The results of a collborative study of more than five years between Cornell, the Memorial Sloan Kettering Cancer Center (MSKCC) and biopharmaceutical company AstraZeneca has been recently announced.
"I've seen beautiful results before, but I've never seen something that eradicates a tumor like this," said study co-lead author Dr. Michelle Bradbury, MSKCC director of intraoperative imaging and professor of radiology at Weill Cornell Medicine.
This announcement is related to a novel cancer therapeutic, combining antibody fragments with molecularly engineered nanoparticles, permanently eradicated gastric cancer in treated mice.
Targeted cancer treatments such as antibody and nanoparticle therapies have seen narrow clinical use because of each therapy's limitations, but the new therapeutic – an evolution of what the researchers call Cornell prime dots, or C' dots – combines the best attributes of both into an ultrasmall, powerfully effective system.
As silica nanoparticles just 6 nanometers in size, C' dots are small enough to penetrate tumors and safely pass through organs once injected into the body. Wiesner first developed them more than 15 years ago and, in collaboration with Bradbury, published a 2018 study that found an antibody fragment-nanoparticle hybrid to be especially effective in finding tumors.
Mice with gastric cancer received three doses of the therapeutic. Not only did the treatment eradicate the disease in every mouse, but there was no evidence of tumor recurrence after nearly 200 days.
"We describe the mode of action as 'hit and run, because the C' dots either target the tumor microenvironment and kill the tumor cells or get safely cleared out of the body via renal clearance as a result of their small size, thereby minimizing off-target accumulation and associated side effects and toxicity."
- Ulrich Wiesner, the Spencer T. Olin Professor, Department of Materials Science and Engineering, at Cornell Engineering
ABSTRACT -
Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core–shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties. Most surprisingly, drawing upon its favorable physicochemical, pharmacokinetic, clearance, and target-specific dual-modality imaging properties in a “hit and run” approach, this conjugate eradicated HER2-expressing gastric tumors without any evidence of tumor regrowth, while exhibiting a wide therapeutic index. Therapeutic response mechanisms are accompanied by the activation of functional markers, as well as pathway-specific inhibition. Results highlight the potential clinical utility of this molecularly engineered particle drug-immune conjugate and underscore the versatility of the base platform as a carrier for conjugating an array of other immune products and payloads.
"I've seen beautiful results before, but I've never seen something that eradicates a tumor like this," said study co-lead author Dr. Michelle Bradbury, MSKCC director of intraoperative imaging and professor of radiology at Weill Cornell Medicine.
This announcement is related to a novel cancer therapeutic, combining antibody fragments with molecularly engineered nanoparticles, permanently eradicated gastric cancer in treated mice.
Targeted cancer treatments such as antibody and nanoparticle therapies have seen narrow clinical use because of each therapy's limitations, but the new therapeutic – an evolution of what the researchers call Cornell prime dots, or C' dots – combines the best attributes of both into an ultrasmall, powerfully effective system.
As silica nanoparticles just 6 nanometers in size, C' dots are small enough to penetrate tumors and safely pass through organs once injected into the body. Wiesner first developed them more than 15 years ago and, in collaboration with Bradbury, published a 2018 study that found an antibody fragment-nanoparticle hybrid to be especially effective in finding tumors.
Mice with gastric cancer received three doses of the therapeutic. Not only did the treatment eradicate the disease in every mouse, but there was no evidence of tumor recurrence after nearly 200 days.
"We describe the mode of action as 'hit and run, because the C' dots either target the tumor microenvironment and kill the tumor cells or get safely cleared out of the body via renal clearance as a result of their small size, thereby minimizing off-target accumulation and associated side effects and toxicity."
- Ulrich Wiesner, the Spencer T. Olin Professor, Department of Materials Science and Engineering, at Cornell Engineering
ABSTRACT -
Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core–shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties. Most surprisingly, drawing upon its favorable physicochemical, pharmacokinetic, clearance, and target-specific dual-modality imaging properties in a “hit and run” approach, this conjugate eradicated HER2-expressing gastric tumors without any evidence of tumor regrowth, while exhibiting a wide therapeutic index. Therapeutic response mechanisms are accompanied by the activation of functional markers, as well as pathway-specific inhibition. Results highlight the potential clinical utility of this molecularly engineered particle drug-immune conjugate and underscore the versatility of the base platform as a carrier for conjugating an array of other immune products and payloads.
