Exploring Nanotechnology to Enhance Treatment, Diagnosis & Drug Discovery


What can you do with a liberal arts degree? Native New Yorker Daniel Heller, PhD, majored in history, added in some basic science courses, and started his working life as a middle school science teacher. After taking some additional chemistry coursework during non-teaching hours, Heller parlayed it all into a doctorate in chemistry from the University of Illinois.

Today he is a biomedical engineer at Memorial Sloan Kettering Cancer Center (MSKCC), New York City, where his Cancer Nanomedicine Laboratory team invents new technologies that can assist health care in helping human kind.

Heller chuckled when mentioning his circuitous life path and some of the stops along the way: performing as a wizard at a Renaissance Fair (“…liquid nitrogen turns into a pretty impressive potion…”), trying to master the Argentine tango, appreciating his brother’s equally non-traditional path as a drummer in heavy metal bands, and happily settling into married life with his wife who is a primary care physician.

In recent years, he has also managed to garner solid industry credentials in the form of awards, including the NSF CAREER Award (2018), Pershing Square Sohn Prize for Young Innovators in Cancer Research (2017), and NIH Director’s New Innovator Award (2012), among others.

“I like inventing,” Heller stated simply. “In my lab, we often think of ourselves as biomedical engineers whose primary goal is invent new technologies to improve cancer research, diagnosis, and therapy.

Only when I arrived at MSKCC did I realize how far that is from the way biologists think. I was trained that our goal is to invent, and to learn new science along the way, while a biologist’s goal is to understand nature and develop tools mainly as a means to an end. I didn’t have a huge biomedical background coming in, but by talking to the people around me at Sloan Kettering and Weill Cornell Medicine [where he is an Assistant Professor], I have learned a great deal.”

As detailed on his laboratory website (www.mskcc.org/research-areas/labs/daniel-heller), Heller and team are “… developing nanomedicines to target precision agents to disease sites, including to metastatic cancers. We are also addressing the problem of the early detection of cancer and other diseases by building implantable nanosensors.

To enable the discovery of new medicines, we also are inventing new nanosensors and imaging tools to accelerate drug development and biomedical research.”

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Nanoparticles in Treatment

Heller told Oncology Times that it all begins with interaction and collaboration. “We are lucky because we get to dig deep with the clinicians, clinician/scientists, and biologists to understand exactly what might be wrong with a particular mode of therapy,” said Heller of his development process. “An oncologist might talk to us about a drug or class of therapies that have particular problems and specific side effects, such as dose-limiting toxicity that prevents people from getting enough of a therapy to adequately inhibit the target in the tumor.”

He added that problems often stem from the fact that a drug negatively affects tissue that is not part of the tumor. “Can we avoid that one vulnerable tissue that will really mess up the use of this drug for treating the tumor? Can we prevent the drug from getting into that tissue?” asked Heller rhetorically. Clearly, he believes it is possible with the help of nanoparticles.

He noted that people erroneously think of nanoparticles as being “the smallest of the small.” But small molecule drugs, and even protein drugs, are much smaller than nanoparticles. Most drugs can diffuse all over the body. “But if we put the drug into a larger nanoparticle, we can keep it from spraying out over all the tissues,” detailed Heller.

His team also must consider how to deliver the nanoparticle containing the drug to a precise location in the tumor site, and whether there is a target that can lead it to that tumor site. “Most of the targets we are looking for are not on the tumor cells themselves, but on the blood vessels that are feeding the tumor,” said Heller. “Our targets are not drug targets, but rather gateways to the tumor, molecules on blood vessels in tumors sites, or sites of inflammation. Then we make sure that the nanoparticle has a molecule on the outside of it that can stick to those targets.”

The research takes the engineering team into the realms of vascular biology, vascular transport, and an understanding of how materials can get across the blood, across the blood/brain barrier, across the tumor barrier. “We are also exploring signaling pathways,” said Heller. “When trying to deliver a kinase inhibitor, for example, we must consider the target we are hitting, where else that target is in the body, and if there any other off-target proteins elsewhere in the body that the drug will hit. We also have to think about resistance mechanisms and compensatory pathways. So as a team we have been learning a lot of physiology.”

Heller says his 5-year-old laboratory contains requisite benches, a tissue culture room, and a studio equipped with lasers and optics for work on sensors. In the basement reside the all-important mice, critical to preclinical development and testing. Looking at target proteins in the body of a mouse, the team is able to determine if a drug encased in a nanoparticle hits the target, if it works better in a nanoparticle, and if it has the same side effects.

The eventual goal is to translate this understanding and these emerging technologies to clinical use and human patients. But it is a long row to hoe. “Once a technology is developed, it must go through the full ‘investigational new drug’ FDA process,” Heller lamented. “Even if a known compound is inside the particle, the whole particle is treated as a new drug.

That means we can’t just give it to clinicians to trial in patients; first the FDA must allow us to start a clinical trial.” Though regulatory delays are a frustration, the researcher said enthusiasm remains high because the potential of the new technologies is so powerful.

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Nanoparticles in Detection

The Cancer Nanomedicine Laboratory also maintains an interest in developing innovative approaches to cancer detection that is “… easier and more predictive. We found that we can detect some cancers earlier by measuring certain biomarkers in a person without having to take blood or biofluids to do it,” said Heller.

Instead, a tiny sensor made of carbon nanotubes is inserted inside a person. The nanotubes give off infrared light that can pass through tissues. “We can implant nanomaterial in a body, shoot light into it from outside the body, and then get a reading externally,” detailed Heller. “These nanomaterials are very sensitive to certain stimuli. We can put an antibody onto the surface of the nanotube and when it binds to an antigen we can see a signal change—a shift in the wavelength of the nanotube fluorescence—through the tissue.” (The team successfully detected ovarian cancer signaling changes in a mouse model. This work was detailed in a paper, Non-Invasive Ovarian Cancer Biomarker Detection via an Optical Nanosensor Implant, coauthored by Heller in Science Advances [2018;4(4):eaaq1090]).

Implications for future use of this technology in humans are significant. Heller said the first possible application could be in people with risk factors for certain diseases. “We could implant a biomarker or panel of biomarkers in people to detect early stage cancer, to measure cancer recurrence, or to monitor treatment and have earlier warning when therapy stops working.”

Asked how early the signaling changes would become apparent, Heller said it depends on the level of a given marker in the tissue. “With ovarian cancer, we would look at the technology as an intrauterine device, placed near the source of the cancer. If we were to wait for biomarkers to reach a high enough level to be detected in the blood, we likely would be dealing with late-stage cancer. If we can measure that biomarker right next to the ovaries or fallopian tube, we would see signal changes at an even earlier point in the life cycle of the cancer.”

Looking downstream of this work, Heller said the team is already questioning if it might be possible to insert a small sensor under the skin, in the blood, or even in a tattoo to measure all kinds of biomarkers, then report a whole panel in real time, at early stages, back to a wearable Fitbit-like device. “The long-term hope is to find super easy ways to measure lots of biomarkers in real time,” said Heller.

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Nanoparticles in Discovery

A third aspect of the work underway in Heller’s lab focuses on making research tools, specifically using carbon nanotubes as sensors in drug discovery assays. Heller believes the sensors will be able to measure things that have not been measurable before, or measured in ways that could not be accomplished before, such as in living cells and living tissue. “By measuring an analyte inside living cells or living tissue in mice, we gain the ability to do studies that cannot be done otherwise. This will allow us to address new hypotheses, and it will be helpful for drug development and for basic researchers at institutions such as MSKCC.”

Heller stressed that it is exactly institutions like MSKCC that can lead the way in helping biomedical engineers interact more fully with biomedical researchers. “Even though both of these concepts have the word ‘biomedical’ in them, ‘biomedical engineering’ departments come from engineering schools, while ‘biomedical research’ comes from places that often do not have engineering schools.

So there is a disconnect,” said Heller. “I realize how valuable it is to me as an engineering researcher to be in a biomedical institution and come in contact with the people who study biomedical questions and understand the medical problems. Biomedical institutions would benefit greatly from organized efforts to bring in engineering researchers whose goal it is to understand and make new technologies to address their problems.”

Heller laughed at the suggestion that some of the things he makes sound like cinematic props from the vintage sci-fi flick, The Incredible Voyage. “Sometimes people think we are the science fiction lab of Memorial Sloan Kettering,” he admitted with humor. And when asked if the younger history student/middle school teacher/or physical scientist in him ever thinks, “I can’t believe I am doing this kind of stuff,” he answered without hesitation, “Yeah, all the time. I think I have gotten to where I am by not defining myself. It’s important to be flexible. Where does it stop? It doesn’t. If you keep changing you can aspire to do anything you want.”

Valerie Neff Newitt is a contributing writer.

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New Targeting strategy developed by Penn State may open door to better cancer drug delivery


Drug delivery targetingstrIn the transition from benign to malignant, cancer cells transition from stiff to soft. Mechanotargeting harnesses mechanics to improve targeting efficiency of nanparticle-based therapeutic agents. Credit: Zhang lab/vecteezy.com

Bioengineers may be able to use the unique mechanical properties of diseased cells, such as metastatic cancer cells, to help improve delivery of drug treatments to the targeted cells, according to a team of researchers at Penn State.

Many labs around the world are developing nanoparticle-based,  to selectively target tumors. They rely on a key-and-lock system in which protein keys on the surface of the nanoparticle click into the locks of a highly expressed protein on the surface of the cancer cell. The cell membrane then wraps around the nanoparticle and ingests it. If enough of the nanoparticles and their drug cargo is ingested, the cancer cell will die.

The adhesive force of the lock and key is what drives the nanoparticle into the cell, said Sulin Zhang, professor of engineering science and mechanics.

“It is almost universal that whenever there is a driving force for a process, there always is a resistive force,” Zhang said. “Here, the driving force is biochemical—the protein-protein interaction.”

The resistive force is the mechanical energy cost required for the membrane to wrap around the nanoparticle. Until now, bioengineers only considered the driving force and designed nanoparticles to optimize the chemical interactions, a targeting strategy called “chemotargeting.” Zhang believes they should also take into account the mechanics of the  to design nanoparticles to achieve enhanced targeting, which forms a new targeting strategy called “mechanotargeting.”

“These two targeting strategies are complementary; you can combine chemotargeting and mechanotargeting to achieve the full potential of nanoparticle-based diagnostic and therapeutic agents,” Zhang said. “The fact is that targeting efficiency requires a delicate balance between driving and resistive forces. For instance, if there are too many keys on the nanoparticle surface, even though these keys only weakly interact with the nonmatching locks on normal cells, these weak, off-target interactions may still provide enough adhesion energy for the nanoparticles to penetrate the  and kill the healthy cells.”

On the other hand, if the adhesion energy is not high enough, the nanoparticle won’t get into the cell.

In “Mechanotargeting: Mechanics-dependent Cellular Uptake of Nanoparticles,” published online ahead of print in the journal Advanced Materials, Zhang and the team report the results of experiments on cancer cells grown on hydrogels of variable stiffness. On soft hydrogels the cells remained cohesive and benign and experienced a nearly constant stress that limited the uptake of the nanoparticles. But on stiff hydrogels the cells became metastatic and adopted a three-dimensional shape, offering more surface area for nanoparticles to adhere, and became less stressed. Under this condition, the cells took up five times the number of nanoparticles as the benign cells.

“The nanoparticles are fluorescent, so we count the number of  that get into the cell by the fluorescence intensity. We found that in the malignant cells the intensity is five times higher,” Zhang said. “That proves that mechanotargeting works.”

 Explore further: Nanoparticle aggregates for destruction of cancer cells

More information: Qiong Wei et al, Mechanotargeting: Mechanics-Dependent Cellular Uptake of Nanoparticles, Advanced Materials (2018). DOI: 10.1002/adma.201707464

 

The University of Texas at Arlington has successfully patented (Europe) an implantable medical device that attracts and kills circulating cancer cells


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The University of Texas at Arlington has successfully patented in Europe an implantable medical device that attracts and kills circulating cancer cells that was invented by a faculty member. This cancer trap can be used for early diagnosis and treatment of metastasized cancer.

“Our cancer trap works just like a roach motel, where you put in some bait and the roach goes there and dies,” said Liping Tang, UTA bioengineering professor and leader of the research. “We are putting biological agents in a cancer trap to attract and kill cancer cells.

“This method is effective for both diagnosing and treating metastasis cancer and can be used in combination with traditional chemotherapy and radiation therapy,” he added.

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Currently, there are many treatments for primary tumors but they do little to prevent metastasis and stray cancer cells from relocating to another part of the body. Surgical removal of cancerous tissue also can spur the spread of cancer in the body. While there are drugs given to patients after surgery to prevent cancer cells from adhering to each other or other tissues, these drugs do not rid the body of cancer cells or collect them to allow an assessment of the patient’s status.

“We have made a nano-sized device that we can put under the skin using an injection needle to recruit the cancer cells into a small area where we can treat them with less overall side effects to the whole body,” Tang said.

“So the cancer trap is really complementary to current cancer treatments and especially beneficial at the early stages when it is difficult to see if the cancer is spreading as there are few cancer cells. We have also found it very effective in late stage cancers to stop the spread of the disease and to prolong lifespan,” he added.

The cancer trap works by releasing different chemokines or regulatory proteins to attract circulating cancer cells and then expose them to chemotherapeutic agents to eradicate potential spreading. The trap has been tested in the lab and proved effective on many kinds of cancer cells, including melanoma, prostate cancer, breast cancer, lung cancer, leukemia and esophageal cancer.

“We are hoping to move toward clinical trials in the next few years as this technology could potentially significantly increase the lifespan of cancer patients,” Tang said.

This work on cancer forms part of a larger program at UTA where more than 30 faculty from different colleges and disciplines are developing new solutions to attack this disease.

With more than $4 million in research expenditures in 2017, UTA’s program for cancer encompasses basic cancer research, identification and diagnostics, as well as in noninvasive, midterm, invasive and postoperative therapies. UTA’s multidisciplinary research teams harness proficiencies from across science, engineering, computer science, nursing and kinesiology to tackle the challenges of precision oncology and cancer treatment.

Tang’s expertise encompasses a broad area, including stem cells, tissue engineering, nanotechnology, biocompatibility, biomaterials, inflammation, infection and fibrosis. He has published many of his work in high impact journals, including BiomaterialsJournal of Clinical InvestigationProceedings of the National Academy of SciencesBloodJournal of Experimental Medicine, and Tissue Engineering.

“Tang is a remarkable innovator and internationally recognized researcher,” said Michael Cho, UTA’s chair of bioengineering. “His work is a clear example of UTA’s strategic focus on health and the human condition and of the strength of multidisciplinary work.”

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New Simple Blood Test can Detect Alzheimer’s 30 Years in Advance + Can Also Detect 8 Cancers: Videos


New Simple Blood Test can Detect Alzheimer’s 30 Years in Advance + Can Also Detect 8 Cancers

#GreatThingsFromSmallThings

Watch the Videos Below

Detecting Alzheimer’s 30 Years in Advance

8 Cancers Detected with ONE Simple Blood Test

Remote-control shoots laser at nano-gold to turn on cancer-killing immune cells – could one day send immune cells on a rampage against a malignant tumor


Nano Thermo Cancer 55092A heat-sensitive gene switch implanted in a sample of T-cells works in an in vitro check. Gentle pulses from a near-infrared laser directed at gold nanoparticles, which are also in the sample with the T-cells, transform into gentle heat and flip the switch on, activating the T-cells. The resulting signal appears as orange dots on a monitor in the background. CREDIT Georgia Tech / Allison Carter

Abstract:
A remote command could one day send immune cells on a rampage against a malignant tumor. The ability to mobilize, from outside the body, targeted cancer immunotherapy inside the body has taken a step closer to becoming reality.

Remote-control shoots laser at nano-gold to turn on cancer-killing immune cells

Bioengineers at the Georgia Institute of Technology have installed a heat-sensitive switch into T-cells that can activate the T-cells when heat turns the switch on. The method, tested in mice and published in a new study, is locally targeted and could someday help turn immunotherapy into a precision instrument in the fight against cancer.

Immunotherapy has made headlines with startling high-profile successes like saving former U.S. President Jimmy Carter from brain cancer. But the treatment, which activates the body’s own immune system against cancer and other diseases, has also, unfortunately, proved to be hit-or-miss.

“In patients where radiation and traditional chemotherapies have failed, this is where T-cell therapies have shined, but the therapy is still new,” said principal investigator Gabe Kwong. “This study is a step toward making it even more effective.”

Laser, gold, and T-cells

In the study, Kwong’s team successfully put their remote-control method through initial tests in mice with implanted tumors (so-called tumor phantoms, specially designed for certain experiments). The remote works via three basic components.

First, the researchers modified T-cells, a type of white blood cell, to include a genetic switch that, when switched on, increased the cells’ expression of specific proteins by more than 200 times. That ability could be used to guide T-cells’ cancer-fighting activities.

The T-cells, with the switch off, were introduced into the tumor phantom which was placed into the mice. The tumor phantom also included gold nanorods, just dozens of atoms in size. The researchers shone pulses of a gentle laser in the near-infrared (NIR) range from outside the mouse’s body onto the spot where the tumor was located.

The nanorods receiving the light waves turned them into useful, localized mild heat, allowing the researchers to precisely warm the tumor. The elevated heat turned on the T-cells’ engineered switch.

Hyper-activated T-cells

This study honed the method and confirmed that its components worked in living animals. It was not the intention of the study to treat cancer yet, although undertaking that is the next step, which is already on its way.

“In upcoming experiments, we are implementing this approach to treat aggressive tumors and establish cancer-fighting effectiveness,” said Kwong, who is an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The researchers published their results in the current edition of the journal ACS Synthetic Biology. The study’s first author was graduate research assistant Ian Miller. The research was funded by the National Institutes of Health, the National Science Foundation, the Burroughs Wellcome Fund, and the Shurl and Kay Curci Foundation.

Better immunotherapy

Bioengineers have been able to do a lot with T-cells already when they’re outside of the body.

“Right now, we’re adept at harvesting a patient’s own T-cells, modifying to target cancer, growing them outside the body until there are hundreds of millions of them,” Kwong said. “But as soon as we inject them back into a patient, we lose control over the T-cells’ activity inside the body.”

Cancer is notoriously wily, and when T-cells crawl into a tumor, the tumor tends to switch off the T-cells’ cancer-killing abilities. Researchers have been working to switch them back on.

Kwong’s remote control has done this in the lab, while also boosting T-cell activity.

T-cell toxicities

Having an off-switch is also important. If T-cells were engineered to be always-on and hyper-activated, as they moved through the body, they could damage healthy tissue.

“There would be off-target toxicities, so you really want to pinpoint their activation,” Kwong said. “Our long-term goal for them is to activate site-specifically, so T-cells can overcome immunosuppression by the tumor and become better killers there.”

When the heat remote is turned off, so are Kwong’s engineered T-cells, because customary body temperatures are not high enough to activate their switch.

Heat-shock switch

The switch is a natural safety mechanism in human cells that has evolved to protect against heat shock and turns on when tissue temperatures rise above the body’s normal operating range, which centers on 37 degrees Celsius (98.6 F). But the researchers re-fitted T-cells with the switch to make it turn on other functions, and it could be used to hyper-activate the cells.

The Georgia Tech bioengineers found that the switch worked in a range of 40 to 42 degrees Celsius (104 – 107.6 F), high enough to not react to the majority of high fevers and low enough to not damage healthy tissue nor the engineered T-cells.

“When the local temperature is raised to 45 degrees (113 F), some cells in our body don’t like it,” Kwong said. “But if heating is precisely controlled in a 40 to 42 degrees window with short pulses of the NIR light, then it turns on the T-cells’ switch, and body cells are still very comfortable.”

Immuno-goals and dreams

The researchers want to combine the switch with some additional cancer-fighting weapons they envision engineering into T-cells.

For example, secreted molecules called cytokines can boost immune cells’ ability to kill cancer, but cytokines, unfortunately, can also be toxic. “Our long-term goal is to engineer T-cells to make and release powerful immune system stimulants like cytokines on command locally and sparingly,” Kwong said.

In other studies, gently heated gold nanorods have been shown to kill tumors or hinder metastasis. But T-cell treatments could be even more thorough and, in addition, hopefully, one day give patients treated with them a long-lasting memory immune response to any recurrence of their cancer.

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Citation: This experimental method is in laboratory stages in mice and is not yet available as a treatment of any type for human patients. The study was co-authored by Marielena Castro, Joe Maenza and Jason Weis of Coulter BME at Georgia Tech. The research was funded by the National Institutes of Health Director’s New Innovator Award (grant #DP2HD091793), the NIH National Center for Advancing Translational Sciences (grant #UL1TR000454), the NIH GT BioMAT Training Grant (#5T32EB006343), the National Science Foundation (grant # DGE-1451512), the Shurl and Kay Curci Foundation, and the Burroughs Wellcome Fund. Any findings or opinions are those of the authors and not necessarily of the funding agencies.

Novel Nanomedicine Inhibits Progression of Pancreatic Cancer in Mice – Tel Aviv University


Nanomedicine I download

Survival rates in pancreatic cancer linked to inverse correlation between specific oncogene and tumor suppressant, Tel Aviv University researchers say

A new Tel Aviv University study pinpoints the inverse correlation between a known oncogene — a gene that promotes the development of cancer — and the expression of an oncosuppressor microRNA as the reason for extended pancreatic cancer survival. The study may serve as a basis for the development of an effective cocktail of drugs for this deadly disease and other cancers.

Nanomedicine III imagesThe study, which was published in Nature Communications, was led by Prof. Ronit Satchi-Fainaro, Chair of the Department of Physiology and Pharmacology at TAU’s Sackler Faculty of Medicine, and conducted by Hadas Gibori and Dr. Shay Eliyahu, both of Prof. Satchi-Fainaro’s multidisciplinary laboratory, in collaboration with Prof. Eytan Ruppin of TAU’s Computer Science Department and the University of Maryland and Prof. Iris Barshack and Dr. Talia Golan of Chaim Sheba Medical Center, Tel Hashomer.

Pancreatic cancer is among the most aggressive cancers known today. The overwhelming majority of pancreatic cancer patients die within just a year of diagnosis. “Despite all the treatments afforded by modern medicine, some 75% of all pancreatic cancer patients die within 12 months of diagnosis, including many who die within just a few months,” Prof. Satchi-Fainaro says.

“But around seven percent of those diagnosed will survive more than five years. We sought to examine what distinguishes the survivors from the rest of the patients,” Prof. Satchi-Fainaro continues. “We thought that if we could understand how some people live several years with this most aggressive disease, we might be able to develop a new therapeutic strategy.”

Nanomedicine I downloadCalling a nano-taxi

The research team examined pancreatic cancer cells and discovered an inverse correlation between the signatures of miR-34a, a tumor suppressant, and PLK1, a known oncogene. The levels of miR-34a were low in pancreatic cancer mouse models, while the levels of the oncogene were high. This correlation made sense for such an aggressive cancer. But the team needed to see if the same was true in humans.

The scientists performed RNA profiling and analysis of samples taken from pancreatic cancer patients. The molecular profiling revealed the same genomic pattern found earlier in mouse models of pancreatic cancer.

The scientists then devised a novel nanoparticle that selectively delivers genetic material to a tumor and prevents side effects in surrounding healthy tissues.

“We designed a nanocarrier to deliver two passengers: (1) miR-34a, which degrades hundreds of oncogenes; and (2) a PLK1 small interfering RNA (siRNA), that silences a single gene,” Prof. Satchi-Fainaro says. “These were delivered directly to the tumor site to change the molecular signature of the cancer cells, rendering the tumor dormant or eradicating it altogether.Nanomedicine II pancreatic-cancer-1140x641

“The nanoparticle is like a taxi carrying two important passengers,” Prof. Satchi-Fainaro continues. “Many oncology protocols are cocktails, but the drugs usually do not reach the tumor at the same time. But our ‘taxi’ kept the ‘passengers’ — and the rest of the body — safe the whole way, targeting only the tumor tissue. Once it ‘parked,’ an enzyme present in pancreatic cancer caused the carrier to biodegrade, allowing the therapeutic cargo to be released at the correct address — the tumor cells.”

Improving the odds

To validate their findings, the scientists injected the novel nanoparticles into pancreatic tumor-bearing mice and observed that by balancing these two targets — bringing them to a normal level by increasing their expression or blocking the gene responsible for their expression — they significantly prolonged the survival of the mice.

“This treatment takes into account the entire genomic pattern, and shows that affecting a single gene is not enough for the treatment of pancreatic cancer or any cancer type in general,” according to Prof. Satchi-Fainaro.

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Research for the study was funded by the European Research Council (ERC), Tel Aviv University’s Cancer Biology Research Center (CBRC) and the Israel Science Foundation (ISF).

American Friends of Tel Aviv University (AFTAU) supports Israel’s most influential, comprehensive and sought-after center of higher learning, Tel Aviv University (TAU). TAU is recognized and celebrated internationally for creating an innovative, entrepreneurial culture on campus that generates inventions, startups and economic development in Israel. For three years in a row, TAU ranked 9th in the world, and first in Israel, for alumni going on to become successful entrepreneurs backed by significant venture capital, a ranking that surpassed several Ivy League universities. To date, 2,400 patents have been filed out of the University, making TAU 29th in the world for patents among academic institutions.

Fighting Cancer and Drug Resistance – A ‘Nanosystem’ Does Both


Cancer is often referred to as “smart,” and this term often refers to the ability of these cells to proliferate without purpose or restraint.

The ability of cancer cells to develop multidrug resistance (MDR), a major problem that patients can face, making treatment against this disease even more elusive.

In an effort to combat both cancer cell proliferation and MDR, a recent study conducted by researchers from the National Health Research Institutes of Taiwan and the National Science Council of Taiwan have developed a nanosystem capable of addressing both challenges in the field of cancer therapy.

Drug Resistance and Cancer

Patients with several forms of blood cancer and solid tumors in the breast, ovaries, lungs and lower gastrointestinal tract can become untreatable as a result of multidrug resistance (MDR).

In MDR, the cancer cells of these patients become resistant to commonly used therapeutic drugs as a result of an overexpression of ATP-binding cassette (ABC) transporters that effectively push out drug molecules following administration.

P-glycoprotein and what is termed as the multidrug resistance-associated protein (MRP) are two of the most studied pumps present in cancer cells that are capable of rejecting chemotherapeutic drugs.

By avoiding the toxic effects of these drugs, cancer cells are able to continue to proliferate and metastasize to other organs of the body.

Unfortunately, some of the most commonly used cancer therapeutic drugs such as colchicine, vinblastine, doxorubicin, etoposide, paclitaxel, certain vinca alkaloids and other small molecules have shown resistance in various cancer cells.

Current research efforts in the field of anticancer drug discovery have looked towards the administration of combinatorial technology to be administered with cancer to effectively prevent cancer cells from physically removing therapeutic drugs when administered together.

While blocking the action of pumps like MRP and P-glycoprotein has shown some efficacy, transcription factors, such as c-Jun, which plays a role in cell, proliferation and MDR, can still potentiate metastasis.

Therefore, there remains a need to develop cancer therapies that work against drug resistance and simultaneously prevent further metastasis.

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The Efficacy of Administering Doxorubicin Mesoporous Silica Nanoparticles (MSNs)

Mesoporous silica nanoparticles (MSNs) are well-documented drug delivery vehicles that allow for a high drug loading capacity with minimal side effects upon administration.

The tunable size properties, thermal stability, photostability and ease of functionalization to different applications make MSNs one of the most promising options for therapeutic delivery systems.

In the recent study published in Nano Futures, the group of scientists led by Leu-Wei Lo covalently conjugated MSNs with doxorubicin and tested the ability of these nanosystems to be taken up by cancer cells in vitro.

The PC-3 cell line of metastatic human prostate carcinoma cells were treated with 100 μg/ml of either Dox-MSNs that were conjugated with DNAzyme, (Dox-MSN-Dz), Dox-MSNs or control MSNs for 24 hours to study the ability of these cells to survive following treatment.

The researchers found the Dox-MSN-Dz reduced cell survival rates by over 80%, whereas the Dox-MSNs alone still reduced cell survival rates by 60%.

The results of this study confirm the therapeutic potential of the developed multifunctional nanosystem, which incorporates doxorubicin, a widely used chemotherapeutic drug, MSNs and DNAzyme.

Not only did this nanosystem improve the cytotoxicity of doxorubicin to a resistance cancer cell line, but it also successfully reduced migration of cancer cells by inhibiting c-Jun.

While further in vivo studies need to be conducted to fully evaluate the ability of Dox-MSN-Dz to prevent metastasis and invade highly resistance cancer cells, the results of this study are promising.

Future research initiatives that incorporate different chemotherapeutic drugs into a similar nanosystem design could also show similar bifunctional properties as presented here.

Image Credit:

fusebulb/Shutterstock.com

References:

1 “A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis” S. Sun, C. Liu, et al. Nano Futures. (2017). DOI: 10.1088/2399-1984/aa996f.

Rice – MD Anderson use Fluorescent Carbon Nanotube probes to detect ovarian cancer – Achieve first In – Vivo Success


 

 

Rice CNTs 57f79f2812948

Abstract:
Researchers at Rice University and the University of Texas MD Anderson Cancer Center have refined and, for the first time, run in vivo tests of a method that may allow nanotube-based probes to locate specific tumors in the body. Their ability to pinpoint tumors with sub-millimeter accuracy could eventually improve early detection and treatment of ovarian cancer.

The noninvasive technique relies on single-walled carbon nanotubes that can be optically triggered to emit shortwave infrared light. The Rice lab of chemist Bruce Weisman, a pioneer in the discovery and interpretation of the phenomenon, reported the new results in the American Chemical Society journal ACS Applied Materials and Interfaces.

Rice Optical Sensor CNTs 0523_SPECTRAL-1-web-txhgun

For this study, the researchers used the technique to pinpoint small concentrations of nanotubes inside rodents. The lab of co-author Dr. Robert Bast Jr., an expert in ovarian cancer and vice president for translational research at MD Anderson, inserted gel-bound carbon nanotubes into the ovaries of rodents to mimic the accumulations that are expected for nanotubes linked to special antibodies that recognize tumor cells. The rodents were then scanned with the Rice lab’s custom-built optical device to detect the faint emission signatures of as little as 100 picograms of nanotubes.

The device irradiated the rodents with intense red light from an array of light-emitting diodes and read fluorescent signals with a specialized sensitive detector. Because different types of tissue absorb emissions from the nanotubes differently, the scanner took readings from many locations to triangulate the tumor’s exact location, as confirmed by later MRI scans.

Weisman said it should be possible to noninvasively find small ovarian tumors within rodents used for medical research by linking nanotubes to antibody biomarkers and administering the biomarkers intravenously. The biomarkers would accumulate at the tumor site. He said more refined versions of the optical scanner may then be able to locate a tumor within seconds, and further advances may extend the method’s application to human cancer detection. The new results suggested that antibody-nanotube probes could potentially detect tumors with as few as 100 ovarian cancer cells, which could make it a valuable tool for early detection. Rice MD Anderson Cancer CNTs 54864

Rice graduate student Ching-Wei Lin is lead author of the paper. Co-authors from the Bast group at MD Anderson are researcher Dr. Hailing Yang and senior research assistants Weiqun Mao and Lan Pang. Rice co-authors are chemistry graduate student Stephen Sanchez and Kathleen Beckingham, a professor of biosciences.

The research was supported by the National Science Foundation, the Welch Foundation, the National Institutes of Health, the John S. Dunn Foundation Collaborative Research Award Program, the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, the National Foundation for Cancer Research, the Mossy Foundation, Golfers Against Cancer, the Roberson Endowment and Stuart and Gaye Lynn Zarrow.

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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.

Rice U: Nano-Shells could deliver more chemo with fewer side effects


Rice Nano shells 171108143658_1_540x360
Researchers from Rice University and Northwestern University loaded light-activated nano-shells (gold and light blue) with the anticancer drug lapatinib (yellow) by encasing the drug in an envelope of albumin (blue). Light from a near-infrared laser (center) was used to remotely trigger the release of the drug (right) after the nano-shells were taken up by cancer cells. Credit: A. Goodman/Rice University

Researchers investigating ways to deliver high doses of cancer-killing drugs inside tumors have shown they can use a laser and light-activated gold nanoparticles to remotely trigger the release of approved cancer drugs inside cancer cells in laboratory cultures.

The study by researchers at Rice University and Northwestern University Feinberg School of Medicine appears in this week’s online Early Edition of the Proceedings of the National Academy of Sciences. It employed gold nanoshells to deliver toxic doses of two drugs — lapatinib and docetaxel — inside breast cancer cells. The researchers showed they could use a laser to remotely trigger the particles to release the drugs after they entered the cells.

Though the tests were conducted with cell cultures in a lab, the research was designed to demonstrate clinical applicability: The nanoparticles are nontoxic, the drugs are widely used and the low-power, infrared laser can noninvasively shine through tissue and reach tumors several inches below the skin.

“In future studies, we plan to use a Trojan-horse strategy to get the drug-laden nanoshells inside tumors,” said Naomi Halas, an engineer, chemist and physicist at Rice University who invented gold nanoshells and has spent more than 15 years researching their anticancer potential. “Macrophages, a type of white blood cell that’s been shown to penetrate tumors, will carry the drug-particle complexes into tumors, and once there we use a laser to release the drugs.”

Co-author Susan Clare, a research associate professor of surgery at the Northwestern University Feinberg School of Medicine, said the PNAS study was designed to demonstrate the feasibility of the Trojan-horse approach. In addition to demonstrating that drugs could be released inside cancer cells, the study also showed that in macrophages, the drugs did not detach prior to triggering.

“Getting chemotherapeutic drugs to penetrate tumors is very challenging,” said Clare, also a Northwestern Medicine breast cancer surgeon. “Drugs tend to get pushed out of tumors rather than drawn in. To get an effective dose at the tumor, patients often have to take so much of the drug that nausea and other side effects become severe. Our hope is that the combination of macrophages and triggered drug-release will boost the effective dose of drugs within tumors so that patients can take less rather than more.”

If the approach works, Clare said, it could result in fewer side effects and potentially be used to treat many kinds of cancer. For example, one of the drugs in the study, lapatinib, is part of a broad class of chemotherapies called tyrosine kinase inhibitors that target specific proteins linked to different types of cancer. Other Federal Drug Administration-approved drugs in the class include imatinib (leukemia), gefitinib (breast, lung), erlotinib (lung, pancreatic), sunitinib (stomach, kidney) and sorafenib (liver, thyroid and kidney).

“All the tyrosine kinase inhibitors are notoriously insoluble in water,” said Amanda Goodman, a Rice alumna and lead author of the PNAS study. “As a drug class, they have poor bioavailability, which means that a relatively small proportion of the drug in each pill is actually killing cancer cells. If our method works for lapatinib and breast cancer, it may also work for the other drugs in the class.”

Halas invented nanoshells at Rice in the 1990s. About 20 times smaller than a red blood cell, they are made of a sphere of glass covered by a thin layer of gold. Nanoshells can be tuned to capture energy from specific wavelengths of light, including near-infrared (near-IR), a nonvisible wavelength that passes through most tissues in the body. Nanospectra Biosciences, a licensee of this technology, has performed several clinical trials over the past decade using nanoshells as photothermal agents that destroy tumors with infrared light.

Clare and Halas’ collaboration on nanoshell-based drug delivery began more than 10 years ago. In earlier work, they showed that a near-IR continuous-wave laser — the same kind that produces heat in the photothermal applications of nanoshells — could be used to trigger the release of drugs from nanoshells.

In the latest study, Goodman contrasted the use of continuous-wave laser triggering and triggering with a low-power pulse laser. Using each type of laser, she demonstrated the remotely triggered release of drugs from two types of nanoshell-drug conjugates. One type used a DNA linker and the drug docetaxel, and the other employed a coating of the blood protein albumin to trap and hold lapatinib. In each case, Goodman found she could trigger the release of the drug after the nanoshells were taken up inside cancer cells. She also found no measureable premature release of drugs in macrophages in either case.

Halas and Clare said they hope to begin animal tests of the technology soon and have an established mouse model that could be used for the testing.

“I’m particularly excited about the potential for lapatinib,” Clare said. “The first time I heard about Naomi’s work, I wondered if it might be the answer to delivering drugs into the anoxic (depleted of oxygen) interior of tumors where some of the most aggressive cancer cells lurk. As clinicians, we’re always looking for ways to keep cancer from coming back months or years later, and I am hopeful this can do that.”

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Converging on Cancer at the Nanoscale


MIT-KI-Marble-Center-Faculty-00_0The Marble Center for Cancer Nanomedicine’s faculty is made up of Koch Institute members who are committed to fighting cancer with nanomedicine through research, education, and collaboration. Top row (l-r) Sangeeta Bhatia, director; Daniel Anderson; and Angela Belcher. Bottom row: Paula Hammond; Darrell Irvine; and Robert Langer. Photo: Koch Institute Marble Center for Cancer Nanomedicine

 Koch Institute – July 2017

Marking its first anniversary, the Koch Institute’s Marble Center for Cancer Nanomedicine goes full steam ahead.

This summer, the Koch Institute for Integrative Cancer Research at MIT marks the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, established through a generous gift from Kathy and Curt Marble ’63.

Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on grand challenges in cancer detection, treatment, and monitoring that can benefit from the emerging biology and physics of the nanoscale.

These challenges include detecting cancer earlier than existing methods allow, harnessing the immune system to fight cancer even as it evolves, using therapeutic insights from cancer biology to design therapies for previously undruggable targets, combining existing drugs for synergistic action, and creating tools for more accurate diagnosis and better surgical intervention. cancer-shapeshiftin

Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the inaugural director for the center.

”A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world,” Bhatia says.

Transforming nanomedicine

The Marble Center joins MIT’s broader efforts at the forefront of discovery and innovation to solve the urgent global challenge that is cancer. The concept of “convergence” — the blending of the life and physical sciences with engineering — is a hallmark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Center’s mission.

“The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care,” says Tyler Jacks, director of the Koch Institute and a David H. Koch Professor of Biology. “It’s transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring — and translational by promoting their development and application in the clinic.”

The center’s faculty — six prominent MIT professors and Koch Institute members — are committed to fighting cancer with nanomedicine through research, education, and collaboration. They are:

Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science;

Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science;

Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering;

Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering;

Darrell J. Irvine, professor in the departments of Biological Engineering and Materials Science and Engineering; and

Robert S. Langer, the David H. Koch Institute Professor.

Extending their collaboration within the walls of the Institute, Marble Center members benefit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center. The Peterson Facility’s array of technological resources and expertise is unmatched in the United States, and gives members of the center, and of the Koch Institute, a distinct advantage in the development and application of nanoscale materials and technologies.

Looking ahead

Figure-1-11-Nanocarriers-for-cancer-theranostics-Nanoparticles-based-strategies-can-beThe Marble Center has wasted no time getting up to speed in its first year, and has provided support for innovative research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to better understand response to cancer immunotherapies, and delivery technologies for several powerful RNA-based therapeutics able to engage specific cancer targets with precision.

As part of its efforts to help foster a multifaceted science and engineering research force, the center has provided fellowship support for trainees — as well as valuable opportunities for mentorship, scientific exchange, and professional development.

Promoting broader engagement, the Marble Center serves as a bridge to a wide network of nanomedicine resources, connecting its members to MIT.nano, other nanotechnology researchers, and clinical collaborators across Boston and beyond. The center has also convened a scientific advisory board, whose members hail from leading academic and clinical centers around the country, and will help shape the center’s future programs and continued expansion.

As the Marble Center begins another year of collaborations and innovation, there is a new milestone in sight for 2018. Nanomedicine has been selected as the central theme for the Koch Institute’s 17th Annual Cancer Research Symposium. Scheduled for June 15, 2018, the event will bring together national leaders in the field, providing an ideal forum for Marble Center members to share the discoveries and advancements made during its sophomore year.

“Having next year’s KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale,” Bhatia says. “The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.”

To learn more about the people and projects of the Koch Institute Marble Center for Cancer Nanomedicine, visit nanomedicine.mit.edu.