November 20, 2013
The development of a probe to measure the body’s immune function could lead to more accurate, individualized doses for cancer patients prescribed nanoparticle-based drugs, according to research conducted at the University of North Carolina.
Nanodrugs are encapsulated in carriers measured at the scale of a one billionth of a meter. They were developed to deliver more chemotherapy to specific tumor sites within the body. One major downside of this class of drugs is that patients’ ability to remove the drug from their body can vary widely among individuals. This leads to wide variations in how people in respond to the drugs.
William Zamboni, PharmD, PhD, of the UNC Eshelman School of Pharmacy collaborated with Paola Gehrig, MD, and colleagues in the UNC Gynecologic Oncology Program, used a UNC-developed probe that measures the function of the mononuclear phagocyte system, or MPS, to help determine the proper dosage of nanoparticle-based drugs to give to patients. Using a blood sample, the researchers were able to use the chemical probe to track a direct relationship between MPS function and clearance of the nanodrug Doxil (pegylated liposomal doxorubicin) in both animal models and in patients with ovarian cancer. Their work is published online in the Journal of Pharmacology and Experimental Therapeutics.
“You could use this probe to individualize the dose of nanoparticle agent that a patient should receive and thus you may increase response and reduce toxicity,” Zamboni says.
While most conventional drugs are cleared from the body by the liver and kidneys, nanoparticles are engulfed and cleared by the monocytes, macrophages, and dendritic cells that make up the MPS. Because the function of the MPS is varies greatly across patients, the ability of physicians to predict the proper dosage for nanodrugs is more difficult than with conventional pharmaceuticals.
“The more active the MPS system, the faster these drugs are cleared from a patient,” Zamboni says.
By establishing the link between MPS function and the clearance of Doxil, Zamboni’s lab hopes to build a data set that will allow researchers and clinicians to develop better methods to establish dosing guidelines for Doxil and other nanodrugs. Doxil, the first nanodrug approved by the Food and Drug Administration, has been in clinical use since 1995. Because it is difficult to tailor a dose to the individual, patients using Doxil can experience strong side effects, such as the sloughing off of skin from the palms and feet. The high degree of variation from patient to patient in the clearance and effects (toxicity and efficacy) appears to occur with most nanoparticle anticancer drugs.
“Most of the research has gone into developing the nanoparticle drugs, not really understanding how they handled and behave in preclinical models and in patients. That’s the next wave of information that’s being developed,” said Zamboni.
In addition to potentially individualizing the dose of Doxil and other nanoparticle agents, the MPS probes can be used as a retrospective marker that can link a patient’s MPS function and the ability of a patient to remove and tolerate nanoparticle agents that are in early clinical development.
Because all nanodrugs — and many other drugs in to 10 to 150 nanometer range, such as monoclonal antibodies — are cleared from the body via the MPS, Zamboni says the probe may be applicable for many classes of pharmaceuticals agents.
“If you can measure this one system, not only can predict the clearance of Doxil, but it looks like you can predict the clearance of other nanoparticle and carrier drugs too. The applicability of this probe isn’t just with Doxil. It’s just what we’ve studied first,” Zamboni says.
Zamboni is an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics and member of the UNC Lineberger Comprehensive Cancer Center.
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