The use of intravesical cisplatin nanoparticles reduces cancer cell proliferation while limiting drug absorption beyond the bladder barrier, according to early findings.
Scientists have developed a way to deliver cisplatin nanoparticles to treat nonmuscle-invasive bladder cancer. In newly published animal studies, they show the approach is less toxic than treatment with regular cisplatin and, potentially, more efficacious.
In short, the use of intravesical cisplatin nanoparticles reduces cancer cell proliferation while limiting drug absorption beyond the bladder barrier, according to early findings published online in Clinical Cancer Research (Aug. 14, 2017).
“One of the reasons that intravesical chemotherapy is thought not to work very well in certain patients is more of a drug delivery problem than an actual chemotherapy problem. Most chemotherapy-when you give it intravesically-does not actually get into the bladder,” said Max Kates, MD, of the James Buchanan Brady Urological Institute and Johns Hopkins University School of Medicine, Baltimore. “So, we designed a platinum-based drug that has increased absorption into the bladder. By modifying chemotherapy to improve bladder absorption, we might make these drugs more effective in our bladder cancer patients.”
Dr. Kates and colleagues tested the delivery model, comparing it to regular cisplatin treatment and no treatment, by conducting a series of in vitro and in vivo studies in murine models.
To start, they delivered cisplatin nanoparticles through a catheter, directly into the animals’ bladders, or used the traditional cisplatin catheter delivery approach. Four hours post administration, they found the bladders of animals that received nanoparticles had more than 20 times better drug absorption than the animals receiving the regular drug. Nanoparticle administration also resulted in at least two to three times less systemic absorption than with the regular drug.
The authors then administered the drug-infused nanoparticles or regular cisplatin to mice’s bladders by catheter once per week for 3 weeks. Detectable levels of the drug’s platinum were identified in the blood of mice in the regular cisplatin group, but not among the mice receiving nanoparticles-confirming the finding that the nanoparticle formulation is associated with less systemic absorption.
And when they administered both drugs to rats with bladder cancer, the nanoparticle delivery resulted in six times the drug concentration in the rats’ bladders 1 hour post treatment and 10 times more drug in the bladder 4 hours after treatment, compared with animals in the regular cisplatin group.
The rats treated with the cisplatin nanoparticles were the only treatment group at 16 weeks to have no evidence of invasive carcinoma. One-fifth or more of the rats treated with regular cisplatin and half of those given no treatment had evidence of high-grade tumors at 4 months.
The findings suggest that by using the nanoparticle drug delivery approach, urologists and other clinicians treating nonmuscle-invasive bladder cancer patients might eventually have a nonsurgical option for those who fail first-line bacillus Calmette-GuÃ©rin (BCG) therapy, according to Dr. Kates, lead author of the paper and one of the owners of a related patent.
“There’s a lot of new interest in chemotherapy, as we begin to sequence bladder tumors-especially early-stage bladder tumors,” Dr. Kates said.
“We know that not all bladder tumors respond to BCG. Increasingly, we’re going to be identifying the genetics of a patient’s bladder tumor and, hopefully, will know in the future whether the patient will respond to BCG or not. There’s a large space for drugs like this that can help treat patients with nonmuscle-invasive bladder cancer,” added Dr. Kates, who worked on the study with Trinity Bivalacqua, MD, PhD, and colleagues.
Delivery of nanoparticle chemotherapy has been used in other cancer types in which the drug has to get across a hostile barrier in the body, such as across vaginal or eye mucosa, according to Dr. Kates.
Dr. Kates said that while these were animal model studies and the approach has not yet been proven in humans, the animal model used has been validated as being reflective of human bladder cancer.
“We are continuing to perform validation studies and pursuing early-phase trials this year,” he said.
Five of the study authors own a patent related to this project. Funding for the study was provided by The Greenberg Bladder Cancer Institute and the Urology Care Foundation.
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