty of Medicine, and Prof. Helena Florindo of the University of Lisbon while on sabbatical at the Satchi-Fainaro lab at TAU; it was conducted by Dr. Anna Scomparin of Prof. Satchi-Fainaro’s TAU lab, and postdoctoral fellow Dr. João Conniot. The results were published on August 5 in Nature Nanotechnology.

Melanoma develops in the skin cells that produce melanin or skin pigment. “The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” says Prof. Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the  to immunotherapies.”

The researchers harnessed tiny particles, about 170 nanometers in size, made of a biodegradable polymer. Within each particle, they “packed” two peptides—short chains of amino acids, which are expressed in melanoma cells. They then injected the nanoparticles (or “nano-vaccines”) into a  bearing melanoma.

“The nanoparticles acted just like known vaccines for viral-borne diseases,” Prof. Satchi-Fainaro explains. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides—that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

The researchers then examined the effectiveness of the vaccine under three different conditions.

First, the vaccine proved to have prophylactic effects. The vaccine was injected into healthy mice, and an injection of melanoma  followed. “The result was that the mice did not get sick, meaning that the vaccine prevented the disease,” says Prof. Satchi-Fainaro.

Second, the nanoparticle was used to treat a primary tumor: A combination of the innovative vaccine and immunotherapy treatments was tested on melanoma model mice. The synergistic treatment significantly delayed the progression of the disease and greatly extended the lives of all treated mice.

Finally, the researchers validated their approach on tissues taken from patients with melanoma brain metastases. This suggested that the nano- can be used to treat brain metastases as well. Mouse models with late-stage melanoma brain metastases had already been established following excision of the primary melanoma lesion, mimicking the clinical setting. Research on image-guided surgery of primary melanoma using smart probes was published last year by Prof. Satchi-Fainaro’s lab.

“Our research opens the door to a completely new approach—the —for effective treatment of , even in the most advanced stages of the disease,” concludes Prof. Satchi-Fainaro. “We believe that our platform may also be suitable for other types of cancer and that our work is a solid foundation for the development of other cancer nano-vaccines.”

More information: Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators, Nature Nanotechnology(2019). DOI: 10.1038/s41565-019-0512-0 , https://nature.com/articles/s41565-019-0512-0

Journal information: Nature Nanotechnology

Provided by Tel Aviv University

Researchers at Oregon State University reach Milestone in use of Nanoparticles to kill Cancer with Heat


Abstract:
Researchers at Oregon State University have developed an improved technique for using magnetic nanoclusters to kill hard-to-reach tumors.

 

Magnetic nanoparticles – tiny pieces of matter as small as one-billionth of a meter – have shown anti-cancer promise for tumors easily accessible by syringe, allowing the particles to be injected directly into the cancerous growth.

Once injected into the tumor, the nanoparticles are exposed to an alternating magnetic field, or AMF. This field causes the nanoparticles to reach temperatures in excess of 100 degrees Fahrenheit, which causes the cancer cells to die.

But for some cancer types such as prostate cancer, or the ovarian cancer used in the Oregon State study, direct injection is difficult. In those types of cases, a “systemic” delivery method – intravenous injection, or injection into the abdominal cavity – would be easier and more effective.

The challenge for researchers has been finding the right kind of nanoparticles – ones that, when administered systemically in clinically appropriate doses, accumulate in the tumor well enough to allow the AMF to heat cancer cells to death.

Olena Taratula and Oleh Taratula of the OSU College of Pharmacy tackled the problem by developing nanoclusters, multiatom collections of nanoparticles, with enhanced heating efficiency. The nanoclusters are hexagon-shaped iron oxide nanoparticles doped with cobalt and manganese and loaded into biodegradable nanocarriers.

Findings were published in ACS Nano.

“There had been many attempts to develop nanoparticles that could be administered systemically in safe doses and still allow for hot enough temperatures inside the tumor,” said Olena Taratula, associate professor of pharmaceutical sciences. “Our new nanoplatform is a milestone for treating difficult-to-access tumors with magnetic hyperthermia. This is a proof of concept, and the nanoclusters could potentially be optimized for even greater heating efficiency.”

The nanoclusters’ ability to reach therapeutically relevant temperatures in tumors following a single, low-dose IV injection opens the door to exploiting the full potential of magnetic hyperthermia in treating cancer, either by itself or with other therapies, she added.

“It’s already been shown that magnetic hyperthermia at moderate temperatures increases the susceptibility of cancer cells to chemotherapy, radiation and immunotherapy,” Taratula said.

The mouse model in this research involved animals receiving IV nanocluster injections after ovarian tumors had been grafted underneath their skin.

“To advance this technology, future studies need to use orthotopic animal models – models where deep-seated tumors are studied in the location they would actually occur in the body,” she said. “In addition, to minimize the heating of healthy tissue, current AMF systems need to be optimized, or new ones developed.”

The National Institutes of Health, the OSU College of Pharmacy and Najran University of Saudi Arabia supported this research.

Also collaborating were OSU electrical engineering professor Pallavi Dhagat, postdoctoral scholars Xiaoning Li and Canan Schumann of the College of Pharmacy, pharmacy graduate students Hassan Albarqi, Fahad Sabei and Abraham Moses, engineering graduate student Mikkel Hansen, and pre-pharmacy undergrads Tetiana Korzun and Leon Wong.

Copyright © Oregon State University

Chemists build a better cancer-killing drill: Rice University designs molecular motors with an upgrade for activation with near-infrared light


Houston, TX | Posted on May 29th, 2019

Researchers at Rice University, Durham (U.K.) University and North Carolina State University reported their success at activating the motors with precise two-photon excitation via near-infrared light. Unlike the ultraviolet light they first used to drive the motors, the new technique does not damage adjacent, healthy cells.

The team’s results appear in the American Chemical Society journal ACS Nano.

The research led by chemists James Tour of Rice, Robert Pal of Durham and Gufeng Wang of North Carolina may be best applied to skin, oral and gastrointestinal cancer cells that can be reached for treatment with a laser. 

In a 2017 Nature paper, the same team reported the development of molecular motors enhanced with small proteins that target specific cancer cells.

Once in place and activated with light, the paddlelike motors spin up to 3 million times a second, allowing the molecules to drill through the cells’ protective membranes and killing them in minutes.

Since then, researchers have worked on a way to eliminate the use of damaging ultraviolet light. In two-photon absorption, a phenomenon predicted in 1931 and confirmed 30 years later with the advent of lasers, the motors absorb photons in two frequencies and move to a higher energy state, triggering the paddles.

A video produced in 2017 explains the basic concept of cell death via molecular motors. Video produced by Brandon Martin/Rice University.

“Multiphoton activation is not only more biocompatible but also allows deeper tissue penetration and eliminates any unwanted side effects that may arise with the previously used UV light,” Pal said. 

The researchers tested their updated motors on skin, breast, cervical and prostate cancer cells in the lab. Once the motors found their targets, lasers activated them with a precision of about 200 nanometers.

In most cases, the cells were dead within three minutes, they reported. They believe the motors also drill through chromatin and other components of the diseased cells, which could help slow metastasis.

Because the motors target specific cells, Tour said work is underway to adapt them to kill antibiotic-resistant bacteria as well.

“We continue to perfect the molecular motors, aiming toward ones that will work with visible light and provide even higher efficacies of kill toward the cellular targets,” he said.

Rice postdoctoral researcher Dongdong Liu is lead author of the paper. Co-authors are Rice alumni Victor Garcia-López, Lizanne Nilewski and Amir Aliyan, visiting research scientist Richard Gunasekera, and senior research scientist Lawrence Alemany and graduate student Tao Jin of North Carolina State.

Wang is an assistant professor of chemistry at North Carolina State. Pal is an assistant professor of chemistry at Durham. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of computer science and of materials science and nanoengineering at Rice.

The Royal Society, the United Kingdom’s Engineering and Physical Sciences Research Council, the Discovery Institute, the Pensmore Foundation and North Carolina State supported the research.

About Rice University
Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 2 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

Follow Rice News and Media Relations via Twitter @RiceUNews.

Copyright © Rice University

Say What? U.S. cancer institute (NCI) cancels nanotech research centers – Why?


The U.S. National Cancer Institute (NCI) in Bethesda, Maryland, will halt funding next year for its long-running Centers of Cancer Nanotechnology Excellence (CCNEs), which are focused on steering advances in nanotechnology to detect and treat cancer.

The shift marks nanotechnology’s “natural transition” from an emerging field requiring dedicated support to a more mature enterprise able to compete head to head with other types of cancer research, says Piotr Grodzinski, who heads NCI’s Nanodelivery Systems and Devices Branch, which oversees the CCNEs. “This doesn’t mean NCI’s interest in nanotechnology is decreasing.”

Nevertheless, cancer nanotechnology experts see the decision as a blow. “It’s disappointing and very shortsighted given the emergence of nanotechnology and medicine,” says Chad Mirkin, who directs a CCNE at Northwestern University in Evanston, Illinois.

CCNEs have spawned dozens of clinical trials for new drugs and drug delivery devices, as well as novel technologies for diagnosing disease, he says. “Cancer research needs new ways of making new types of medicines. Nanotechnology represents a way to do that,” he says.

Nanotechnology also has a unique place in cancer research, where making advances requires multiple disciplines, including chemistry, physics, cell biology, and patient care, to design novel drugs and drug carriers that can navigate the body and seek out and destroy tumors.

“We’re talking about a different beast here,” says Michelle Bradbury, a radiologist at Memorial Sloan Kettering Cancer Center in New York City, who co-directs the Sloan Kettering-Cornell University CCNE. “The center format is perfect for that.”

NCI launched eight CCNEs in 2005 for an initial 5-year term. Nine received funding in 2010 for the project’s second phase, and six in 2015 for phase three. In total, CCNEs received about $330 million over 15 years, Grodzinski says, with an additional $70 million in funding for training and other types of nanotechnology research centers.

That, he says, represents between 10% to 20% of NCI’s funding for nanotechnology research, depending on the specific 5-year phase. NCI will continue to support nanotechnology through R01 and other grant mechanisms, Grodzinski says. But Bradbury and others are concerned that a more piecemeal funding approach might be less successful. “You might not see the integration between disciplines,” she says.

Army research may be used to treat cancer, Heal combat wounds


RESEARCH TRIANGLE PARK, N.C. — Army research is the first to develop computational models using a microbiology procedure that may be used to improve novel cancer treatments and treat combat wounds.

Using the technique, known as electroporation, an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, or DNA to be introduced into the cell.

For example, electro-chemotherapy is a cutting-edge cancer treatment that uses electroporation as a means to deliver chemotherapy into cancerous cells.

The research, funded by the U.S. Army and conducted by researchers at University of California, Santa Barbara and Université de Bordeaux, France, has developed a computational approach for parallel simulations that models the complex bioelectrical interaction at the tissue scale.

Previously, most research has been conducted on individual cells, and each cell behaves according to certain rules.

“When you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” said Pouria Mistani, a researcher at UCSB. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”

This new research, published in the Journal of Computational Physics, is funded by the U.S. Combat Capabilities Development Command’s Army Research Lab, the Army’s corporate research laboratory known as ARL, through its Army Research Office.

“Mathematical research enables us to study the bioelectric effects of cells in order to develop new anti-cancer strategies,” said Dr. Joseph Myers, Army Research Office mathematical sciences division chief.

“This new research will enable more accurate and capable virtual experiments of the evolution and treatment of cells, cancerous or healthy, in response to a variety of candidate drugs.”

Researchers said a crucial element in making this possible is the development of advanced computational algorithms.

“There is quite a lot of mathematics that goes into the design of algorithms that can consider tens of thousands well-resolved cells,” said Frederic Gibou, a faculty member in the Department of Mechanical Engineering and Computer Science at UCSB.

Another potential application is accelerating combat wound healing using electric pulsation.

“It’s an exciting, but mainly unexplored area that stems from a deeper discussion at the frontier of developmental biology, namely how electricity influences morphogenesis,” — or the biological process that causes an organism to develop its shape — Gibou said. “In wound healing, the goal is to externally manipulate electric cues to guide cells to grow faster in the wounded region and accelerate the healing process.”

The common factor among these applications is their bioelectric physical nature. In recent years, it has been established that the bioelectric nature of living organisms plays a pivotal role in the development of their form and growth.

To understand bioelectric phenomena, Gibou’s group considered computer experiments on multicellular spheroids in 3-D. Spheroids are aggregates of a few tens of thousands of cells that are used in biology because of their structural and functional similarity with tumors.

“We started from the phenomenological cell-scale model that was developed in the research group of our colleague, Clair Poignard, at the Université de Bordeaux, France, with whom we have collaborated for several years,” Gibou said.

This model, which describes the evolution of transmembrane potential on an isolated cell, has been compared and validated with the response of a single cell in experiments.

“From there, we developed the first computational framework that is able to consider a cell aggregate of tens of thousands of cells and to simulate their interactions,” he said. “The end goal is to develop an effective tissue-scale theory for electroporation.”

One of the main reasons for the absence of an effective theory at the tissue scale is the lack of data, according to Gibou and Mistani. Specifically, the missing data in the case of electroporation is the time evolution of the transmembrane potential of each individual cell in a tissue environment. Experiments are not able to make those measurements, they said.

“Currently, experimental limitations prevent the development of an effective tissue-level electroporation theory,” Mistani said. “Our work has developed a computational approach that can simulate the response of individual cells in a spheroid to an electric field as well as their mutual interactions.”

Each cell behaves according to certain rules. 

“But when you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” Mistani said. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”

The effects of electroporation used in cancer treatment, for example, depend on many factors, such as the strength of the electric field, its pulse and frequency.

“This work could bring an effective theory that helps understand the tissue response to these parameters and thus optimize such treatments,” Mistani said. “Before our work, the largest existing simulations of cell aggregate electroporation only considered about one hundred cells in 3-D, or were limited to 2-D simulations. Those simulations either ignored the real 3-D nature of spheroids or considered too few cells for tissue-scale emergent behaviors to manifest.”

The researchers are currently mining this unique dataset to develop an effective tissue-scale theory of cell aggregate electroporation.

_______________________________________

The CCDC Army Research Laboratory (ARL) is an element of the U.S. Army Combat Capabilities Development Command. As the Army’s corporate research laboratory, ARL discovers, innovates and transitions science and technology to ensure dominant strategic land power. Through collaboration across the command’s core technical competencies, CCDC leads in the discovery, development and delivery of the technology-based capabilities required to make Soldiers more effective to win our Nation’s wars and come home safely. CCDC is a major subordinate command of the U.S. Army Futures Command.

____________________________

University of Georgia – Microfluidic device may help researchers better understand (and isolate) Metastatic Cancer – “Finding the Needle in the Haystack”


Needle Cancer U Georgia d2_JEHjN

Instead of searching for a needle in a haystack, what if you were able to sweep the entire haystack to one side, leaving only the needle behind? That’s the strategy researchers in the University of Georgia College of Engineering followed in developing a new microfluidic device that separates elusive circulating tumor cells (CTCs) from a sample of whole blood.

CTCs break away from cancerous tumors and flow through the bloodstream, potentially leading to new metastatic tumors. The isolation of CTCs from the blood provides a minimally invasive alternative for basic understanding, diagnosis and prognosis of metastatic cancer. But most studies are limited by technical challenges in capturing intact and viable CTCs with minimal contamination.
“A typical sample of 7 to 10 milliliters of blood may contain only a few CTCs,” said Leidong Mao, a professor in UGA’s School of Electrical and Computer Engineering and the project’s principal investigator. “They’re hiding in whole blood with millions of white blood cells. It’s a challenge to get our hands on enough CTCs so scientists can study them and understand them.”
Leidong Mao (right) and graduate student Yang Liu in lab
Leidong Mao (right) and graduate student Yang Liu stand in Mao’s lab at UGA.
Circulating tumor cells are also difficult to isolate because within a sample of a few hundred CTCs, the individual cells may present many characteristics. Some resemble skin cells while others resemble muscle cells. They can also vary greatly in size.
“People often compare finding CTCs to finding a needle in a haystack,” said Mao. “But sometimes the needle isn’t even a needle.”
To more quickly and efficiently isolate these rare cells for analysis, Mao and his team have created a new microfluidic chip that captures nearly every CTC in a sample of blood ­- more than 99% – a considerably higher percentage than most existing technologies.
The team calls its novel approach to CTC detection “integrated ferrohydrodynamic cell separation,” or iFCS. They outline their findings in a study published in Lab on a Chip (“Tumor antigen-independent and cell size variation-inclusive enrichment of viable circulating tumor cells”).
The new device could be “transformative” in the treatment of breast cancer, according to Melissa Davis, an assistant professor of cell and developmental biology at Weill Cornell Medicine and a collaborator on the project.
“Physicians can only treat what they can detect,” Davis said. “We often can’t detect certain subtypes of CTCs, but with the iFCS device we will capture all the subtypes of CTCs and even determine which subtypes are the most informative concerning relapse and disease progression.”
Davis believes the device may ultimately allow physicians to gauge a patient’s response to specific treatments much earlier than is currently possible.
While most efforts to capture circulating tumor cells focus on identifying and isolating the few CTCs lurking in a blood sample, the iFCS takes a completely different approach by eliminating everything in the sample that’s not a circulating tumor cell.
The device, about the size of a USB drive, works by funneling blood through channels smaller in diameter than a human hair. To prepare blood for analysis, the team adds micron-sized magnetic beads to the samples. The white blood cells in the sample attach themselves to these beads. As blood flows through the device, magnets on the top and bottom of the chip draw the white blood cells and their magnetic beads down a specific channel while the circulating tumor cells continue into another channel.
The device combines three steps in one microfluidic chip, another advance over existing technologies that require separate devices for various steps in the process.
“The first step is a filter that removes large debris in the blood,” said Yang Liu, a doctoral student in UGA’s department of chemistry and the paper’s co-lead author. “The second part depletes extra magnetic beads and the majority of the white blood cells. The third part is designed to focus remaining white blood cells to the middle of channel and to push CTCs to the side walls.”
Wujun Zhao is the paper’s other lead author. Zhao, a postdoctoral scholar at Lawrence Berkeley National Laboratory, worked on the project while completing his doctorate in chemistry at UGA.
“The success of our integrated device is that it has the capability to enrich almost all CTCs regardless of their size profile or antigen expression,” said Zhao. “Our findings have the potential to provide the cancer research community with key information that may be missed by current protein-based or size-based enrichment technologies.”
The researchers say their next steps include automating the iFCS and making it more user-friendly for clinical settings. They also need to put the device through its paces in patient trials. Mao and his colleagues hope additional collaborators will join them and lend their expertise to the project.
Source: University of Georgia