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


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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.

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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.

Swedish Researchers develop Precision Nanomaterials to selectively kill Cancer Cells


precisionnan cancer cellsDendrimers loaded with organic sulfur compounds (OSC) accumulate in cancer cells, where they are broken down and release reactive oxygen radicals (ROS). The elevation of ROS levels eventually spells death for the cancer cell. Credit: KTH The Royal Institute of Technology

Researchers in Sweden have succeeded in taking the next step toward using man-made nanoscale compounds in the fight against cancer. A recent proof-of-concept study showed that dendrimers, which were first introduced in the 1980s, may be used to introduce compounds that essentially trick cancer cells into performing self-destructive tasks.

Dendrimers, or cascade molecules, are organically synthesized large molecules that match nature’s peptides and proteins with respect to size and structure. Researchers from KTH Royal Institute of Technology took advantage of these qualities – and cancer cells’ appetite for adsorbing large molecules – by loading the material with an organic sulfur compound (OSC) which is also a key ingredient in amino acids, peptides and proteins.

Applying these to cultured human cancer cells sets in motion a process that distracts cancer cells from their normal task of multiplying, and instead go to work on picking apart disulfide bonds in the dendrimers, says Michael Malkoch, a professor of fiber and polymer technology at KTH.

Malkoch says that this activity releases an increased concentration of reactive oxygen radicals (ROS), which eventually induces cell death. Unlike treatments like chemotherapy, the effect is selective toward , leaving the healthy ones unaffected since  have a higher tolerance for ROS.

The nanomaterial is finally broken down by the body, he says.

The article was published in Journal of the American Chemical Society, and is co-authored by Malkoch, KTH doctoral student Oliver Andrén and Aristi P. Fernandes of Karolinska Institutet.

Their results show that the platform is worth continued research with clinical tests in which dendrimers are preprogrammed with large and specific numbers of organic , Malkoch says.

“We’ve just scratched the surface for what you can do with . We have previously tested using similar materials as a part of a leg patch – a type of adhesive that in some cases enables treatment of bone fractures without screws and plates,” he says. “You can imagine future applications where the material is used to coat implants around  tumors and thereby enable therapy treatment at a localized level.”

 Explore further: ‘Spiders’ that battle cancer

More information: Oliver C. J. Andrén et al. Heterogeneous Rupturing Dendrimers, Journal of the American Chemical Society (2017). DOI: 10.1021/jacs.7b10377

 

‘Swiss army knife’ Nanovaccine carries multiple weapons to battle tumors – cancer


Swiss Army Knife of Nano Ps 171129163851_1_540x360
Source: National Institute of Biomedical Imaging and Bioengineering
Summary: Researchers have developed a synergistic cancer nanovaccine packing DNA and RNA sequences that modulate the immune response, along with anti-tumor antigens, into one small nanoparticle.
(Above) Large particles (left) containing the DNA and RNA components are coated with electronically charged molecules that shrink the particle. The tumor-specific neoantigen is then complexed with the surface to complete construction of the nanovaccine. Upper left: electron micrograph of large particle. Credit: Zhu, et al. Nat Comm.

 

 

Scientists are using their increasing knowledge of the complex interaction between cancer and the immune system to engineer increasingly potent anti-cancer vaccines. The nanovaccine produced an immune response that specifically killed tumor tissue, while simultaneously inhibiting tumor-induced immune suppression to block lung tumor growth in a mouse model of metastatic colon cancer.

Now researchers at the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have developed a synergistic nanovaccine packing DNA and RNA sequences that modulate the immune response, along with anti-tumor antigens, into one small nanoparticle. The nanovaccine produced an immune response that specifically killed tumor tissue, while simultaneously inhibiting tumor-induced immune suppression. Together this blocked lung tumor growth in a mouse model of metastatic colon cancer.

The molecular dance between cancer and the immune system is a complex one and scientists continue to identify the specific molecular pathways that rev up or tamp down the immune system. Biomedical engineers are using this knowledge to create nanoparticles that can carry different molecular agents that target these pathways. The goal is to simultaneously stimulate the immune system to specifically attack the tumor while also inhibiting the suppression of the immune system, which often occurs in cancer patients. The aim is to press on the gas pedal of the immune system while also releasing the emergency brake.

A key hurdle is to design a system to reproducibly and efficiently create a nanoparticle loaded with multiple agents that synergize to mount an enhanced immune attack on the tumor. Engineers at the NIBIB report the development and testing of such a nanovaccine in the November issue of Nature Communications.

Making all the parts fit

Guizhi Zhu, Ph.D., a post-doctoral fellow in the NIBIB Laboratory of Molecular Imaging and Nanomedicine (LOMIN) and lead author on the study, explains the challenge. “We are very excited about putting multiple cooperating molecules that have anti-cancer activity into one nanovaccine to increase effectiveness. However, the bioengineering challenge is fitting everything in to a small particle and designing a way to maintain its structural integrity and biological activity.”

Zhu and his colleagues have created what they call a “self-assembling, intertwining DNA-RNA nanocapsule loaded with tumor neoantigens.” They describe it as a synergistic vaccine because the components work together to stimulate and enhance an immune attack against a tumor.

The DNA component of the vaccine is known to stimulate immune cells to work with partner immune cells for antitumor activation. The tumor neoantigens are pieces of proteins that are only present in the tumor; so, when the DNA attracts the immune cells, the immune cells interact with the tumor neoantigens and mount an expanded and specific immune response against the tumor. The RNA is the component that inhibits suppression of the immune system. The engineered RNA binds to and degrades the tumor’s mRNA that makes a protein called STAT3. Thus, the bound mRNA is blocked from making STAT3, which may suppress the immune system. The result is an enhanced immune response that is specific to the tumor and does not harm healthy tissues.

In addition to engineering a system where the DNA, RNA and tumor neoantigens self-assemble into a stable nanoparticle, an important final step in the process is shrinking the particle. Zhu explains: “Shrinking the particle is a critical step for activating an immune response. This is because a very small nanoparticle can more readily move through the lymphatic vessels to reach the parts of the immune system such as lymph nodes. A process that is essential for immune activation.”

The method for shrinking also had to be engineered. This was achieved by coating the particle with a positively charged polypeptide that interacts with the negatively charged DNA and RNA components to condense it to one-tenth of its original size.

Testing the nanovaccine

To create a model of metastatic colon cancer, the researchers injected human colon cancer cells into the circulation of mice. The cells infiltrate different organs and grow as metastatic colon cancer. One of the prime sites of metastasis is the lung.

The nanovaccine was injected under the skin of the mice 10, 16, and 22 days after the colon cancer cells were injected. To compare to the nanovaccine, two control groups of mice were analyzed; one group was injected with just the DNA and the neoantigen in solution but not formed into a nanovaccine particle, and the second control group was injected with an inert buffer solution.

At 40 days into the experiment, lung tumors from the nanovaccine-treated and the control groups were assessed by PET-CT imaging, and then removed and weighed. In mice treated with the nanovaccine, tumors were consistently one tenth the size of the tumors that were found in mice in both control groups.

Further testing revealed that mice receiving the nanovaccine had a significant increase in circulating cytotoxic T lymphocytes (CTLs) that specifically targeted the neoantigen on the colon cancer cells. CTLs are cells that attack and kill virus-infected cells and those damaged in other ways, such as cancerous cells.

An important aspect of the nanovaccine approach is that it mounts an anti-tumor immune response that circulates through the system, and therefore is particularly valuable for finding and inhibiting metastatic tumors growing throughout the body.

The researchers view their nanovaccine as an important part of eventual therapies combining immunotherapy with other cancer killing approaches.

Story Source:

Materials provided by National Institute of Biomedical Imaging and BioengineeringNote: Content may be edited for style and length.


Journal Reference:

  1. Guizhi Zhu, Lei Mei, Harshad D. Vishwasrao, Orit Jacobson, Zhantong Wang, Yijing Liu, Bryant C. Yung, Xiao Fu, Albert Jin, Gang Niu, Qin Wang, Fuwu Zhang, Hari Shroff, Xiaoyuan Chen. Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapyNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01386-7

Researchers use nanoparticles to target and kill endometrial cancer


Cancer Killer 57-researchersuUI researchers loaded nanoparticles with two cancer drugs and injected them into lab mice with type II endometrial cancer. The super-lethal nanoparticles reduced tumor growth and extended survival rates. In this photo, tiny green …more

Tumor-targeting nanoparticles loaded with a drug that makes cancer cells more vulnerable to chemotherapy’s toxicity could be used to treat an aggressive and often deadly form of endometrial cancer, according to new research by the University of Iowa College of Pharmacy.

For the first time, researchers combined traditional chemotherapy with a relatively new cancer  that attacks chemo-resistant  cells, loaded both into tiny nanoparticles, and created an extremely selective and lethal . Results of the three-year lab study were published today in the journal Nature Nanotechnology.

The new treatment could mean improved survival rates for the roughly 6,000 U.S. women diagnosed with type II endometrial cancer every year and also represents an important step in the development of targeted cancer therapies. In contrast to chemotherapy, the current standard in cancer treatment that exposes the entire body to anti-cancer drugs, targeted treatments deliver drugs directly to the tumor site, thereby protecting healthy tissue and organs and enhancing drug efficacy.

“In this particular study, we took on one of the biggest challenges in cancer research, which is tumor targeting,” said Kareem Ebeid, a UI pharmacy science graduate student and lead researcher on the study. “And for the first time, we were able to combine two different tumor-targeting strategies and use them to defeat deadly type II endometrial cancer. We believe this treatment could be used to fight other cancers, as well.”

In their effort to create a highly selective cancer treatment, Ebeid and his team started with tiny nanoparticles. In recent years, there has been increased interest in using nanoparticles to treat cancer, in large part because of their small size. Tumors grow quickly, and the blood vessels they create to feed their growth are defective and full of holes. Nanoparticles are small enough to slip through the holes, thereby allowing them to specifically target tumors.

Researchers then fueled the nanoparticles with two anti-cancer drugs: paclitaxel, a type of chemotherapy used to treat endometrial cancer, and nintedanib, or BIBF 1120, a relatively new drug used to restrict tumor blood vessel growth. However, in the UI study, the drug was used for a different purpose. Besides limiting , nintedanib also targets tumor cells with a specific mutation. The mutation, known as Loss of Function p53, interrupts the normal life cycle of tumor cells and makes them more resistant to the lethal effects of chemotherapy.

Chemotherapy kills cells when they are in the process of mitosis, or cell division, and tumor cells with the Loss of Function p53 mutation often are stuck in a limbo state that slows this process. Cancers that are resistant to chemotherapy are much harder to treat and have less favorable outcomes.

Nintedanib attacks tumor cells with the Loss of Function p53 mutation and compels them to enter mitosis and divide, at which point they are more easily killed by chemotherapy. Ebeid says this is the first time that researchers have used nintedanib to force tumor  into mitosis and kill them—a phenomenon scientists refer to as “synthetic lethality.”

“Basically, we are taking advantage of the ‘ Achilles heel—the Loss of Function mutation—and then sweeping in and killing them with chemotherapy,” Ebeid says. “We call this a synthetically lethal situation because we are creating the right conditions for massive cell death.”

The treatment—and cellular death that it incites—could be used to treat other cancers as well, including types of ovarian and lung cancers that also carry the Loss of Function p53 mutation.

“We believe our research could have a positive impact beyond the treatment of endometrial cancer,” says Aliasger K. Salem, professor of pharmaceutical sciences at the UI and corresponding author on the study. “We hope that since the drugs used in our study have already been approved for clinical use, we will be able to begin working with patients soon.”

Incidence and mortality rates for endometrial cancer have been on the rise in the U.S. in recent years, especially in Iowa. Type I endometrial cancer, which feeds on the hormone estrogen, accounts for about 80 percent of new cases annually. Type II endometrial cancer is less common, accounting for roughly 10 percent to 20 percent of cases, but is much more aggressive, resulting in 39 percent of total endometrial  deaths every year.

“For two decades, the standard therapy for type II  has been  and radiation,” says Kimberly K. Leslie, professor and chair of the Department of Obstetrics and Gynecology at the UI Roy J. and Lucille A. Carver College of Medicine. “The possibility of a new  that is both highly selective and highly effective is incredibly exciting.”

 Explore further: Genetic targets to chemo-resistant breast cancer identified

More information: Synthetically lethal nanoparticles for treatment of endometrial cancer, Nature Nanotechnology (2017). nature.com/articles/doi:10.1038/s41565-017-0009-7

 

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.

MIT: Researchers Develop Nanoparticles that Deliver the CRISPR genome-editing system – Big Step Forward for Cancer Research


In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes in mice.

The team used nanoparticles to carry the CRISPR components, eliminating the need to use viruses for delivery.

Using the new delivery technique, the researchers were able to cut out certain genes in about 80 percent of liver cells, the best success rate ever achieved with CRISPR in adult animals.

“What’s really exciting here is that we’ve shown you can make a nanoparticle that can be used to permanently and specifically edit the DNA in the liver of an adult animal,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

One of the genes targeted in this study, known as Pcsk9, regulates cholesterol levels. Mutations in the human version of the gene are associated with a rare disorder called dominant familial hypercholesterolemia, and the FDA recently approved two antibody drugs that inhibit Pcsk9.

However these antibodies need to be taken regularly, and for the rest of the patient’s life, to provide therapy. The new nanoparticles permanently edit the gene following a single treatment, and the technique also offers promise for treating other liver disorders, according to the MIT team.

Anderson is the senior author of the study, which appears in the Nov. 13 issue of Nature Biotechnology. The paper’s lead author is Koch Institute research scientist Hao Yin.

Other authors include David H. Koch Institute Professor Robert Langer of MIT, professors Victor Koteliansky and Timofei Zatsepin of the Skolkovo Institute of Science and Technology, and Professor Wen Xue of the University of Massachusetts Medical School.

Targeting Disease

Many scientists are trying to develop safe and efficient ways to deliver the components needed for CRISPR, which consists of a DNA-cutting enzyme called Cas9 and a short RNA that guides the enzyme to a specific area of the genome, directing Cas9 where to make its cut.

In most cases, researchers rely on viruses to carry the gene for Cas9, as well as the RNA guide strand. In 2014, Anderson, Yin, and their colleagues developed a nonviral delivery system in the first-ever demonstration of curing a disease (the liver disorder tyrosinemia) with CRISPR in an adult animal. However, this type of delivery requires a high-pressure injection, a method that can also cause some damage to the liver.

Later, the researchers showed they could deliver the components without the high-pressure injection by packaging messenger RNA (mRNA) encoding Cas9 into a nanoparticle instead of a virus. Using this approach, in which the guide RNA was still delivered by a virus, the researchers were able to edit the target gene in about 6 percent of hepatocytes, which is enough to treat tyrosinemia.

While that delivery technique holds promise, in some situations it would be better to have a completely nonviral delivery system, Anderson says.

One consideration is that once a particular virus is used, the patient will develop antibodies to it, so it couldn’t be used again.

Also, some patients have pre-existing antibodies to the viruses being tested as CRISPR delivery vehicles.

In the new Nature Biotechnology paper, the researchers came up with a system that delivers both Cas9 and the RNA guide using nanoparticles, with no need for viruses.

To deliver the guide RNAs, they first had to chemically modify the RNA to protect it from enzymes in the body that would normally break it down before it could reach its destination.

The researchers analyzed the structure of the complex formed by Cas9 and the RNA guide, or sgRNA, to figure out which sections of the guide RNA strand could be chemically modified without interfering with the binding of the two molecules. Based on this analysis, they created and tested many possible combinations of modifications.

“We used the structure of the Cas9 and sgRNA complex as a guide and did tests to figure out we can modify as much as 70 percent of the guide RNA,” Yin says. “We could heavily modify it and not affect the binding of sgRNA and Cas9, and this enhanced modification really enhances activity.”

Reprogramming the Liver

The researchers packaged these modified RNA guides (which they call enhanced sgRNA) into lipid nanoparticles, which they had previously used to deliver other types of RNA to the liver, and injected them into mice along with nanoparticles containing mRNA that encodes Cas9.

They experimented with knocking out a few different genes expressed by hepatocytes, but focused most of their attention on the cholesterol-regulating Pcsk9 gene. The researchers were able to eliminate this gene in more than 80 percent of liver cells, and the Pcsk9 protein was undetectable in these mice. They also found a 35 percent drop in the total cholesterol levels of the treated mice.

The researchers are now working on identifying other liver diseases that might benefit from this approach, and advancing these approaches toward use in patients.

“I think having a fully synthetic nanoparticle that can specifically turn genes off could be a powerful tool not just for Pcsk9 but for other diseases as well,” Anderson says.

“The liver is a really important organ and also is a source of disease for many people. If you can reprogram the DNA of your liver while you’re still using it, we think there are many diseases that could be addressed.”

“We are very excited to see this new application of nanotechnology open new avenues for gene editing,” Langer adds.

Materials provided by MIT News.Note: Content may be edited for style and length. 

Nanotechnology delivers medicine to cancer cells while protecting healthy cells ~ “Fooling Cancer”



Cancer treatments, including chemotherapy, have helped many of those who have been diagnosed with the disease to go on to live healthy lives.

Nevertheless, chemotherapy takes a toll on the body. During treatment, chemotherapy attacks all of the body’s cells, not just cancer cells. The result destroys healthy cells, causing many patients to suffer major side effects during and after treatment.

And because current treatments aren’t specifically targeted to cancer cells, only 0.01 percent of chemotherapy drugs actually reach the tumor and its diseased cells.

“I’m working on figuring out how we can deliver more of the chemotherapy drugs to the tumor and less to healthy cells,” says Sofie Snipstad, who recently graduated from the Department of Physics at the Norwegian University of Science and Technology (NTNU). Last year, she won a Norwegian science communication competition for PhD candidates called Researcher Grand Prix. When she made her winning presentation about her research during the competition finals, she was in the middle of testing a new method of cancer treatment on mice.

Now her research has shown that the method can cure cancer in mice.

Her study has just been published in the academic journal Ultrasound in Medicine and Biology (“Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts”).


Blood vessels supplying the cancer cells (kreftceller in the illustration) have porous walls, while the sections of blood vessels passing through healthy cells are not porous. This protects healthy cells from the chemotherapy. (Image: NTNU)

Promising results

Snipstad’s method targets cancerous tumors with chemotherapy so that more of the drug reaches cancer cells while protecting healthy cells. The experiments were conducted in mice with an aggressive breast cancer type (triple negative).

Researchers undertook many laboratory experiments before conducting their tests with mice — which were the first actual tests using this delivery method for chemotherapy. In addition to causing the tumors to disappear during treatment, the cancer has not returned in the trial animals.

“This is an exciting technology that has shown very promising results. That the first results from our tests in mice are so good, and that the medicine does such a good job right from the start is very promising,” Snipstad says.

Here’s how the treatment works

Instead of being injected straight into the bloodstream and transported randomly to both sick and healthy cells, the chemotherapy medicine is encapsulated in nanoparticles. When nanoparticles containing the cancer drugs are injected into the bloodstream, the nanoparticles are so large that they remain in the blood vessels in most types of healthy tissues. This prevents the chemotherapy from harming healthy cells.

Blood vessels in the tumor, however, have porous walls, so that the nanoparticles containing the chemotherapy can work their way into the cancerous cells.

“My research shows that this method allows us to supply 100 times more chemotherapy to the tumor compared to chemotherapy alone. That’s good,” Snipstad says.

However, the nanoparticles can only reach cells that are closest to the blood vessels that carry the drug-laden particles, she said. That means that cancer cells that are far from the blood vessels that supply the tumour do not get the chemotherapy drugs.

“For the treatment to be effective, it has to reach all parts of the tumor. So our nanoparticles need help to deliver the medicine,” she said.

Ultrasound is the key

The nanoparticles used by Snipstad and her research team were developed at SINTEF in Trondheim. SINTEF is one of Europe’s largest independent research organizations. The particles are unusual because they can form small bubbles. The nanoparticles are in the surface of the bubbles.

These bubbles are an important part of the cancer treatment. Another essential part is the use of ultrasound, which is Snipstad’s area of research.

nanobubbles in ultrasound treatments

To make the bubbles behave the way they wanted, the researchers tested many different ultrasound treatments, and measured how many of the nanoparticles were delivered to cancerous tissues in mice. Many of the ultrasound treatments had little effect, but Sofie Snipstad found one that worked quite well. (Image: NTNU)

The bubbles that contain the chemotherapy-laden nanoparticles are injected into the bloodstream. Ultrasound is then applied to the tumor. The ultrasound causes the bubbles to vibrate and eventually burst, so that the nanoparticles are released. The vibrations also massage the blood vessels and tissues to make them more porous. 

This helps push the nanoparticles further into the cancerous tumor, instead of only reaching the cancer cells closest to the blood vessels.

“By using ultrasound to transport the chemotherapy-laden nanoparticles into the tumors, our research on mice has shown that we can deliver about 250 times more of the drug to the tumor compared to just injecting chemotherapy into the bloodstream alone,” she says.

Three groups, three clear results

The mice were divided into three groups:

Group 1 received no treatment, and the tumor continued to grow.

Group 2 received the treatment using drug-laden nanoparticles. The growth of the tumor stagnated after time, but the tumour did not disappear.

Group 3 received the treatment using drug-laden nanoparticles, bubbles and ultrasound. In this group, the tumor shrank until it disappeared. One hundred days after the treatment was discontinued, the mice were still cancer-free.

Fooling cancer cells

“For the treatment to be effective, we have to trick the cancer cells to take up the nanoparticles so that the chemotherapy reaches its target,” Snipstad says.

To study this process, she has grown cancer cells and examined them under a microscope. Here, she has seen that the nanoparticles camouflage the chemotherapy drug, allowing the cancer cells to take them up. But for the treatment to work, the nanoparticles have to release the cancer drug exactly when and where it is needed.

“We can do that by changing the chemical composition of the nanoparticles so that we can tailor properties, including determining how quickly the nanoparticles break down. After the cell takes up the nanoparticle, the nanoparticle dissolves and releases the cancer drug inside the cell. That causes the cancer cell to stop dividing, and it will eventually shrink and die.

Close interdisciplinary cooperation

NTNU physics professor Catharina Davies heads the research group of which Snipstad is part. The group mainly works with nanoparticles.

The NTNU group works closely with SINTEF and St. Olavs Hospital in Trondheim. NTNU conducts the animal tests and studies the cancer cells. SINTEF has developed the bubbles containing nanoparticles, which provides the research platform. The cancer clinic and ultrasound group at St. Olavs contribute with their clinical skills.

“One of the things that I like about this project is that so many good people with different backgrounds are involved. Trondheim has a very good interdisciplinary environment, and this project needs all of these different disciplines for us to make progress,” Snipstad said.

No human trials anytime soon

While research results are very promising, it will still be some time before the method can be used in humans.

“It can take from 10-20 years from the time a discovery is made in the lab until it can be used as a treatment,” Snipstad said. “We’ve been working on this about six years, so we still have a lot to learn. 
We need to understand more about the mechanisms behind our success and we have to do much more work using microscopes to understand what is happening inside the tissues.”

Snipstad said that the find also has researchers excited to test the method on other types of cancers, because each type of cancer is different.

Possible treatment for brain cancer

This combination of bubbles, nanoparticles and ultrasound also opens the door on the possibility of treating brain diseases. The brain is protected by a special blood-brain barrier, which makes it difficult to deliver drugs to the brain for treatment. This barrier allows only substances that the brain needs to pass through the barrier, which means that for many brain diseases, there is no treatment whatsoever.

“But there is hope. By using ultrasound and our bubbles we have managed to deliver nanoparticles and drugs to the brain. This may be promising for the treatment of cancer and other diseases in the brain,” Snipstad said.

Source: Norwegian University of Science and Technology

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Nano Therapeutics to Nanobots ~ Nanotechnology is creating new opportunities for fighting disease (w/video)



Nanotechnology is creating new opportunities for fighting disease – from delivering drugs in smart packaging to nanobots powered by the world’s tiniest engines.

Chemotherapy benefits a great many patients but the side effects can be brutal.


When a patient is injected with an anti-cancer drug, the idea is that the molecules will seek out and destroy rogue tumour cells. However, relatively large amounts need to be administered to reach the target in high enough concentrations to be effective. As a result of this high drug concentration, healthy cells may be killed as well as cancer cells, leaving many patients weak, nauseated and vulnerable to infection.

One way that researchers are attempting to improve the safety and efficacy of drugs is to use a relatively new area of research known as nanothrapeutics to target drug delivery just to the cells that need it.

Professor Sir Mark Welland is Head of the Electrical Engineering Division at Cambridge. In recent years, his research has focused on nanotherapeutics, working in collaboration with clinicians and industry to develop better, safer drugs. He and his colleagues don’t design new drugs; instead, they design and build smart packaging for existing drugs.


Nanotherapeutics come in many different configurations, but the easiest way to think about them is as small, benign particles filled with a drug. They can be injected in the same way as a normal drug, and are carried through the bloodstream to the target organ, tissue or cell. 
At this point, a change in the local environment, such as pH, or the use of light or ultrasound, causes the nanoparticles to release their cargo.

Nano-sized tools are increasingly being looked at for diagnosis, drug delivery and therapy. “There are a huge number of possibilities right now, and probably more to come, which is why there’s been so much interest,” says Welland. Using clever chemistry and engineering at the nanoscale, drugs can be ‘taught’ to behave like a Trojan horse, or to hold their fire until just the right moment, or to recognise the target they’re looking for.

“We always try to use techniques that can be scaled up – we avoid using expensive chemistries or expensive equipment, and we’ve been reasonably successful in that,” he adds. “By keeping costs down and using scalable techniques, we’ve got a far better chance of making a successful treatment for patients.”


In 2014, he and collaborators demonstrated that gold nanoparticles could be used to ‘smuggle’ chemotherapy drugs into cancer cells in glioblastoma multiforme, the most common and aggressive type of brain cancer in adults, which is notoriously difficult to treat. The team engineered nanostructures containing gold and cisplatin, a conventional chemotherapy drug. A coating on the particles made them attracted to tumour cells from glioblastoma patients, so that the nanostructures bound and were absorbed into the cancer cells.

Once inside, these nanostructures were exposed to radiotherapy. This caused the gold to release electrons that damaged the cancer cell’s DNA and its overall structure, enhancing the impact of the chemotherapy drug. The process was so effective that 20 days later, the cell culture showed no evidence of any revival, suggesting that the tumour cells had been destroyed.

While the technique is still several years away from use in humans, tests have begun in mice. Welland’s group is working with MedImmune, the biologics R&D arm of pharmaceutical company AstraZeneca, to study the stability of drugs and to design ways to deliver them more effectively using nanotechnology.

“One of the great advantages of working with MedImmune is they understand precisely what the requirements are for a drug to be approved. We would shut down lines of research where we thought it was never going to get to the point of approval by the regulators,” says Welland. “It’s important to be pragmatic about it so that only the approaches with the best chance of working in patients are taken forward.”

The researchers are also targeting diseases like tuberculosis (TB). With funding from the Rosetrees Trust, Welland and postdoctoral researcher Dr Íris da luz Batalha are working with Professor Andres Floto in the Department of Medicine to improve the efficacy of TB drugs.

Their solution has been to design and develop nontoxic, biodegradable polymers that can be ‘fused’ with TB drug molecules. As polymer molecules have a long, chain-like shape, drugs can be attached along the length of the polymer backbone, meaning that very large amounts of the drug can be loaded onto each polymer molecule. The polymers are stable in the bloodstream and release the drugs they carry when they reach the target cell. Inside the cell, the pH drops, which causes the polymer to release the drug.

In fact, the polymers worked so well for TB drugs that another of Welland’s postdoctoral researchers, Dr Myriam Ouberaï, has formed a start-up company, Spirea, which is raising funding to develop the polymers for use with oncology drugs. Ouberaï is hoping to establish a collaboration with a pharma company in the next two years.

“Designing these particles, loading them with drugs and making them clever so that they release their cargo in a controlled and precise way: it’s quite a technical challenge,” adds Welland. “The main reason I’m interested in the challenge is I want to see something working in the clinic – I want to see something working in patients.”

Could nanotechnology move beyond therapeutics to a time when nanomachines keep us healthy by patrolling, monitoring and repairing the body?


Nanomachines have long been a dream of scientists and public alike. But working out how to make them move has meant they’ve remained in the realm of science fiction.

But last year, Professor Jeremy Baumberg and colleagues in Cambridge and the University of Bath developed the world’s tiniest engine – just a few billionths of a metre in size. It’s biocompatible, cost-effective to manufacture, fast to respond and energy efficient.

The forces exerted by these ‘ANTs’ (for ‘actuating nano-transducers’) are nearly a hundred times larger than those for any known device, motor or muscle. To make them, tiny charged particles of gold, bound together with a temperature-responsive polymer gel, are heated with a laser. As the polymer coatings expel water from the gel and collapse, a large amount of elastic energy is stored in a fraction of a second. On cooling, the particles spring apart and release energy.

The researchers hope to use this ability of ANTs to produce very large forces relative to their weight to develop three-dimensional machines that swim, have pumps that take on fluid to sense the environment and are small enough to move around our bloodstream.

Working with Cambridge Enterprise, the University’s commercialisation arm, the team in Cambridge’s Nanophotonics Centre hopes to commercialise the technology for microfluidics bio-applications. The work is funded by the Engineering and Physical Sciences Research Council and the European Research Council.

“There’s a revolution happening in personalised healthcare, and for that we need sensors not just on the outside but on the inside,” explains Baumberg, who leads an interdisciplinary Strategic Research Network and Doctoral Training Centre focused on nanoscience and nanotechnology.

“Nanoscience is driving this. We are now building technology that allows us to even imagine these futures.”

Source: By Sarah Collins, University of Cambridge

Nanoparticle vaccine shows potential as immunotherapy to fight multiple cancer types


Researchers from UT Southwestern Medical Center have developed a first-of-its-kind nanoparticle vaccine immunotherapy that targets several different cancer types.

The nanovaccine consists of tumor antigens – tumor proteins that can be recognized by the immune system – inside a synthetic polymer nanoparticle. Nanoparticle vaccines deliver minuscule particulates that stimulate the immune system to mount an immune response. The goal is to help people’s own bodies fight cancer.

“What is unique about our design is the simplicity of the single-polymer composition that can precisely deliver tumor antigens to immune cells while stimulating innate immunity. These actions result in safe and robust production of tumor-specific T cells that kill cancer cells,” said Dr. Jinming Gao, a Professor of Pharmacology and Otolaryngology in UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

A study outlining this research, published online today in Nature Nanotechnology (“A STING-activating nanovaccine for cancer immunotherapy”), reported that the nanovaccine had anti-tumor efficacy in multiple tumor types in mice.

Laser light can be seen scattered by nanoparticles in a solution of the UTSW-developed nanovaccine. (Image: UT Southwestern)

The research was a collaboration between the laboratories of study senior authors Dr. Gao and Dr. Zhijian “James” Chen, Professor of Molecular Biology and Director of the Center for Inflammation Research. 

The Center was established in 2015 to study how the body senses infection and to develop approaches to exploit this knowledge to create new treatments for infection, immune disorders, and autoimmunity.

Typical vaccines require immune cells to pick up tumor antigens in a “depot system” and then travel to the lymphoid organs for T cell activation, Dr. Gao said. Instead, nanoparticle vaccines can travel directly to the body’s lymph nodes to activate tumor-specific immune responses.

“For nanoparticle vaccines to work, they must deliver antigens to proper cellular compartments within specialized immune cells called antigen-presenting cells and stimulate innate immunity,” said Dr. Chen, also a Howard Hughes Medical Institute Investigator and holder of the George L. MacGregor Distinguished Chair in Biomedical Science. “Our nanovaccine did all of those things.”

In this case, the experimental UTSW nanovaccine works by activating an adaptor protein called STING, which in turn stimulates the body’s immune defense system to ward off cancer.

The scientists examined a variety of tumor models in mice: melanoma, colorectal cancer, and HPV-related cancers of the cervix, head, neck, and anogenital regions. In most cases, the nanovaccine slowed tumor growth and extended the animals’ lives.

Other vaccine technologies have been used in cancer immunotherapy. However, they are usually complex – consisting of live bacteria or multiplex biological stimulants, Dr. Gao said. This complexity can make production costly and, in some cases, lead to immune-related toxicities in patients.

With the emergence of new nanotechnology tools and increased understanding of polymeric drug delivery, Dr. Gao said, the field of nanoparticle vaccines has grown and attracted intense interest from academia and industry in the past decade.

“Recent advances in understanding innate and adaptive immunity have also led to more collaborations between immunologists and nanotechnologists,” said Dr. Chen. “These partnerships are critical in propelling the rapid development of new generations of nanovaccines.”

The investigative team is now working with physicians at UT Southwestern to explore clinical testing of the STING-activating nanovaccines for a variety of cancer indications. 

Combining nanovaccines with radiation or other immunotherapy strategies such as “checkpoint inhibition” can further augment their anti-tumor effectiveness.

Source: UT Southwestern Medical Center