Many traditional cancer treatments, such as chemotherapy and radiation, effectively destroy cancer cells but often lead to severe side effects that leave patients feeling even more sick.

Two 91探花 researchers are developing treatments that aim to simultaneously treat cancer and improve patients’ quality of life. , 91探花professor of materials science and engineering and of neurological surgery in the 91探花School of Medicine, develops tiny systems that deliver cancer treatment specifically to cancer cells. , 91探花assistant professor of materials science and engineering and of radiology in the 91探花School of Medicine, uses interventional radiology to precisely deliver cancer treatment to the body.

Both Zhang and Som are studying a cancer treatment method called , where a patient’s own immune cells are trained to target and destroy cancer cells. The two researchers are now collaborating with the goal of getting their therapeutics into the clinic.

For World Cancer Day, 91探花News asked Zhang and Som to discuss their novel materials and how these materials can treat both the cancer and the patient.

Tell us about your research in this area.聽

Miqin Zhang: One of our key research areas is developing biocompatible nanoplatforms for cancer diagnosis, treatment and therapy-response monitoring. For example, one of our recent advances is using tiny particles called nanoparticles to deliver immunotherapies or vaccines in preclinical animal models. The payloads from these nanoparticles activate immune cells to eradicate drug-resistant solid tumors and metastases.

In general, our nanoplatforms provide tumor specificity in two unique ways:

• The nanoparticles can carry diverse payloads 鈥� including chemotherapeutics and genetic materials 鈥� to address tumor heterogeneity
• We can use different methods to trigger our nanoparticles to release their payloads, such as changing the temperature or pH. Other methods include using enzymes or magnetic fields.

Our systems are designed for versatility and can work in tandem with various tumor-targeting and therapeutic agents.

Avik Som: I am a physician-scientist with clinical training in interventional radiology, with a specific focus in interventional oncology. In this field we often deliver therapy directly to single lesions using small needles and wires. This eliminates the need for invasive surgery in patients who are often too sick for surgery.

My research expertise has focused on developing novel drug delivery materials and techniques for interventional radiologists to use, including in the field of immunotherapy. Interventional radiologists have long succeeded at delivering therapy highly precisely within the body. Using the best of material science, my lab looks at changing what we鈥檙e delivering to heal our patients of both their cancer and the underlying ravages that the cancer has caused.

How can your materials both extend patients’ lives and improve their quality of life?

MZ: Our new nanoparticle materials promise more effective and less harmful treatments in a variety of ways. First, the nanoparticles target cancer cells specifically, which minimizes side effects and enables controlled drug release to maintain therapeutic levels without toxicity spikes.

Next, we design these nanoparticles using biocompatible materials, such as iron oxide and chitosan coatings, which reduce immune-response reactions and make the nanoparticles more compatible with long-term use.

Cancer’s complex and variable nature means that treatments that are effective for one patient might not work for another, which makes it difficult to create one-size-fits-all solutions. But our nanoparticles support personalized medicine because we can target specific mutated genes in individual patients. Furthermore, we can develop nanoparticles that are multifunctional. For example, a single nanoparticle can have capabilities that enable both monitoring as well as treatment.

AS: The concepts of extending patients’ lives and improving their quality of life have effectively been done in parallel for years. For example, the 91探花has extensive history and expertise in tissue engineering. But it usually isn’t combined with cancer care because the two goals often feel contradictory: Tissue engineering results from inducing cell growth, while historically cancer therapy has directly focused on killing cells. So the fields have diverged.

But we can design novel materials to do both: One material can use different release rates to stagger the anti-cancer versus tissue-engineering effects. For example, we can use interventional radiology to implant a material directly into a tumor. The material can have an initial burst of drug release that has an anti-cancer effect. And then, after killing the tumor, the residual material can release factors that recruit normal cells to fill in the gap where the cancer was.

Alternatively, as radiologists, we can see where cancer is and isn鈥檛. It is therefore possible to selectively deliver anti-cancer agents to the cancer, while simultaneously delivering pro-tissue engineering agents to normal tissue.

Are any of these treatments currently available in the clinic?

MZ: The process of getting a treatment like this approved is complex and resource-intensive, because it requires extensive research, clinical trials and regulatory approvals. To reduce clinical trial costs, our nanoparticle platform is adaptable for multiple genetic therapies, which offers regulatory advantages and paves the way for FDA approval.

Right now, our nanoparticles are still at the basic research stage and have not yet entered clinical trials. They have, however, demonstrated their efficacy in various pre-clinical animal models. We are now prepared to engage with venture capitalists and major pharmaceutical companies to advance our nanoparticles into clinical trials.

AS: Our research is also still in the basic stage for the moment. We need to determine the best type of material and safest way to deliver it into patients through rigorous pre-clinical testing.

That being said, at the Fred Hutch Cancer Center and 91探花Medicine, we are leading an intratumoral therapy group that is ramping up clinical trials for patients using therapies that are in development around the country. In addition, we are working on bringing on more minimally invasive tissue engineering trials to the clinic soon.

What part of this collaboration is the most exciting to you?

AS: I was fortunate to meet Miqin during my interview at UW, and we struck up a vibrant conversation. Miqin has been a leader in the fields of biomaterials and drug delivery, and she is an ideal mentor to help me with my goal of bringing these advances to the clinic.

MZ: I have more than 15 years of experience in cancer research, and I strongly believe that interventional radiology is transforming cancer care by offering minimally invasive, precise treatment options that reduce side effects and improve patient outcomes. I am thrilled to collaborate with Avik so that we can apply our advanced materials and his innovative approaches to enhance interventional radiology for cancer treatment and tissue growth in a way that minimizes side effects and improves patients鈥� quality of life.

Zhang’s research is funded by the Kuni Foundation and the National Institutes of Health. Zhang is also a faculty researcher with the 91探花Institute for Nano-Engineered Systems and the Molecular Engineering and Sciences Institute. Som’s research has been funded by the Radiologic Society of North America and the National Institutes of Health.

For more information, contact Zhang at mzhang@uw.edu and Som at aviksom@uw.edu.

Nanoparticles are a promising type of drug delivery system. Also known as nanocarriers, these tiny particles can bind to drugs and protect them from degradation until they enter tumor cells. But their effectiveness as drug carriers and drug protectors, as well as potential toxicity in patients, depends significantly on their size, composition and chemical properties. Balancing these competing factors is a delicate process. Although researchers have made significant advances in nanomedicine in the last decade, it remained a formidable challenge to design and synthesize small, stable nanoparticles that could deliver sufficient drugs to treat solid tumors.

Earlier this year scientists at the 91探花 announced that they have achieved such a balancing act with a nanoparticle-based drug delivery system that can ferry a potent anti-cancer drug through the bloodstream safely. As they report in a published in May in Materials Today, their nanoparticle is derived from , a natural and organic polymer that, among other things, makes up the outer shells of shrimp.

The team, led by , a 91探花professor of materials science and engineering and of neurological surgery, demonstrated that their chitin-derived system can successfully ferry , a potent anti-cancer drug that is also known as paclitaxel, through the bloodstream and inhibit tumor growth and spread, also known as metastasis, in mice. The nanoparticles showed no adverse side effects, likely since they are derived in part from naturally occurring polymer.

鈥淭his could form the basis of a new class of nanoparticle delivery systems that can transport anti-cancer therapeutics through the body safely, with no toxic side effects from the nanoparticle material,鈥� said Zhang, who is also a faculty researcher with the 91探花 and the .

The nanoparticles, once loaded with Taxol, are about 20.6 nanometers in diameter. That鈥檚 about 1/4000th the width of a human hair, the U.S. National Nanotechnology Initiative. The particles are small enough to travel through blood vessels and get to potentially compact tumor sites.

Zhang鈥檚 team started by loading Taxol particles onto much longer strands of , a material derived from chitin. The nanofibers break down to form nanoparticles when exposed to serum, a blood protein, either in the lab or in the body. Researchers showed that drug-loaded nanofibers, when injected into mice, broke down rapidly into the tiny nanoparticles 鈥� thanks to serum proteins in the blood 鈥� and could circulate freely in the bloodstream, enter organs and reach tumor sites.

The team subjected Taxol-loaded nanoparticles to a barrage of experiments to see what they could do to tumors. In cell cultures of mouse mammary cancer cells, a majority of cancer cells showed signs of cell death 48 hours after treatment, indicating that nanoparticle-associated Taxol could enter cancer cells and impair cell growth at least as well as free-floating Taxol. In mice, Taxol-loaded nanofibers, which broke down into nanoparticles, showed 90% inhibition of mammary tumor growth compared to about 66% inhibition for Taxol injected in the clinical solution used widely today. The nanoparticles also inhibited melanoma tumor growth in mice by up to 75%. In separate experiments in mice, Taxol-loaded nanoparticles also prevented spread of mammary cancer to other parts of the body, unlike Taxol in a clinical solution.

In addition to these promising findings with tumors, the team found that the nanoparticles kept Taxol circulating in the bloodstream longer, giving the drug more time to reach the tumor site. In the bloodstream of mice, the half-life of Taxol-associated nanoparticles was nearly 25 hours, compared to less than 2 hours for Taxol injected in the clinical solution. Mice injected with the nanofibers showed no signs of toxic side effects, indicating that the nanoparticles themselves weren鈥檛 causing harm to tissues. In contrast, the clinical solution used widely today for Taxol can cause liver toxicity in mice, among other side effects.

Zhang believes that the chitosan-derived nanoparticles could form the basis of a non-toxic drug delivery system for cancer that keeps therapeutics in the body longer to inhibit tumor growth and metastasis.

鈥淭his is a very promising finding. Many drug delivery systems used today for anti-cancer drugs come with toxic side effects, and don鈥檛 protect the drug for very long in the patient鈥檚 body,鈥� said Zhang. 鈥淭he nanoparticles have all the characteristics you could hope for in getting the drug to into tumor cells. The small chitosan-based nanocarrier, made in situ, with unique biocompatibility and biodegradability, offers a new strategy for anti-cancer drug delivery and has great potential for rapid translation to the clinic.鈥�

Co-authors on the paper are Qingxin Mu, Guanyou Lin, Zachary Stephen, Seokhwan Chung and Hui Wang in the 91探花Department of Materials Science & Engineering; Victoria Patton in the 91探花Department of Chemical Engineering; and Rachel Gebhart in the 91探花Department of Chemistry. The research was funded by the National Institutes of Health and the National Science Foundation.

For more information, contact Zhang at mzhang@uw.edu.

, a professor of materials science and engineering at the 91探花, is looking for ways to help the body heal itself when injury, disease or surgery cause large-scale damage to one type of tissue in particular: skeletal muscle. Muscles have a limited ability to regenerate, repair and realign themselves properly after certain types of damage.

Zhang and her team are taking a synthetic approach to muscle regeneration. Their goal is to create a synthetic, porous, biologically compatible “scaffold” that mimics the normal extracellular environment of skeletal muscle 鈥� onto which human cells could migrate and grow new replacement fibers.

As she recently showed in a published online Nov. 16 in , this endeavor builds on decades of work into the growth, repair and behavior of normal skeletal muscle, but also relies on keen knowledge of engineering and materials science. Zhang sat down with 91探花Today to explain the project’s goals and progress to date.

What drew you to work on tissue engineering?

I suppose it’s easier to say first where I didn’t come from in choosing to work on this problem: I’m not a biologist. I’m an engineer. That is my training and that is how I like to work 鈥� building things up one at a time to solve problems.

And a lot of the problems I like to work on are in biology or medicine, but I come at them from an engineering standpoint. So engineering solutions for these biological “problems” 鈥� like or 鈥� means assembling components that are compatible with our bodies, which our cells can respond to.

For tissue engineering and repair, we’ve been focusing lately on skeletal muscle. There’s really a medical need for platforms or scaffolds for muscle fiber regeneration, since after injury the body’s abilities to repair skeletal muscle are really quite limited.

How so?

Skeletal muscle makes up a large part of the human body 鈥� 40 to 50 percent by weight. And when damage occurs to skeletal muscle on a small scale, we’ve seen that skeletal muscle possesses innate repair mechanisms. Through these mechanisms, a new fiber can grow, for example, essentially repairing or replacing the damaged one.

But above a critical threshold of damage to skeletal muscle, our bodies no longer employ those effective repair mechanisms. Instead, the body forms scar tissue at the wound site 鈥� and then you’ve essentially lost control of that muscle function. You can’t get it back. Surgically, you could graft in skeletal muscle. But that depends on the availability of donor tissue.

So we know that the body can repair skeletal muscle. It just doesn’t do so beyond a certain threshold of damage.

What do you envision as a solution to the problem of scar tissue formation?

Natural skeletal muscle is surrounded by a complex extracellular matrix that supports muscle fibers as they form and grow in the body. What we would like to do in this field, which many researchers are working on, is to create an artificial extracellular matrix into which we could introduce a progenitor type of cell 鈥� like stem cells or muscle progenitor cells 鈥� and then provide them with the proper signals to differentiate into muscle fibers. We believe that scaffold and signals are what is needed to grow new muscle fibers, which you could then transplant to the site of damage.

What types of materials are these scaffolds made of?

In general, with designing scaffolds for cell growth, the material we work with really depends on the type of cell we’d like to introduce into the scaffold to proliferate. For bone tissue regeneration, , we created a scaffold made of chitosan 鈥� a complex polysaccharide, essentially long chains of sugar-like molecules 鈥� combined with other materials to create a calcified scaffold.

For skeletal muscle, we and other researchers work with a variety of anisotropic materials.

What are anisotropic materials?

These are materials with physical properties that differ based on direction or orientation. They form the basis of the scaffolds and are usually complex polymer materials. The innate “directionality” of anisotropic materials helps the progenitor cells grow into three-dimensional forms like a , which is a precursor to a muscle fiber.

But there are structural challenges to overcome. The scaffold must be micropatterned to promote cell migration, growth and proliferation in the right direction. This involves nanoscale design details, and some polymers are better for this than others. 聽The production of highly aligned nanofibers in a large area remains a great challenge.

We have developed several methods to produce nanofibers made of natural polymers with a high degree of alignment and uniformity over large areas. In addition, we often coat the scaffold with biomolecules that help the cells stick to the scaffold and provide them with the right signals to grow and differentiate.

What types of biomolecules provide these signals?

There are adhesion proteins, growth factors and transcription factors that deliver specific messages to cells depending on their structure and location in the scaffold. We have used growth factors in combination of anisotropic materials to successfully induce high-level and rapid differentiation of human embryonic cells into muscle cells. As I said before, I approach this project from an engineering perspective. But the knowledge basis we use comes from cell biology and physiology 鈥� because in the end, we’re trying to get cells to grow, differentiate and form tissues on a large scale.

Are there other uses for these scaffolds beyond tissue regeneration?

Of course! In my lab, we have also used them certain cancer cells, such as stem cell-like cells in . By changing what we make the scaffolds out of, the protein messages we coat them with or the nanopore structures within the scaffolds, we can reveal many different properties of cells. We can also test the types of external signals, be it a structural feature of the scaffold or a protein message, that can promote or inhibit cell growth. And those are just the sorts of information we need to understand to create effective cancer cell treatments.

It uses the same principle 鈥� using nanoscale scaffolding polymers 鈥� but to find better ways of doing the opposite: inhibit cell growth rather than promote it. That really demonstrates the utility of these technologies. And we’re at the right time to combine biological and engineering approaches to make it happen.

###

For more information, contact Zhang at mzhang@uw.edu or 206-616-9356.

But in published Sept. 27 in the journal , scientists at the 91探花 describe a new system to encase chemotherapy drugs within tiny, synthetic “” packages, which could be injected into patients and disassembled at the tumor site to release their toxic cargo.

The group, led by 91探花professor of materials science and engineering , is not the first to work on nanocarriers. But the nanocarrier package developed by Zhang’s team is a hybrid of synthetic materials, which gives the nanocarrier the unique ability to ferry not just drugs, but also tiny fluorescent or magnetic particles to stain the tumor and make it visible to surgeons.

“Our nanocarrier system is really a hybrid addressing two needs 鈥� drug delivery and tumor imaging,” said Zhang, who is senior author on the paper. “First, this nanocarrier can deliver chemotherapy drugs and release them in the tumor area, which spares healthy tissue from toxic side effects. Second, we load the nanocarrier with materials to help doctors visualize the tumor, either using a microscope or by MRI scan.”

Their hybrid nanocarrier builds on years of research into the types of synthetic materials that could package drugs for delivery into a specific part of a patient’s body. In previous attempts, scientists would often first try make an empty nanocarrier out of a synthetic material. Once assembled, they would load the nanocarrier with a therapeutic drug. But this approach was inefficient, and carried a high risk of damaging the fragile drugs and rendering them ineffective.

“Most chemotherapy drugs have complex structures 鈥� essentially, they’re very fragile 鈥� and they do no good if they are broken by the time they reach the tumor,” said Zhang.

Zhang’s team worked around this problem by designing a nanocarrier that could be assembled and loaded simultaneously. Their approach is akin to laying cargo within a shipping container even as the container’s walls, floor and roof are being assembled and bolted together.

This “load during assembly” technique also let Zhang’s team incorporate multiple chemical components into the nanocarrier’s structure, which could help hold cargo in place and make the tumor easy to image in clinical settings.

Their nanocarrier sports a core of iron oxide, which provides structure but can also be used as an imaging agent in MRI scans. A shell of silica surrounds the core, and was designed to efficiently stack the chemotherapy drug . They also included space in the nanocarrier for carbon dots, tiny particles that can “stain” tissue and make it easier to see under a microscope, helping doctors resolve the boundaries between cancerous and healthy tissue for further treatment or surgery. The intensity of many imaging agents fades over time, but Zhang said this nanocarrier can provide sustained imaging for months.

Yet despite holding so much cargo, the fully loaded nanocarriers are less than the thickness of a sheet of flimsy notebook paper.

The silica shell keeps the nanocarriers watertight. In addition, they do not interfere with healthy tissue, as Zhang’s team showed by injecting healthy mice with empty nanocarriers or nanocarriers loaded with drug cargo. Five days after injection, they checked vital organs in the mice for evidence of toxicity and found none.

“This would indicate that the nanocarriers themselves do not trigger an adverse reaction in the body, and that the loaded nanocarriers are keeping their toxic cargo shielded from the body,” said Zhang.

The 91探花team also designed the nanocarriers to be easily disassembled once they reached a desired location. Gentle heating from low-level infrared light was sufficient to make the nanocarriers break apart and disgorge their cargo, which is something doctors could apply to the tumor site during treatment.

As their final test of the nanocarrier effectiveness, Zhang’s team turned to mice with a form of transmissible cancer. Mice that they injected with empty nanocarriers showed no reduction in tumor size. But tumors shrank significantly in mice injected with nanocarriers that were loaded with paclitaxel. They saw a similar affect on human cancer cells cultured and tested in the lab.

“These results show that the nanocarriers can deliver their cargo intact to the tumor site,” said Zhang. “And while we designed this nanocarrier specifically to accommodate paclitaxel, it is possible to adjust this technique for other drugs.”

There are still mountains to climb before this technology is proven safe and effective for humans. But Zhang hopes her team’s approach and promising results will accelerate the ascent.

Lead authors on the paper are Hui Wang and Kui Wang in the 91探花Department of Materials Science & Engineering. Co-authors are Bowei Tian in the 91探花Department of Applied Mathematics and Richard Revia, Qingxin Mu, Mike Jeon, Fei-Chien Chang 鈥� all in the Department of Materials Science & Engineering. The research was funded by the National Institutes of Health and the 91探花.

###

For more information, contact Zhang at mzhang@uw.edu or 206-616-9356.

Grant number: R01CA161953.