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Grantee: Xiuling Lu, PhD
Institution: University of Connecticut School of Pharmacy
Area of Focus: Experimental Therapeutics
Grant Term: 7/1/2015 - 12/31/2020
The Challenge: For stage III ovarian cancer—meaning the cancer has advanced but has not spread out of the abdomen (the peritoneal cavity)—doctors sometimes recommend that chemotherapy drugs be injected into the abdomen through a thin tube called a catheter or port. This procedure is known as intraperitoneal (IP) chemotherapy.
Giving chemotherapy this way allows the most concentrated dose of the drugs to be delivered directly to cancer cells that are on the surfaces of organs within the abdomen. Although IP chemotherapy can help some women live longer than IV chemotherapy alone, it can also cause different, and sometimes, more severe side effects.
Using nanoparticles is a new technique to deliver therapeutics, like chemotherapy drugs, to ovarian tumors that have spread to the abdomen. A nanoparticle is a tiny piece of matter, between 1 to 100 nanometers, which is 1-billionth of a meter—too small to be seen by the human eye.
These extremely tiny, nano-size particles are engineered to be attracted to the tumor microenvironment, especially the collagen-enriched extracellular matrix. This allows the nanoparticles to deliver therapeutics directly to the tumor microenvironment, increasing the amount of drug the cancer cells receive and reducing the damage to healthy cells in the body.
So far, delivery of drugs through nanoparticles is still largely being studied in animals to better understand how the drug-carrying nanoparticles accumulate in tumors. That information is crucial to developing effective delivery systems for tumor-specific treatments.
The Research: Xiuling Lu, PhD, and her colleagues are investigating how best to design drug-carrying nanoparticles that, when injected into the peritoneal cavity, would accumulate specifically on the surface of ovarian tumors to deliver the therapeutic drug they carry.
To do this, her lab manufactures nanoparticles of different sizes and materials, and then tests how they work, looking at their stability, distribution, and interactions with structures around ovarian tumors (known as the extracellular matrix) in mice and in tumors cultured in the lab.
In previous studies, Lu and her team found that, following intraperitoneal (IP) injection, a porous silica nanoparticle (called an MCM-41 type) selectively accumulates on ovarian tumors. When using an intravenous (IV) injection, only about 1% of a chemotherapy dose is delivered to tumors, with most nanoparticles accumulating in the liver instead. But with IP-administration, up to 82% of the dose reached the tumors.
In a recently published study that was funded in part by the American Cancer Society (ACS), Lu and colleagues reported findings from their lab tests. They found that treatment-carrying nanoparticles tend to stick around the tumors spread in the abdomen, largely because of their strong interaction with the collagen-rich extracellular matrix.
Lu’s team found that modifying the tumor extracellular matrix by removing the collagen reduced the binding of nanoparticles to the tumor’s surface.
They also demonstrated that certain immune cells, called macrophages, in the peritoneal cavity don’t significantly alter nanoparticle accumulation to tumors.
Why it Matters: Currently, no nanoparticle-based product has been approved for intraperitoneal delivery of cancer treatments in humans. Knowing how best to design nanoparticles in the lab that optimize delivery of cancer drugs and minimize side effects is critical for moving this treatment into clinical trials where they can be tested in humans.