Skip to main content

drug delivery

Building Nanoparticles for Kidney Disease

Posted on by

Eun Ji Chung
Photo courtesy of Eun Ji Chung

Great things sometimes come in small packages. That’s certainly true in the lab of Eun Ji Chung at the University of Southern California, Los Angeles. Chung and her team each day wrap their brains around bioengineering 3-D nanoparticles, molecular constructs that measure just a few billionths of a meter.

Chung recently received an NIH Director’s 2018 New Innovator Award to bring the precision of nanomedicine to autosomal dominant polycystic kidney disease (ADPKD), a relatively common inherited disorder that affects about 600,000 Americans and 12 million people worldwide.

By age 60, about half of those battling ADPKD will have kidney failure, requiring dialysis or a kidney transplant to stay alive. For people with ADPKD, a dominantly inherited gene mutation causes clusters of fluid-filled cysts to form in the kidneys that grow larger over time. The cysts can grow very large and displace normal kidney tissue, progressively impairing function.

For Chung, the goal is to design nanoparticles of the right size and configuration to deliver therapeutics to the kidneys in safe, effective amounts. Our kidneys constantly filter blood, clearing out wastes that are removed via urine. So, Chung and her team will exploit the fact that most molecules in the bloodstream measuring less than 10 nanometers in diameter enter the kidneys, where they are gradually processed and eliminated from the body. This process will give nanoparticles time to bind there and release any therapeutic molecules they may be carrying directly to the cysts that cluster on the kidneys of people with ADPKD.

Chung’s research couldn’t be more timely. Though ADPKD isn’t curable right now, the Food and Drug Administration (FDA) last year approved Jynarque™ (tolvaptan), the first treatment in the United States to slow the decline in kidney function in ADPKD patients, based on tests of the rate of kidney filtration. Other approved drugs, such as metformin and rapamycin, have shown potential for repurposing to treat people with ADPKD. So, getting these and other potentially life-saving drugs directly to the kidneys, while minimizing the risk of serious side effects in the liver and elsewhere in the body, will be key.

Most FDA-approved nanoparticle therapies are administered intravenously, often for treatment of cancer. Because ADPKD is chronic and treatment can last for decades, Chung wants to develop an easy-to-take pill to get these nanoparticles into the kidneys.

But oral administration raises its own set of difficulties. The nanoparticles must get from the stomach and the rest of the gastrointestinal tract to the bloodstream. And then if nanoparticles exceed 10 nanometers in diameter, the body typically routes them to the liver for clearance, rather than the kidneys.

While Chung brainstorms strategies for oral administration, she’s also considering developing a smart bandage to allow the nanoparticles to pass readily through the skin and, eventually, into the bloodstream. It would be something similar to the wearable skin patch already featured on the blog.

In the meantime, Chung continues to optimize the size, shape, and surface charge of her nanoparticles. Right now, they have components to target the kidneys, provide a visual signal for tracking, enhance the nanoparticle’s lifespan, and carry a therapeutic molecule. Because positively charged molecules are preferentially attracted to the kidney, Chung has also spent untold hours adjusting the charge on her nanoparticles.

But through all the hard work, Chung and her team continue to prove that great things may one day come in very small packages. And that could ultimately prove to be a long-awaited gift for the millions of people living with ADPKD.

Links:

Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Video: Faculty Profile – Eun Ji Chung (University of Southern California, Los Angeles)

Chung Laboratory (USC)

Chung Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases


Tracking Peptides in Cell Soup

Posted on by

Lipid Morphology

Credit: William Wimley, Tulane University, New Orleans

If you think this soup looks unappealing for this year’s Thanksgiving feast, you’re right! If you were crazy enough to take a sip, you’d find it to be virtually flavorless—just a salty base (red) with greasy lipid globules (green) floating on top. But what this colorful concoction lacks in taste, it makes up for as a valuable screening tool for peptides, miniature versions of proteins that our bodies use to control many cellular processes.

In this image, William Wimley, an NIH-supported researcher at Tulane University, New Orleans, has stirred up the soup and will soon add some peptides. These peptides aren’t made by our cells, though. They’re synthesized in the lab, allowing Wimley and team to tweak their chemical structures and hopefully create ones with therapeutic potential, particularly as smart-delivery systems to target cells with greater precision and deliver biological cargoes such as drugs [1].


Seven More Awesome Technologies Made Possible by Your Tax Dollars

Posted on by

We live in a world energized by technological advances, from that new app on your smartphone to drones and self-driving cars. As you can see from this video, NIH-supported researchers are also major contributors, developing a wide range of amazing biomedical technologies that offer tremendous potential to improve our health.

Produced by the NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), this video starts by showcasing some cool fluorescent markers that are custom-designed to light up specific cells in the body. This technology is already helping surgeons see and remove tumor cells with greater precision in people with head and neck cancer [1]. Further down the road, it might also be used to light up nerves, which can be very difficult to see—and spare—during operations for cancer and other conditions.

Other great things to come include:

  • A wearable tattoo that detects alcohol levels in perspiration and wirelessly transmits the information to a smartphone.
  • Flexible coils that produce high quality images during magnetic resonance imaging (MRI) [2-3]. In the future, these individualized, screen-printed coils may improve the comfort and decrease the scan times of people undergoing MRI, especially infants and small children.
  • A time-release capsule filled with a star-shaped polymer containing the anti-malarial drug ivermectin. The capsule slowly dissolves in the stomach over two weeks, with the goal of reducing the need for daily doses of ivermectin to prevent malaria infections in at-risk people [4].
  • A new radiotracer to detect prostate cancer that has spread to other parts of the body. Early clinical trial results show the radiotracer, made up of carrier molecules bonded tightly to a radioactive atom, appears to be safe and effective [5].
  • A new supercooling technique that promises to extend the time that organs donated for transplantation can remain viable outside the body [6-7]. For example, current technology can preserve donated livers outside the body for just 24 hours. In animal studies, this new technique quadruples that storage time to up to four days.
  • A wearable skin patch with dissolvable microneedles capable of effectively delivering an influenza vaccine. This painless technology, which has produced promising early results in humans, may offer a simple, affordable alternative to needle-and-syringe immunization [8].

If you like what you see here, be sure to check out this previous NIH video that shows six more awesome biomedical technologies that your tax dollars are helping to create. So, let me extend a big thanks to you from those of us at NIH—and from all Americans who care about the future of their health—for your strong, continued support!

References:

[1] Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. Wiley Interdiscip Rev Syst Biol Med. 2018 Feb 23.

[2] Screen-printed flexible MRI receive coils. Corea JR, Flynn AM, Lechêne B, Scott G, Reed GD, Shin PJ, Lustig M, Arias AC. Nat Commun. 2016 Mar 10;7:10839.

[3] Printed Receive Coils with High Acoustic Transparency for Magnetic Resonance Guided Focused Ultrasound. Corea J, Ye P, Seo D, Butts-Pauly K, Arias AC, Lustig M. Sci Rep. 2018 Feb 21;8(1):3392.

[4] Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals. Bellinger AM, Jafari M1, Grant TM, Zhang S, Slater HC, Wenger EA, Mo S, Lee YL, Mazdiyasni H, Kogan L, Barman R, Cleveland C, Booth L, Bensel T, Minahan D, Hurowitz HM, Tai T, Daily J, Nikolic B, Wood L, Eckhoff PA, Langer R, Traverso G. Sci Transl Med. 2016 Nov 16;8(365):365ra157.

[5] Clinical Translation of a Dual Integrin avb3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD. Zhang J, Niu G, Lang L, Li F, Fan X, Yan X, Yao S, Yan W, Huo L, Chen L, Li Z, Zhu Z, Chen X. J Nucl Med. 2017 Feb;58(2):228-234.

[6] Supercooling enables long-term transplantation survival following 4 days of liver preservation. Berendsen TA, Bruinsma BG, Puts CF, Saeidi N, Usta OB, Uygun BE, Izamis ML, Toner M, Yarmush ML, Uygun K. Nat Med. 2014 Jul;20(7):790-793.

[7] The promise of organ and tissue preservation to transform medicine. Giwa S, Lewis JK, Alvarez L, Langer R, Roth AE, et a. Nat Biotechnol. 2017 Jun 7;35(6):530-542.

[8] The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. Rouphael NG, Paine M, Mosley R, Henry S, McAllister DV, Kalluri H, Pewin W, Frew PM, Yu T, Thornburg NJ, Kabbani S, Lai L, Vassilieva EV, Skountzou I, Compans RW, Mulligan MJ, Prausnitz MR; TIV-MNP 2015 Study Group.

Links:

National Institute of Biomedical Imaging and Bioengineering (NIH)

Center for Wearable Sensors (University of California, San Diego)

Hyperpolarized MRI Technology Resource Center (University of California, San Francisco)

Center for Engineering in Medicine (Massachusetts General Hospital, Boston)

Center for Drug Design, Development and Delivery (Georgia Tech University, Atlanta)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases


Creative Minds: Giving Bacteria Needles to Fight Intestinal Disease

Posted on by

Cammie Lesser

Cammie Lesser

For Salmonella and many other disease-causing bacteria that find their way into our bodies, infection begins with a poke. That’s because these bad bugs are equipped with a needle-like protein filament that punctures the outer membrane of human cells and then, like a syringe, injects dozens of toxic proteins that help them replicate.

Cammie Lesser at Massachusetts General Hospital and Harvard Medical School, Cambridge, and her colleagues are now on a mission to bioengineer strains of bacteria that don’t cause disease to make these same syringes, called type III secretion systems. The goal is to use such “good” bacteria to deliver therapeutic molecules, rather than toxins, to human cells. Their first target is the gastrointestinal tract, where they hope to knock out hard-to-beat bacterial infections or to relieve the chronic inflammation that comes with inflammatory bowel disease (IBD).


Snapshots of Life: Biological Bubble Machine

Posted on by

plasma membrane vesicles

Credit: Chi Zhao, David Busch, Connor Vershel, Jeanne Stachowiak, University of Texas at Austin

As kids, most of us got a bang out of blowing soap bubbles and watching them float around. Biologists have learned that some of our cells do that too. On the right, you can see two cells (greenish yellow) in the process of forming bubbles, or plasma membrane vesicles (PMVs). During this blebbing process, a cell’s membrane temporarily disassociates from its underlying cytoskeleton, forming a tiny pouch that, over the course of about 30 minutes, is “inflated” with a mix of proteins and lipids from inside the cell. After the PMVs are fully filled, these bubble-like structures are pinched off and released, like those that you see in the background. Certain cells constantly release PMVs, along with other types of vesicles, and may use those to communicate with other cells throughout the body.

This particular image, an entrant in the Biophysical Society’s 2017 Art of Science Image Contest, was produced by researchers working in the NIH-supported lab of Jeanne Stachowiak at the University of Texas at Austin. Stachowiak’s group is among the first to explore the potential of PMVs as specialized drug-delivery systems to target cancer and other disorders [1].

Until recently, most efforts to exploit vesicles for therapeutic uses have employed synthetic versions of a different type of vesicle, called an exosome. But Stachowiak and others have realized that PMVs come with certain built-in advantages. A major one is that a patient’s own cells could in theory serve as the production facility.


Next Page