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Grattoni Lab Takes Nanomedicine Research to New Heights, Literally

Oct. 29, 2021 - Eden McCleskey

Nanomedicine is a nebulous concept for most Americans, even among the physician and researcher set. That's probably because it's got about as many definitions, applications and nuances as a strand of human hair has nanometers (approximately 100,000).

Nanomedicine is officially defined as a branch of medicine that seeks to apply nanotechnology — the manipulation and manufacture of materials and devices that are roughly 1-100 nanometers in size — to the prevention of disease and the imaging, diagnosis, monitoring, treatment, repair and regeneration of biological systems.

Alessandro Grattoni, Ph.D., chair of the Houston Methodist Department of Nanomedicine, says, "It's a multidisciplinary field merging physics, chemistry and biology. It's been around for decades, but then someone started calling it nanomedicine and it developed a sort of mystique."

No matter what you call it, it's clearly big right now. And some of the most exciting and widely applicable medical advances — covering all major disease types, including cardiovascular, cancer, endocrine, neurodegenerative, musculoskeletal and inflammatory — are being turned out by departments and labs like the ones Grattoni leads.

Grattoni and his 15-person research team have eight ongoing projects, more than $15 million in grants and 12 major partnerships within their primary area of focus — developing implantable drug delivery systems for the treatment of chronic diseases. For a fifth time now, Grattoni also has a research project currently located 250 miles above earth as part of a long-term collaboration with the International Space Station National Laboratory and NASA.

Keep reading to get the latest on the Grattoni Lab's efforts to put new medical technologies into orbit.

Sustained, refillable drug delivery systems

Nearly half of all Americans suffer from a chronic condition, and among people over the age of 65, that number rises to more than 80%.

The typical way to treat these conditions is with medicine, either oral pills or injections.

Although this has been the norm for quite some time, it has its drawbacks. Pills have to go through the digestive tract, requiring a higher dose. You have to remember to take them on time, every time. And you experience concentration peaks and valleys, only staying in the therapeutic range part of the time.

"We believe that there are better ways to deliver treatments, especially for certain types of diseases where you can benefit from steady drug dosing or when the stakes are very high if you forget to take one or two pills," Grattoni says.

The researchers have developed small subcutaneous implants, ranging in size from a dress shirt button to a silver dollar, that hold a reservoir of medication that can last for several months to several years. Like sand trickling through an hourglass, the medication is released through a nanochannel membrane that acts as a sieve, ensuring a steady, optimal dose is administered for as long as there's medication in the reservoir.

The implants feature a refillable port, which you can access using needles, instead of needing to perform repeated surgeries on the patient to remove and replace the device every time the drug runs out.

Medications being tested using this platform include hormone replacement therapy, anti-obesity and metabolic syndrome medications, muscle atrophy prevention and HIV prevention.

"Medication that is highly effective at preventing the transmission of HIV exists, but if you miss one or two doses a week, you could be unprotected," Grattoni explains.

The lab has received NIH funding to eliminate the medication adherence issue by developing an implant that dispenses it automatically. It has already been tested in non-human primates, a clinically relevant animal model for HIV, and Grattoni says the implant could be in human clinical trials within two years.

Remotely tunable drug delivery

Some diseases don't require a constant amount of drug per unit of time; instead, they benefit from a drug being delivered at a specific time of day. Consider sleeping pills or ADHD stimulant medications.

Although subcutaneous implants could have similar benefits for this population of patients when it comes to adherence and minimizing the drug dose, the drug release mechanism needs to be controllable, not constant.

"We use the same technology as in the constant drug delivery implant, but we've evolved it so we can now control it via Bluetooth," Grattoni says. "The silicon membrane has electrodes embedded within it, underneath the surface of nanochannels. By using a smartphone app that we have developed, we can modulate the release of drug, changing the electrostatics to initiate delivery at a specific time, stop delivery, slow it down or ramp it up."

The team has tested it with various medications, but is focusing primarily on hypertension and rheumatoid arthritis, where the patient benefits from therapeutics being delivered at specific times of the day.

Intratumoral cancer radio-immunotherapy

Immunotherapy triggers the immune system to fight cancer by injecting targeted antibodies into the patient's bloodstream.

What if you could deliver the immunotherapy directly inside the tumor itself, 24 hours a day, seven days a week, from the comfort of home? Would it improve outcomes for triple-negative breast cancer or pancreatic cancer, which have few, if any, effective therapeutic regimens?

Would it be able to trigger the coveted abscopal effect in metastatic breast cancer, lung cancer or melanoma, destroying the tumor where it was implanted and the metastatic sites as well?

These are the questions the Grattoni Lab pondered while developing a tiny intratumoral drug delivery implant for cancer patients.

Not only has the team's early research shown that the intratumoral insert, which is smaller than the size of a grain of rice and can be inserted via a biopsy needle, was as effective as delivering the drug intratumorally via IV, but the animal models it was tested on lived significantly longer and showed no adverse side effects.

Other important benefits of the device: It is radio-opaque, so you can locate it through imaging and perform image-guided radiotherapy at the same time, and it can be easily removed when the tumor is surgically excised, as often is standard practice for solid tumors.

Endocrine cell transplantation

Switching gears from drug delivery platforms to cell transplantation, the Grattoni Lab has also been working on developing a treatment for Type 1 diabetes that effectively creates a mini-pancreas for patients who don't have working models of their own.

The typical treatment for type-1 diabetes is exogenous insulin administration, where the patient measures their blood glucose frequently, calculates and delivers an appropriate dose of insulin for themselves. There are also automated systems, such as infusion pumps, which can take the human error and guesswork out of the equation, but they are prone to infections and are cumbersome, especially in the pediatric population.

Another option, pancreatic transplantation, is limited by organ donor availability, highly invasive, and has not been proven to have high success rates. One final option, pancreatic islet donation from a living donor, has theoretical promise but, in reality, the transplanted cells lose their viability quickly, perhaps due to spending time under hypoxic conditions.

Another drawback of pancreatic cell transplantation is the need for lifelong systemic immune suppression, which, as we all know from COVID-19, is a big risk factor for contracting different diseases, including opportunistic infections.

To counter all these challenges, Grattoni and his research team have developed a 3D-printed implant with two different chambers. The central chamber is where the transplanted islet cells are stored, and the outer chamber is a reservoir that contains the immunosuppressants that enable immune suppression where the cells are transplanted, abrogating the need for systemic immune suppression.

"We were able to 'functionally cure' diabetes, for a long period of time," Grattoni says. "The rats we used had glucose levels that were sky high. And after we implanted our device, the glucose level fell within euglycemic levels, identical to non-diabetic rats. And they maintained that for as long as we kept the implant in subcutaneously, which was 190 days."

Because the early results were so positive, the team is now conducting studies in non-human primates and aiming for human clinical trials as soon as possible.

Nanomedicine, but in space

Grattoni has a gift for demystifying the decidedly exotic, which he puts to use when asked why — and how — his research wound up in space.

"The ISS National Lab and NASA put out a request for proposal, similar to what the NIH and other federal agencies do," Grattoni says. "They were asking for experiment ideas that could only work in space. We applied and we were funded, and that's how we started collaborating with them. Obviously, every time you use the International Space Station, there is a significant cost to it, so you need to have a really good reason why you need to use it."

The Grattoni Lab's was a microgravity experiment to study the diffusion of drug-like particles. At the time, the research team did not have a clear understanding of the physics of drug particles diffusing through tight nanochannels.

"Studying microparticles directly through a fluorescent microscope in microgravity for three weeks allowed us to scale up our nanofluidic system to a microfluidic model," Grattoni explains. "Essentially, it sped up the development of all our other drug delivery platforms, allowing us to, hopefully, get them to patients that much faster."

The Center for Space Nanomedicine, part of the Houston Methodist Department of Nanomedicine, was formed in 2016 just prior to the lab's first launch into space. In addition to nanotherapeutics for targeted drug delivery, the center focuses on the development and testing of diagnostic and therapeutic biomedical devices for precision medicine, regenerative medicine and tissue engineering.

The center's next space project partnered them with pharmaceutical company Novartis to test the delivery of an anti-muscle atrophy drug using Grattoni's implant.

"Muscle atrophy is a significant challenge for astronauts in space; it is also a comorbidity of several diseases affecting the general population," Grattoni says. "The microgravity-induced muscle wasting in rodents is an outstanding model of the disease that cannot be fully reproduced on Earth. Our project demonstrated the efficacy of both the implant and the drug at significantly reducing the amount of muscle tissue lost during space flight."

Another study was focused on material science, specifically evaluating the performance of a new carbon fiber manufactured by automobile maker, Lamborghini. A small box containing material samples was mounted outside the ISS and exposed directly to the harsh conditions of space, including microgravity, increased radiation and temperature swings from -250° F to 250° F. In addition to being examined for use in cars, the material could be useful in biomedical devices and implants, planes, rockets, satellites, drones and various other products.

The most recent space-bound experiment, launched Aug. 28, 2021, examines the researchers' ability to communicate with and control a Bluetooth-enabled drug delivery implant from Earth to the ISS. If the technology demonstration is successful, the remotely operated device could open new doors for telemedicine applications and personalized medicine on Earth and provide new avenues for medical research in space.


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