Normalizing Tumor Blood Vessels Improves Delivery of Only the Smallest Nanomedicines
Combining two strategies designed to improve the results of cancer treatment—anti–angiogenesis drugs and nanomedicines—may only be successful if the smallest nanomedicines are used. A new study from researchers from the Harvard Medical School and the Massachusetts Institute of Technology (MIT) has found that normalizing blood vessels within tumors, which improves the delivery of standard chemotherapy drugs, can block the delivery of larger nanotherapy molecules. This study also showed that the smallest nanomedicines are inherently better than larger nanomedicines at penetrating tumors, suggesting that smaller nanomedicines may be ideal for cancer therapy.
Rakesh Jain and Dai Fukamura of Harvard and Moungi Bawendi from MIT led this study. They and their collaborators published the results of their study in the journal Nature Nanotechnology.
Tumors need to generate their own blood supply to continue growing, but vessels supplying tumors tend to be disorganized, oversized, and leaky. Not only does this prevent the delivery of chemotherapy drugs to cells not close to tumor vessels, but the leakage of plasma out of blood vessels increases pressure within the tumor, further reducing the ability of drugs to penetrate tumors. Treatment with drugs that inhibit angiogenesis—the process by which new vessels are generated—reduces some of these abnormalities, a process called vascular normalization that has been shown to improve treatment of some cancers with standard chemotherapy drugs.
Nanomedicines are actually designed to exploit tumor vessel abnormality. While the molecules of standard chemotherapy drugs are about one nanometer—a billionth of a meter—nanomedicine molecules are from 10 to 100 times larger, too large to penetrate the pores of blood vessels in normal tissues but small enough to pass through the oversized pores of tumor vessels. Since the size of nanomedicines should keep them out of normal tissues, they are prescribed to reduce the negative side effects of chemotherapy.
The current study was designed to investigate whether the use of anti–angiogenesis drugs to normalize tumor vasculature would improve or impede delivery of nanomedicines to tumor cells. In studies using a mouse model of breast cancer, the investigators first confirmed that treatment with DC101, an antibody to a molecule essential to blood vessel growth, temporarily decreased the diameter of enlarged tumor blood vessels. They then showed that this vascular normalization improved the penetration into tumors of 12–nanometer particles but not of 60– or 125–nanometer molecules.
A mathematical model prepared by the MGH team predicted that while the abnormally large pores in the walls of tumor blood vessels lead to increased pressure within the tumor that impedes the entry of drugs, reducing pore size by anti–angiogenesis treatment would relieve pressure within the tumor, allowing the entry of those molecules that fit through the smaller pores. To test this prediction, they treated mice with implanted breast tumors either with DC101 and Doxil, a 100–nanometer version of the chemotherapy drug doxorubicin, or with DC101 and Abraxane, a 10–nanometer version of paclitaxel. Although treatment with both chemotherapeutics delayed tumor growth, vascular normalization with DC101 improved the effectiveness only of Abraxane and had no effect on Doxil treatment.
This finding, say the researchers, may suggest that combining smaller nanomedicines with antiangiogenic therapies may have a synergistic effect and that smaller nanomedicines should inherently penetrate tumors faster than larger nanomedicines, due to the physical principles that govern drug penetration.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Normalization of tumour blood vessels improves the delivery of nanomedicines in a size–dependent manner." An abstract of this paper is available at the journal's website.