How To Use Potato Virus To Delay Tumor Progression

Researchers from Case Western Reserve University School of Medicine in collaboration with researchers from Dartmouth Geisel School of Medicine and RWTH Aachen University (Germany) have adapted virus particles—that normally infect potatoes—to serve as cancer drug delivery devices for mice. But in a recent article published in Nano Letters, the team showed injecting the virus particles alongside chemotherapy drugs, instead of packing the drugs inside, may provide an even more potent benefit.

The researchers discovered injecting potato virus particles into melanoma tumor sites activates an anti-tumor immune system response. And simultaneously injecting the nanoscale plant virus particles and a chemotherapy drugdoxorubicin—into tumor sites further helps halt tumor progression in mice. But surprisingly, when the researchers created and injected combination nanoparticles, where the chemo drug is physically attached to the virus particles, there was not a significant added benefit.

The results are the first to show “vaccinating” mice with potato virus nanoparticles at a cancer site can generate an anti-tumor response. But the results also suggest more complex nanoparticles may not correspond to added therapeutic benefit.

It’s attractive to want to create multifunctional nanoparticles that can ‘do it all,’” said Nicole F. Steinmetz, PhD, senior author on the study, George J. Picha Professor in Biomaterials, member of the Case Comprehensive Cancer Center, and Director of the Center for Bio-Nanotechnology at Case Western Reserve School of Medicine.But this study shows significant therapeutic efficacy, including prolonging survival, requires a more step-wise approach. When the plant-based virus particles and the drugs were able to work on their own, we saw the greatest benefit.”

Wrote the authors, “While the nanomedicine field strives to design multifunctional nanoparticles that integrate several functions and therapeutic regimens into single nanoparticle – our data suggest a paradigm shift; some therapeutics may need to be administered separately to synergize and achieve most potent therapeutic outcome.”


Blood Cells Deliver Drugs To Kill Cancer

For the first time, WSU researchers have demonstrated a way to deliver a drug to a tumor by attaching it to a blood cell. The innovation could let doctors target tumors with anticancer drugs that might otherwise damage healthy tissues.

To develop the treatment, a team led by Zhenjia Wang, an assistant professor of pharmaceutical sciences, worked at the microscopic scale using a nanotherapeutic particle so small that 1,000 of them would fit across the width of a hair. By attaching a nanoscale particle to an infection-fighting white blood cell, the team showed they can get a drug past the armor of blood vessels that typically shield a tumor. This has been a major challenge in nanotechnology drug delivery.

Working with colleagues in Spokane and China, Wang implanted a tumor on the flank of a mouse commonly chosen as a model for human diseases. The tumor was exposed to near-infrared light, causing an inflammation that released proteins to attract white blood cells, called neutrophils, into the tumor. The researchers then injected the mouse with gold nanoparticles treated with antibodies that mediate the union of the nanoparticles and neutrophils. When the tumor was exposed to infrared light, the light’s interaction with the gold nanoparticles produced heat that killed the tumor cells, Wang said. In the future, therapists could attach an anticancer drug like doxorubicin to the nanoparticle. This could let them deliver the drug directly to the tumor and avoid damaging nearby tissues, Wang said.

We have developed a new approach to deliver therapeutics into tumors using the white blood cells of our body,” Wang said. “This will be applied to deliver many anticancer drugs, such as doxorubicin, and we hope that it could increase the efficacy of cancer therapies compared to other delivery systems.”

Wang and Chu’s colleagues on the research are postdoctoral researcher Dafeng Chu, Ph.D. student Xinyue Dong, Jingkai Gu of Jilin University and Jingkai Gu of the University of Macau.

The researchers reported on the technique in the latest issue of the journal Advanced Materials.


How To Fast Manufacture NanoRobots

A team of researchers led by Biomedical Engineering Professor Sam Sia at Columbia Engineering has developed a way to manufacture microscale machines from biomaterials that can safely be implanted in the body. Working with hydrogels, which are biocompatible materials that engineers have been studying for decades, Sia has invented a new technique that stacks the soft material in layers to make devices that have three-dimensional, freely moving parts. The study, published online January 4, 2017, in Science Robotics, demonstrates a fast manufacturing method Sia calls “implantable microelectromechanical systems” (iMEMS).

By exploiting the unique mechanical properties of hydrogels, the researchers developed a “locking mechanism” for precise actuation and movement of freely moving parts, which can function as valves, manifolds, rotors, pumps, and drug delivery systems. They were able to tune the biomaterials within a wide range of mechanical and diffusive properties and to control them after implantation without a sustained power supply, such as a toxic battery. They then tested the payload delivery in a bone cancer model and found that the triggering of releases of doxorubicin from the device over 10 days showed high treatment efficacy and low toxicity, at 1/10th of the standard systemic chemotherapy dose.

implantable nanorobot

Overall, our iMEMS platform enables development of biocompatible implantable microdevices with a wide range of intricate moving components that can be wirelessly controlled on demand and solves issues of device powering and biocompatibility,” says Sia, also a member of the Data Science Institute. “We’re really excited about this because we’ve been able to connect the world of biomaterials with that of complex, elaborate medical devices.  Our platform has a large number of potential applications, including the drug delivery system demonstrated in our paper which is linked to providing tailored drug doses for precision medicine.”


Nano-Terminators Target Cancer

Researchers at North Carolina State University (NC State) and the University of North Carolina at Chapel Hill  (NC-CH) have developed a new drug delivery technique that uses a biodegradable liquid metal to target cancer cells. The liquid metal drug delivery method promises to boost the effect of cancer drugs. To date, the technique has only been tested in an animal model.

Liquid-Metal nanoterminator

The advance here is that we have a drug-delivery technique that may enhance the effectiveness of the drugs being delivered, can help doctors locate tumors, can be produced in bulk, and appears to be wholly biodegradable with very low toxicity,” says Zhen Gu, corresponding author of a Nature Communications paper on the work and an assistant professor in the joint biomedical engineering program at NC State and UNC-CH. “And one of the advantages of this technique is that these liquid metal drug carriers – or ‘nano-terminators’ – are very easy to make.”

To create the nano-terminators, researchers place the bulk liquid metal (gallium indium alloy) into a solution that contains two types of molecules called polymeric ligands. The solution is then hit with ultrasound, which forces the liquid metal to burst into nanoscale droplets approximately 100 nanometers in diameter. The ligands in the solution attach to the surface of the droplets as they break away from the bulk liquid metal. Meanwhile, an oxidized “skin” forms on the surface of the nanodroplets. The oxidized skin, together with the ligands, prevents the nanodroplets from fusing back together.

The anticancer drug doxorubicin (Dox) is then introduced into the solution. One of the ligands on the nanodroplet sucks up the Dox and holds on to it. These drug-laden nanodroplets can then be separated from the solution and introduced into the bloodstream. The second type of ligand on the nanodroplets effectively seeks out cancer cells, causing receptors on the surface of the cancer cell to latch on to the nanodroplets. The cancer cell then absorbs the nanodroplets.

.Once absorbed, the higher level of acidity inside the cancer cell dissolves the oxidized skin of the nanodroplets. This releases the ligands, which will go on to release the Dox inside the cell. “Without the oxidized skin and ligands, the nanodroplets fuse together, forming larger drops of liquid metal,” says Michael Dickey, a co-author on this paper and professor in the Department of Chemical and Biomolecular Engineering at NC State. “These larger droplets are fairly easy to detect using diagnostic techniques, which can potentially help doctors locate tumors.”


How To Kill Cancer Stem Cells To Avoid Recurrence

Nanoparticles packed with a clinically used chemotherapy drug and coated with an oligosaccharide derived from the carapace of crustaceans might effectively target and kill cancer stem-like cells, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Cancer stem-like cells have characteristics of stem cells and are present in very low numbers in tumors. They are highly resistant to chemotherapy and radiation and are believed to play an important role in tumor recurrence. This laboratory and animal study showed that nanoparticles coated with the oligosaccharide called chitosan and encapsulating the chemotherapy drug doxorubicin can target and kill cancer stem-like cells six times more effectively than free doxorubicin.


Our findings indicate that this nanoparticle delivery system increases the cytotoxicity of doxorubicin with no evidence of systemic toxic side effects in our animal model,” says principal investigator Xiaoming (Shawn) He, PhD, associate professor of Biomedical Engineering and a member of the OSUCCC – James Translational Therapeutics Program.

We believe that chitosan-decorated nanoparticles could also encapsulate other types of chemotherapy and be used to treat many types of cancer”.

This study, reported in the journal ACS Nano, showed that chitosan binds with a receptor on cancer stem-like cells called CD44, enabling the nanoparticles to target the malignant stem-like cells in a tumor.


Liver Cancer: Hope Is Coming From Plants

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated death worldwide. Also called malignant hepatoma, HCC is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis). These regrettably poor prognoses are due to the difficulty in treating this cancer using conventional chemotherapeutic drugs such as doxorubicin, epirubicin, cisplatin, 5-fluorouracil, etoposide or combinations therein. This may be attributed to that the conventional medicines are not able to reach in a sufficient concentration in the liver tumor cells at levels that are not harmful to the rest of the body.

Now a team of scientists, led by Prof. Taeghwan Hyeon at the Institute for Basic Science (IBS)/Seoul National University and Prof. Kam Man Hui at the National Cancer Center Singapore, has screened a library containing hundreds of natural products against a panel of HCC cells to search a better drug candidate. The screen uncovered a compound named triptolide, a traditional Chinese medicine isolated from the thunder god vine (Tripterygium wilfordii (Latin) or lei gong teng (Chinese)) which was found to be far more potent than current therapies. Studies from other researchers corroborate the findings as triptolide has also found to be very effective against several other malignant cancers including; pancreatic, neuroblastoma and cholangiocarcinoma. However this excitement was tempered when the drug was administered to mice as the increased potency was coupled with increased toxicity as well. Prof. Hyeon et al. endeavoured to alleviate the toxic burden by increasing the specific delivery of the drug to the tumor using a nanoformulation. The designed formulation was a pH-sensitive nanogel coated with the nucleotide precursor, folate.

Nanoflowers Deliver Drugs To Cancer Cells

Biomedical engineering researchers have developed daisy-shaped, nanoscale structures that are made predominantly of anti-cancer drugs and are capable of introducing a “cocktail” of multiple drugs into cancer cells. The researchers are all part the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill.
To make the “nanodaisies,” the researchers begin with a solution that contains a polymer called polyethylene glycol (PEG). The PEG forms long strands that have much shorter strands branching off to either side. Researchers directly link the anti-cancer drug camptothecin (CPT) onto the shorter strands and introduce the anti-cancer drug doxorubicin (Dox) into the solution. Once injected, the nanodaisies float through the bloodstream until they are absorbed by cancer cells. Once in a cancer cell, the drugs are released.

Early tests of the “nanodaisy” drug delivery technique show promise against a number of cancers
We found that this technique was much better than conventional drug-delivery techniques at inhibiting the growth of lung cancer tumors in mice,” says Dr. Zhen Gu, senior author of the paper. “And based on in vitro tests in nine different cell lines, the technique is also promising for use against leukemia, breast, prostate, liver, ovarian and brain cancers.”

Cancer-Killing Time Bomb

Biomedical engineering researchers have developed an anti-cancer drug delivery method that essentially smuggles the drug into a cancer cell before triggering its release. The method can be likened to keeping a cancer-killing bomb and its detonator separate until they are inside a cancer cell, where they then combine to destroy the cell.

This is an efficient, fast-acting way of delivering drugs to cancer cells and triggering cell death,” says Dr. Ran Mo, lead author of a paper on the work and a postdoctoral researcher in the joint biomedical engineering program at North Carolina State University and the University of North Carolina at Chapel Hill. “We also used lipid-based nanocapsules that are already in use for clinical applications, making it closer to use in the real world.”

The technique uses nanoscale lipid-based capsules, or liposomes, to deliver both the drug and the release mechanism into cancer cells. One set of liposomes contains adenosine-5’-triphosphate (ATP), the so-called “energy molecule.” A second set of liposomes contains an anti-cancer drug called doxorubicin (Dox) that is embedded in a complex of DNA molecules. When the DNA molecules come into contact with high levels of ATP, they unfold and release the Dox.


Fighting Cancer: Breakthrough In China

Nanoparticles capable of delivering drugs to specifically targeted cancer cells have been created by a group of researchers from China. The multifunctional ‘smartgold nanoshells could lead to more effective cancer treatments by overcoming a major limitation of modern chemotherapy techniques—the ability to target cancer cells specifically and leave healthy cells untouched.

Small peptides situated on the surface of the nanoshells are the key to the improved targeting ability, guiding the nanoshells to specific cancer cells and attaching to markers on the surface of the cells. The acidic environment of the cancer cells then triggers the offloading of the anticancer drugs.

The specific nanostructure of the gold nanoshells could also allow near-infrared light to be absorbed and converted into heat, opening up the possibility of using the nanoshells in targeted hyperthermia treatment — another form of cancer treatment whereby cancer cells are exposed to slightly higher temperatures than usual to destroy them. The researchers, from East China Normal University and Tongji University, used the gold nanoshells as a building block to which they attached the commonly used anticancer drug Doxorubicin (DOX) and a specific peptide known as A54. The gold nanoshells had diameters of around 200 nanometres— more than 50 times smaller than a red blood cell. When tested on human liver cancer cells, the uptake of the nanoshells that had the A45 peptide was three times greater than the uptake of the control nanoshells without the peptide. There was also a significantly reduced uptake of both types of nanoshell by normal healthy cells. The cancer cells were also treated with the gold nanoshells in a heated water bath and were shown to deliver a notable therapeutic effect compared to just the chemotherapy, demonstrating the potential of the hyperthermia treatment.

The therapeutic activity of most anticancer drugs is limited by their systematic toxicity to proliferating cells, including some normal cells. Overcoming this problem remains a great challenge for chemotherapy. In our study we placed a targeting peptide on the nanoshells, which have been demonstrated to be specific to live cancer cells, improving the targeting ability and drug delivery of the gold nanoshells. The next step of our research is to test the ‘smart’ gold nanoshells in vivo on a liver cancer mouse model. We will also examine how the size of the nanoshells changes their efficacy and how efficient the nanoshells are at converting near-infrared light into heat” said lead author of the study Dr Shunying Liu, from East China Normal University.
The first results of the nanoshells’ performance have been published in IOP Publishing’s journal Biomedical Materials.


Nanoparticles To Cure Myeloma

One of the difficulties doctors face in treating multiple myeloma (MM) comes from the fact that cancer cells of this type start to develop resistance to the leading chemotherapeutic treatment, doxorubicin, when they adhere to tissue in bone marrow. Now researchers from the University of Notre Dame have engineered nanoparticles that show great promise for the treatment of the MM, an incurable cancer of the plasma cells in bone marrow.

The nanoparticles are coated with a special peptide that targets a specific receptor on the outside of multiple myeloma cells. These receptors cause the cells to adhere to bone marrow tissue and turn on the drug resistance mechanisms. But through the use of the newly developed peptide, the nanoparticles are able to bind to the receptors instead and prevent the cancer cells from adhering to the bone marrow in the first place.

Our research on mice shows that the nanoparticle formulation reduces the toxic effect doxorubicin has on other tissues, such as the kidneys and liver,” says Tanyel Kiziltepe , a research assistant professor with the Department of Chemical and Biomolecular Engineering and AD&T at Notre Dame University.