Where Promising Drugs Fail: Rethinking How We Deliver Advanced Therapies
Drug delivery should not be the weak link in getting treatments to patients.
Unless the delivery method is up to scratch, even the most well-designed and effective treatment will have a very limited impact on patients. A poor drug delivery approach can dilute the potency of treatments, or worse, result in potentially harsh side effects.
Today’s advanced therapies are very different from traditional drugs. Cell therapies and large molecule drugs present unique challenges for drug delivery, which researchers are working hard to overcome.
Advanced therapy delivery shouldn’t be the bottleneck or the weak link in treatment, believes Lisa Stehno-Bittel, PhD, president and founder of Likarda. Stehno-Bittel, also a professor emeritus at the University of Kansas Medical Center, has led the development of Likarda’s Core-Shell Spherification® technology, designed to improve the encapsulation of advanced therapies and keep them protected as they move through the body, delivering them directly to their target.
Technology Networks spoke with Stehno-Bittel to learn more about why drug delivery remains one of biotech’s most pressing challenges, the various innovations that are helping to break down barriers and what this means for patients.
What are some of the limitations seen in current drug delivery methods for advanced therapies?
Lisa Stehno-Bittel, PhD (LSB):
Every drug we take is packaged with inactive ingredients that ensure the drug is safe and effective. However, the inactive ingredients used to package traditional drugs simply don't work for the new classes of complex advanced therapies like cells, exosomes and large molecules. Most of them are cytotoxic and cannot be used as carriers for fragile cell therapies.
A new method of packaging had to be discovered for complex therapies. Encapsulation was one of the first attempts to deliver therapeutic cells to patients. It is achieved by trapping active ingredients into small microspheres that can be injected. The first polymer utilized for microencapsulation was alginate. It is inexpensive and easy to fabricate, but once implanted in the body, it induces a foreign body response with localized inflammation that concludes with a wall of collagen around each microsphere. This response is so strong that when alginate was used in a clinical trial to deliver cells to treat hemophilia, the immune rejection of the alginate required the removal of the microspheres from the patients' peritoneum.
AB:
Why have these challenges been so overlooked in biotech development?
LSB:
The negative outcomes with alginate have cast a shadow over the field of microencapsulation. But the problem with those early versions of microencapsulation was due to alginate's immunogenic properties, not the physical format of microencapsules. It was the lack of options for the delivery of cells that led to the creation of Likarda's Core-Shell Spherification (CSS), a proprietary, novel method of microencapsulation that avoids alginate.
AB:
Can you tell us more about how this CSS technology works and what makes it different to traditional delivery methods?
LSB:
Our goal at Likarda was to encapsulate cells and large molecules using materials that were already being implanted into the body and familiar to regulatory bodies. The compounds also needed to be:
- Biocompatible
- Non-cytotoxic
- Safe
- Customizable
- Immune protective
- Porous
- Inexpensive
The first examples that met those criteria included polyethylene glycol, hyaluronic acid and polyvinyl alcohol. Unfortunately, the binding kinetics of those polymers were not compatible with the microencapsulation instruments that were available at the time; they crosslink too slowly. We had to design and build a new instrument that could provide the time needed for these polymers to fully crosslink. The result was Core-Shell Spherification. With CSS, an instantaneous shell is created around each microcapsule, entrapping the active ingredient.
AB:
This technology has been demonstrated in a recent Tissue Engineering paper, where it was examined both in vitro and in vivo with a cell therapy for treating chronic liver disease. Can you tell us more about this study?
LSB:
This study was completed in collaboration with scientists from Takeda and resulted in the co-authored paper.
The goal of the study was to identify a polymer that could support liver cell health long-term and release human albumin in an animal model. Liver cell aggregates rapidly die in culture and after implantation. Encapsulating the liver spheroids in Likarda's VitaCell™ supported cell health and function. When implanted in mice, the VitaCell encapsulated liver aggregates continued to secrete albumin for the study duration. In contrast, cells encapsulated in ultra-pure alginate lost function and illustrated signs of rejection.
AB:
What might better targeted delivery methods mean for liver failure and liver disease patients? More broadly, are there other applications that might benefit from the CSS technology?
LSB:
There is no cell therapy currently approved for liver diseases. Cell therapies in the pipeline are designed predominantly for acute liver failure, a dangerous situation commonly leading to encephalopathy and death if not treated. Depending on the severity of the disease, the patient may only live for a few days after diagnosis unless they receive a liver transplant.
Cell therapies have the potential to save lives during this important period between liver failure and an organ transplant. Encapsulated cells secrete factors that the liver normally produces that can mitigate symptoms and extend life until a matched donor organ can be found.
AB:
Looking to the next 5–10 years, how do you see hydrogel encapsulation technologies and other novel targeted delivery methods reshaping the field of advanced therapeutics? Are there any notable challenges/opportunities on the horizon?
LSB:
Cell therapies offer immense potential to cure diseases rather than simply treat the symptoms. With the exception of blood cancers like lymphoma and leukemia, that promise has yet to be realized. The addition of inactive ingredients for these complex therapies holds multiple advantages:
- Potency preservation
- Improved safety
- Durable solutions
- Better patient experience
Innovations in delivery will determine whether advanced therapies remain niche products or become widely accessible, life-saving medicines.
