Tumour study reveals size limitations for new drugs

Combining two strategies that are designed to improve the results of cancer treatment - angiogenesis inhibitors and nanomedicines - may only be successful if the smallest nanomedicines are used.
A new study led by researchers at the Harvard School of Engineering and Applied Sciences (SEAS) and Massachusetts General Hospital (MGH) has found that normalising blood vessels within tumours, which improves the delivery of standard chemotherapy drugs, can actually block the delivery of larger nanotherapy molecules.
"We found that vascular normalisation only increases the delivery of the smallest nanomedicines to cancer cells," says lead author Vikash P Chauhan, a graduate student in bioengineering at SEAS. "We 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."
The results have been published in Nature Nanotechnology.
Angiogenesis, the tumour-driven creation of new blood vessels, provides growing cancers with a food source - but it also provides a potential channel for drug delivery.
The problem is that the vessels supplying tumours tend to be disorganised, oversized, and leaky. These abnormalities prevent the delivery of chemotherapy drugs to cells that are not close to the tumor vessels. The leakage of plasma out of blood vessels also increases pressure within the tumour, further reducing the drugs' ability to penetrate the tissue. Fortunately, drugs that inhibit angiogenesis can reduce some of these problems in a process called vascular normalisation.
"Anti-angiogenic agents are prescribed to a large number of cancer patients in combination with conventional therapeutics," explains principal investigator Rakesh K. Jain, Cook Professor of radiation oncology (Tumor Biology) at Harvard Medical School and director of the Steele Laboratory of Tumor Biology at MGH. Jain is also Chauhan's PhD adviser.
The combination of standard chemotherapy drugs and normalisation therapy has previously been shown to improve the effectiveness of treatment on some types of cancer.
New nanomedicines, on the other hand, are designed to exploit the abnormality of tumour vessels. Nanomedicines, despite the name, are actually about 10 to 100 times larger than standard chemotherapy drugs - too large to penetrate the pores of blood vessels in normal tissues, but still small enough to pass through the oversized pores of tumor vessels. Because nanomedicines generally cannot penetrate normal tissues, they are expected to cause fewer side effects.
The question in the Harvard-MGH study was whether vascular normalization would help or hinder the delivery of nanomedicines to tumours. The researchers found, through both theory and in vivo experimentation, that it depends on the size of the nanomedicines.
Their mathematical model predicted that inhibiting angiogenesis would simultaneously reduce the size of the pores in the blood vessels and relieve pressure in the tumor, allowing small particles to penetrate.
Confirming this experimentally in a mouse model of breast cancer, the investigators showed that vascular normalization (using an antibody called DC101) improved the penetration of 12-nanometre particles but not of 60- or 125-nanometre particles.
They treated mice with implanted breast tumours either with DC101 and Doxil, a 100-nanometre version of the chemotherapy drug doxorubicin, or with DC101 and Abraxane, a 10-nanometre version of paclitaxel. 

Although treatment with both chemotherapeutics delayed tumour growth, vascular normalisation with DC101 improved the effectiveness only of Abraxane and had no effect on Doxil treatment.
"A variety of anticancer nanomedicines are currently in use or in clinical trials," says Chauhan, who completed the work at MGH. "Our findings suggest that combining smaller nanomedicines with anti-angiogenic 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. While it looks like future development of nanomedicines should focus on making them small - around 12 nanometres in size - we also need to investigate ways to improve delivery of the larger nanomedicines that are currently in use."