Penn State: Camouflaged nanoparticles deliver killer ‘knock-out’ protein to cancer


Killer Protein for Cancer Treatment 180615094843_1_540x360

Extracellular vesicle-like metal-organic framework nanoparticles are developed for the intracellular delivery of biofunctional proteins. The biomimetic nanoplatform can protect the protein cargo and overcome various biological barriers to achieve systemic delivery and autonomous release. Credit: Zheng Lab/Penn State

 

A biomimetic nanosystem can deliver therapeutic proteins to selectively target cancerous tumors, according to a team of Penn State researchers.

A biomimetic nanosystem can deliver therapeutic proteins to selectively target cancerous tumors, according to a team of Penn State researchers. Using a protein toxin called gelonin from a plant found in the Himalayan mountains, the researchers caged the proteins in self-assembled metal-organic framework (MOF) nanoparticles to protect them from the body’s immune system. To enhance the longevity of the drug in the bloodstream and to selectively target the tumor, the team cloaked the MOF in a coating made from cells from the tumor itself.

Blood is a hostile environment for drug delivery. The body’s immune system attacks alien molecules or else flushes them out of the body through the spleen or liver. But cells, including cancer cells, release small particles called extracellular vesicles that communicate with other cells in the body and send a “don’t eat me” signal to the immune system.

“We designed a strategy to take advantage of the extracellular vesicles derived from tumor cells,” said Siyang Zheng, associate professor of biomedical and electrical engineering at Penn State. “We remove 99 percent of the contents of these extracellular vesicles and then use the membrane to wrap our metal-organic framework nanoparticles. If we can get our extracellular vesicles from the patient, through biopsy or surgery, then the nanoparticles will seek out the tumor through a process called homotypic targeting.”

Gong Cheng, lead author on a new paper describing the team’s work and a former post-doctoral scholar in Zheng’s group now at Harvard, said, “MOF is a class of crystalline materials assembled by metal nodes and organic linkers. In our design, self-assembly of MOF nanoparticles and encapsulation of proteins are achieved simultaneously through a one-pot approach in aqueous environment. The enriched metal affinity sites on MOF surfaces act like the buttonhook, so the extracellular vesicle membrane can be easily buckled on the MOF nanoparticles. Our biomimetic strategy makes the synthetic nanoparticles look like extracellular vesicles, but they have the desired cargo inside.”

The nanoparticle system circulates in the bloodstream until it finds the tumor and locks on to the cell membrane. The cancer cell ingests the nanoparticle in a process called endocytosis. Once inside the cell, the higher acidity of the cancer cell’s intracellular transport vesicles causes the metal-organic framework nanoparticles to break apart and release the toxic protein into cytosol and kill the cell.

“Our metal-organic framework has very high loading capacity, so we don’t need to use a lot of the particles and that keeps the general toxicity low,” Zheng said.

The researchers studied the effectiveness of the nanosystem and its toxicity in a small animal model and reported their findings in a cover article in the Journal of the American Chemical Society.

The researchers believe their nanosystem provides a tool for the targeted delivery of other proteins that require cloaking from the immune system. Penn State has applied for patent protection for the technology.

Story Source:

Materials provided by Penn State. Original written by Walt Mills. Note: Content may be edited for style and length.

 

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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

 

Nanorobots successfully target and kill cancerous tumors


Science fiction no more

In an article out today in Nature Biotechnology, scientists were able to show tiny autonomous bots have the potential to function as intelligent delivery vehicles to cure cancer in mice.

These DNA nanorobots do so by seeking out and injecting cancerous tumors with drugs that can cut off their blood supply, shriveling them up and killing them.

“Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth,” the paper explains.

DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.

DNA nanorobots, Nature Biotechnology 2018

The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor’s vessels and cutting off their blood supply, leading to their death.

Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they’d been programmed to target, according to the paper.

The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.

The goal, say the scientists behind the paper, is to eventually prove these bots can do the same thing in humans. Of course, more work will need to be done before human trials begin.

Regardless, this is a huge breakthrough in cancer research. The current methods of either using chemotherapy to destroy every cell just to get at the cancer cell are barbaric in comparison. Using targeted drugs is also not as exact as simply cutting off blood supply and killing the cancer on the spot. Should this new technique gain approval for use on humans in the near future it could have impressive affects on those afflicted with the disease.

New nanoparticle may aid cancer detection


Cellular Messenger Cornell 9-scientistsdiAn intricate pattern – a molecular model of the influenza virus. The influenza virion (as the infectious particle is called) is roughly spherical. It is an enveloped virus – that is, the outer layer is a lipid membrane which is taken from the host cell in which the virus multiplies. 

A new nanoparticle, at the cellular level, may reveal how cancer cells move to different locations in the human body. This process involves co-opting the human body’s inter-cellular delivery service.

The insight into the cellular messenger system comes from Weill Cornell Medicine scientists. The discovery is of importance since it could help medical scientists to understand how cancer cells can spread to various other locations.

 

With the research, the medics have used a novel technique called asymmetric flow field-flow fractionation. Through this the researchers were able to shift and sort a particular type of nano-sized particles termed exosomes. These particles are secreted by cancer cells and they are formed of DNA, RNA, fats and proteins.

 

Exosomes are cell-derived vesicles that are present in many cell fluids, including blood, and urine; they provide a means of intercellular communication and of transmission of macromolecules between cells. In medicine exosomes can potentially be used for prognosis, for therapy, and as biomarkers for health and disease.

 

By using the asymmetric flow field-flow fractionation, the scientists were able to separate out two distinct exosome subtypes. This has led to the discovery of the new type of nanoparticle. Asymmetrical flow field flow fractionation is a common and state-of-the art method for fractionation and separation of macromolecules and particles in a suspension.

 

Metastatic breast cancer in pleural fluid.

Metastatic breast cancer in pleural fluid. euthman/flickr

 

Discussing the research with Controlled Environments magazine, lead researcher Dr. David Lyden explains further: We found that exomeres are the most predominant particle secreted by cancer cells. They are smaller and structurally and functionally distinct from exosomes. Exomeres largely fuse with cells in the bone marrow and liver, where they can alter immune function and metabolism of drugs.”

 

The researcher adds: “The latter finding may explain why many cancer patients are unable to tolerate even small doses of chemotherapy due to toxicity.”

 

Importantly exosomes and exomeres have different biophysical characteristics, like stiffness and electric charge. With this, the findings show, the more rigid the particle, the easier it is likely taken up by cells, rendering exomeres more effective messengers of transferring tumor information to recipient cells.

 

The research further shows how exosomes and exomeres differ in relation to their influence in triggering cancer. Exomeres can carry metabolic enzymes to the liver. Here exomeres are able to cause the liver to “reprogram” its metabolic function and trigger tumor progression.

 

The researchers plan to patent the new technology and develop a diagnostic tool to assist with cancer detection. This will help medics to understand how cancers grow and spread to other organs.

 

The research has been published in the journal Nature Cell Biology. The research paper is titled “Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation.”

 

In related news, Digital Journal has previously reported that researchers have used nanotechnology to improve drug delivery. This is in the form of tailorable nanoscale emulsions which effectively interact with their intended targets (see: “Delivering drugs via nanoscale emulsion.”)

 

Essential Science

 

Demonstrating the need for good cleaning and disinfection using ultraviolet light to show how easy i...

Demonstrating the need for good cleaning and disinfection using ultraviolet light to show how easy it is to miss parts of a surface when cleaning. Tim Sandle

 

This article is part of Digital Journal’s regular Essential Science columns. Each week Tim Sandle explores a topical and important scientific issue. Last week the association between household cleaning chemicals and respiratory problems was examined in light of a new study from the University of Bergen in Norway, which raises concerns about the longer-term health impact.

 

The week before the topic of nanotechnology and the development of a new generation of antimalarial drugs was discussed.

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.

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


 

 

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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.

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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.