Supramolecular nanoparticle for better chemotherapy
Since the dawn of nanotechnology, researchers have envisioned using nanoscale drug delivery devices for chemotherapy drugs designed to fight cancer more effectively than is possible with more traditional drug delivery methods. However, the cancer drugs haven’t always been compatible with the nanoparticles designed to transport them to the tumors.
Now, researchers at Brigham and Women’s Hospital have developed a new approach that doesn’t attempt to create nanoscale drug “delivery” vehicles; instead, the approach re-engineers the drugs themselves so that they become nanomedicines, according to lead author Shiladitya Sengupta, Ph.D., associate bioengineer at the hospital.
“We propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension,” Dr. Sengupta and colleagues wrote in a paper published this week in the Proceedings of the National Academy of Sciences.
The researchers used cisplatin, a widely used chemotherapy drug typically prescribed for cancers that include sarcoma, certain lung cancers, breast cancer, lymphoma and ovarian cancer, but which poses significant challenges for nanoformulations, the researchers said.
Cisplatin served as a template, and the researchers designed a cisplatin nanoparticle incorporating a unique platinum (II) tethered to a cholesterol “backbone.” This specially built nanoparticle helped create an environment that facilitated efficient drug nanoparticle self-assembly, according to the study.
The researchers then tested the resulting nanoscale cisplatin drug in vitro against lung cancer and breast cancer cells, and found it was more effective than cisplatin against both types of cells. They also tested the nanoparticles in a cisplatin-resistant hepatocellular carcinoma cell line, and found they were more effective than cisplatin in that cell line.
The study also reported testing in vivo in mice with breast cancer tumors, comparing the nanoparticles to cisplatin and carboplatin, another chemotherapy drug in the same class as cisplatin. All the platinates resulted in significant tumor inhibition compared to a control group, but the nanoparticles resulted in the most tumor inhibition.
In addition, although treatment with carboplatin or cisplatin provided only a minor survival advantage over the control group, the mice treated with the nanoparticles showed a significantly increased overall survival trend. In addition, lower doses of the nanoparticles were needed when compared to cisplatin dosing, and the mice taking the nanoparticles lost less overall body weight, indicating less systemic toxicity than cisplatin.
Nephrotoxicity remains a major problem with cisplatin when it’s used as a chemotherapy drug. However, the nanoparticles were more easily cleared by the kidneys than regular cisplatin, and so exhibited limited cisplatin-associated nephrotoxicity. “At this dose, cisplatin resulted in significantly higher platinum build-up in the kidney, which could account for cisplatin-associated nephrotoxicity, compared with the [nanoparticles]-treated groups,” the researchers said.
Although cisplatin is the drug of choice as a first or second line chemotherapy for most cancers, its clinical efficacy is dose-limited due to its nephrotoxicity, but this novel nanoformulation of the drug appears to overcome that problem, the researchers said.
“Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development,” the study concludes. “Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.”