Cornell start-up to test novel paradigm for cancer drug delivery
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A start-up co-founded by researchers at Cornell University has initiated the first therapeutic trial evaluating fluorescent silica nanoparticles, known as “Cornell dots,” as a potential treatment for cancer.
Their ultrasmall size, below the cutoff for renal clearance, sets the Cornell dots apart from previous drug delivery vehicles promising high safety and efficacy.
Originally created in the lab of Ulrich B. Wiesner, PhD, Cornell dots have already demonstrated diagnostic efficacy in finding tumors in the clinical setting.
Since the technology’s introduction, Elucida Oncology Inc., a biotechnology company Wiesner co-founded, has further developed the nanoparticles, now known as C’Dots, and will assess them for therapeutic use in targeted drug delivery among patients with advanced, recurrent or refractory cancers.
“Lots of drugs on the shelves of pharmaceutical companies have not made the cut because they may have had severe side effects,” Wiesner told Healio. “When you put them onto ultrasmall delivery vehicles like C’Dots, it could make all the difference. As a result of their rapid renal clearance, they reach the tumor and are efficacious but without the side effects. Once we verify this ‘target-or-clear’ paradigm, there’s no end to what is possible.”
Wiesner spoke with Healio about the development of C’Dots, their efficacy in diagnostic applications, and their potential to provide unprecedented therapeutic outcomes.
Healio: What are C’Dots?
Wiesner: These multifunctional constructs are made of a silica core. Silica is a biogenic material. It has played a big role in the evolution of biology because silicon is one of the most abundant elements on the planet. Silica, the amorphous oxide of silicon, is in our food; it’s in plants in the form of silica deposits. We eat it all the time, so our bodies are well-accustomed to dealing with silica. It’s also a rather rigid material. That rigidity, when you incorporate a fluorescent molecule like a dye, leads to an enormous brightness enhancement. We discovered this early on, so we thought, “Why don’t we just develop these particles into a diagnostic platform that a surgeon can use during surgery to make better-informed decisions of what to take out and what not to take out?” That’s the original iteration of the technology we developed. With our collaborators at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, we brought that into clinical trials. We recently published a report of the phase 1/2a trial results showing that shortly before surgery, a surgeon operating in the head and neck region can inject these particles peritumorally. Targeted C’Dots get through the lymphatic system to the nearest lymph node. If the lymph node carries a tumor burden, they get attracted to the tumor cells and get stuck there, which lights up the nodes. That has really helped surgeons because otherwise, they need to make decisions on what to take out based to a large extent on their experience. Now the surgeon has a bright signal, such that sometimes even through the skin, he or she can see the nearest lymph node. That shortens the operating time, accelerates healing and makes certain the surgeon sees nodes containing cancerous tissue.
Healio: How did you discover the potential utility of these particles for therapeutic use?
Wiesner: Through the work with our MSKCC collaborators, we created the “target-or-clear” paradigm — particles either target the tumor or are eliminated via the kidneys and do not accumulate elsewhere in the body — for diagnostic applications. But we quickly saw that we also get good accumulation within solid tumors. Because the particles are so small, they diffuse much more rapidly than larger particles. This faster diffusion enables them to penetrate solid tumors much more effectively than larger entities.
This is true even with the most successful current developments in cancer therapy, which are basically antibody drug conjugates (ADCs). These don’t get cleared through the kidneys, so they are often plagued with issues of off-target accumulation in organs like the liver and associated side effects.
The other major issue for next-generation therapies to overcome is that antibodies, for example, don’t really penetrate tumors very much. They get stuck on the tumor surface. In early clinical trials, we resected tumor tissue and saw that C’Dots, which are fluorescent and easy to see, distributed beautifully through these solid tumors — that got us very excited about therapeutic applications.
Over many years, the Cornell-MSKCC team developed a platform based on these ultrasmall particles that combines several properties geared toward overcoming known issues in cancer therapeutic drug delivery. This platform showed a range of properties that seemed to be very beneficial. The startup company, Elucida Oncology, then successfully developed a targeted C’Dot with a specific drug conjugated to the surface that recently received FDA investigational new drug approval for cancer therapy.
Healio: What will the therapeutic trial entail?
Wiesner: At the beginning, it is a dose-escalation safety study. We are currently dosing patients very carefully with an increasing amount of the C’Dot therapeutic to make sure the particles are well-tolerated up to high doses to show therapeutic effects. The second part of the trial will be a tumor group expansion study. Overall, this is a basket trial where the particles will be injected into patients with a range of tumors to find out for which tumor we see the highest efficacy. Tumors identified as being especially susceptible to this drug delivery system will then go into a group expansion study, where more patients with that tumor type will receive therapeutic C’Dot doses. Then we will see how effective the particle platform really is.
Healio: How many patients will you enroll?
Wiesner: The dose-escalation portion will enroll 25 patients. Then, depending on how many of those tumors respond well to the C’Dot drug conjugates (CDCs), the tumor expansion studies will include another 15 patients per cohort.
Healio: What are the potential implications of this technology?
Wiesner: We’ve molecularly engineered this delivery system so that it overcomes well-known issues of existing therapies, including those of the current gold standard in cancer therapy, ADCs. Some of these issues include off-target accumulation with associated side effects and poor tumor penetration resulting in low tumor regression. ADCs are about 15 nanometers in size. They typically carry about five drugs on their surface. Antibodies are globular proteins. Drugs conjugated to their surface can’t hide anywhere, so they make the antibody much more hydrophobic. If it gets too hydrophobic, the antibodies become unstable in solution and aggregate. This limits their drug-loading capacity.
Another huge advantage of our CDCs is their unusually high drug-loading capacity relative to ADCs. The silica cores of CDCs are covered with a shell of poly(ethylene glycol) (PEG) oligomers. This polymer has been used for many years in the pharmaceutical industry; when you add PEG to a normal drug, it increases the drug’s circulation time in the body. From the beginning, we thought it would be a good shell, and indeed PEG forms a polymer brush layer on C’Dots, providing excellent colloidal stability and preventing the formation of protein layers when injected into the bloodstream. Most intriguing, when we engineered the particle surface with drugs, we found the drugs can hide between the individual PEG chains of this hydrophilic brush layer. Drugs are typically quite hydrophobic; they are not fond of being in water. So they hide between the PEG chains, and that keeps the surface of the particles very hydrophilic. As it turns out, we can load up to 60 drugs or more on a single particle. As a result, CDCs are not only two to three times smaller than an ADC, they also can carry 10 times as many drugs.
What is most remarkable is that the drugs don’t significantly alter the biological properties of CDCs, such as their favorable biodistribution and pharmacokinetic profiles. So, in addition to the “target or clear” paradigm — which we hope will lead to fewer side effects — we also hope that CDCs are more efficacious because of their very high drug-loading capacity.
For more information:
Ulrich B. Wiesner, PhD, can be reached at the Department of Materials, Science and Engineering, 330 Bard Hall, Cornell University, Ithaca, NY 14853; email: ubw1@cornell.edu.
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