A new method could help the smallest of medicines hit their targets
Its strength is in its lack of size.
Using materials on the minuscule scale of nanometers (billionths of a meter), nanomedicines have the ability to provide treatment more precise than any other form of medicine. Under optimal circumstances, they can target specific cells and perform feats like altering the expression of proteins in tumors so that the tumors shrink.
Another appealing concept about nanomedicine is that treatment on a nano-scale, which is smaller yet than individual cells, can greatly decrease exposure to parts of the body outside the target area, thereby mitigating side effects.
But this young field's huge potential has met with an ongoing obstacle: the recipient's immune system tends to regard incoming nanomedicines as a threat and launches a complement protein attack. These complement proteins, which act together through a wave of reactions to get rid of troubling microorganisms, have had more than 500 million years to refine their craft, so they are highly effective.
Seeking to overcome a half-billion-year disadvantage, nanomaterials engineers have tried such strategies as creating so-called stealth nanoparticles.
“All new technologies face technical barriers, and it is the job of innovators to engineer solutions to them,” Brenner says.
Despite these clever attempts, nanomedicines largely keep failing to arrive at their intended destinations. According to the most comprehensive meta-analysis of nanomedicines in oncology, fewer than 1 percent of nanoparticles manage to reach their targets. The remaining 99-plus percent are expelled to the liver, spleen, or lungs – thereby squandering their therapeutic potential. Though these numbers seem discouraging, systems biologist Jacob Brenner remains undaunted. “All new technologies face technical barriers, and it is the job of innovators to engineer solutions to them,” he says.
Brenner and his fellow researchers at the Perelman School of Medicine at the University of Pennsylvania have recently devised a method that, in a study published in late 2021 involving sepsis-afflicted mice, saw a longer half-life of nanoparticles in the bloodstream. This effect is crucial because “the longer our nanoparticles circulate, the more time they have to reach their target organs,” says Brenner, the study's co-principal investigator. He works as a critical care physician at the Hospital of the University of Pennsylvania, where he also serves as an assistant professor of medicine.
The method used by Brenner's lab involves coating nanoparticles with natural suppressors that safeguard against a complement attack from the recipient's immune system. For this idea, he credits bacteria. “They are so much smarter than us,” he says.
Brenner points out that many species of bacteria have learned to coat themselves in a natural complement suppressor known as Factor H in order to protect against a complement attack.
Humans also have Factor H, along with an additional suppressor called Factor I, both of which flow through our blood. These natural suppressors “are recruited to the surface of our own cells to prevent complement [proteins] from attacking our own cells,” says Brenner.
Coating nanoparticles with a natural suppressor is a “very creative approach that can help tone and improve the activity of nanotechnology medicines inside the body,” says Avi Schroeder, an associate professor at Technion - Israel Institute of Technology, where he also serves as Head of the Targeted Drug Delivery and Personalized Medicine Group.
Schroeder explains that “being able to tone [down] the immune response to nanoparticles enhances their circulation time and improves their targeting capacity to diseased organs inside the body.” He adds how the approach taken by the Penn Med researchers “shows that tailoring the surface of the nanoparticles can help control the interactions the nanoparticles undergo in the body, allowing wider and more accurate therapeutic activity.”
Brenner says he and his research team are “working on the engineering details” to streamline the process. Such improvements could further subdue the complement protein attacks which for decades have proven the bane of nanomedical engineers.
Though these attacks have limited nanomedicine's effectiveness, the field has managed some noteworthy successes, such as the chemotherapy drugs Abraxane and Doxil, the first FDA-approved nanomedicine.
And amid the COVID-19 pandemic, nanomedicines became almost universally relevant with the vast circulation of the Moderna and Pfizer-BioNTech vaccines, both of which consist of lipid nanoparticles. “Without the nanoparticle, the mRNA would not enter the cells effectively and would not carry out the therapeutic goal,” Schroeder explains.
These vaccines, though, are “just the start of the potential transformation that nanomedicine will bring to the world,” says Brenner. He relates how nanomedicine is “joining forces with a number of other technological innovations,” such as cell therapies in which nanoparticles aim to reprogram T-cells to attack cancer.
With a similar degree of optimism, Schroeder says, “We will see further growing impact of nanotechnologies in the clinic, mainly by enabling gene therapy for treating and even curing diseases that were incurable in the past.”
Brenner says that in the next 10 to 15 years, “nanomedicine is likely to impact patients” contending with a “huge diversity” of conditions. “I can't wait to see how it plays out.”
After his grandmother’s dementia diagnosis, one man invented a snack to keep her healthy and hydrated.
On a visit to his grandmother’s nursing home in 2016, college student Lewis Hornby made a shocking discovery: Dehydration is a common (and dangerous) problem among seniors—especially those that are diagnosed with dementia.
Hornby’s grandmother, Pat, had always had difficulty keeping up her water intake as she got older, a common issue with seniors. As we age, our body composition changes, and we naturally hold less water than younger adults or children, so it’s easier to become dehydrated quickly if those fluids aren’t replenished. What’s more, our thirst signals diminish naturally as we age as well—meaning our body is not as good as it once was in letting us know that we need to rehydrate. This often creates a perfect storm that commonly leads to dehydration. In Pat’s case, her dehydration was so severe she nearly died.
When Lewis Hornby visited his grandmother at her nursing home afterward, he learned that dehydration especially affects people with dementia, as they often don’t feel thirst cues at all, or may not recognize how to use cups correctly. But while dementia patients often don’t remember to drink water, it seemed to Hornby that they had less problem remembering to eat, particularly candy.
Where people with dementia often forget to drink water, they're more likely to pick up a colorful snack, Hornby found. alzheimers.org.uk
Hornby wanted to create a solution for elderly people who struggled keeping their fluid intake up. He spent the next eighteen months researching and designing a solution and securing funding for his project. In 2019, Hornby won a sizable grant from the Alzheimer’s Society, a UK-based care and research charity for people with dementia and their caregivers. Together, through the charity’s Accelerator Program, they created a bite-sized, sugar-free, edible jelly drop that looked and tasted like candy. The candy, called Jelly Drops, contained 95% water and electrolytes—important minerals that are often lost during dehydration. The final product launched in 2020—and was an immediate success. The drops were able to provide extra hydration to the elderly, as well as help keep dementia patients safe, since dehydration commonly leads to confusion, hospitalization, and sometimes even death.
Not only did Jelly Drops quickly become a favorite snack among dementia patients in the UK, but they were able to provide an additional boost of hydration to hospital workers during the pandemic. In NHS coronavirus hospital wards, patients infected with the virus were regularly given Jelly Drops to keep their fluid levels normal—and staff members snacked on them as well, since long shifts and personal protective equipment (PPE) they were required to wear often left them feeling parched.
In April 2022, Jelly Drops launched in the United States. The company continues to donate 1% of its profits to help fund Alzheimer’s research.
Last week, researchers at the University of Oxford announced that they have received funding to create a brand new way of preventing ovarian cancer: A vaccine. The vaccine, known as OvarianVax, will teach the immune system to recognize and destroy mutated cells—one of the earliest indicators of ovarian cancer.
Understanding Ovarian Cancer
Despite advancements in medical research and treatment protocols over the last few decades, ovarian cancer still poses a significant threat to women’s health. In the United States alone, more than 12,0000 women die of ovarian cancer each year, and only about half of women diagnosed with ovarian cancer survive five or more years past diagnosis. Unlike cervical cancer, there is no routine screening for ovarian cancer, so it often goes undetected until it has reached advanced stages. Additionally, the primary symptoms of ovarian cancer—frequent urination, bloating, loss of appetite, and abdominal pain—can often be mistaken for other non-cancerous conditions, delaying treatment.
An American woman has roughly a one percent chance of developing ovarian cancer throughout her lifetime. However, these odds increase significantly if she has inherited mutations in the BRCA1 or BRCA2 genes. Women who carry these mutations face a 46% lifetime risk for ovarian and breast cancers.
An Unlikely Solution
To address this escalating health concern, the organization Cancer Research UK has invested £600,000 over the next three years in research aimed at creating a vaccine, which would destroy cancerous cells before they have a chance to develop any further.
Researchers at the University of Oxford are at the forefront of this initiative. With funding from Cancer Research UK, scientists will use tissue samples from the ovaries and fallopian tubes of patients currently battling ovarian cancer. Using these samples, University of Oxford scientists will create a vaccine to recognize certain proteins on the surface of ovarian cancer cells known as tumor-associated antigens. The vaccine will then train that person’s immune system to recognize the cancer markers and destroy them.
The next step
Once developed, the vaccine will first be tested in patients with the disease, to see if their ovarian tumors will shrink or disappear. Then, the vaccine will be tested in women with the BRCA1 or BRCA2 mutations as well as women in the general population without genetic mutations, to see whether the vaccine can prevent the cancer altogether.
While the vaccine still has “a long way to go,” according to Professor Ahmed Ahmed, Director of Oxford University’s ovarian cancer cell laboratory, he is “optimistic” about the results.
“We need better strategies to prevent ovarian cancer,” said Ahmed in a press release from the University of Oxford. “Currently, women with BRCA1/2 mutations are offered surgery which prevents cancer but robs them of the chance to have children afterward.
Teaching the immune system to recognize the very early signs of cancer is a tough challenge. But we now have highly sophisticated tools which give us real insights into how the immune system recognizes ovarian cancer. OvarianVax could offer the solution.”