Top panels: Control setups. Bottom panels: Mammary tumor tissue after normalization of blood vessels. Left: Few of the large nanoparticles are visible. Right: The smaller nanoparticles have penetrated well. Images: Vikash Chauhan/Nature Nanotech |
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 normalizing blood vessels within tumors,
which improves the delivery of standard chemotherapy drugs, can actually block
the delivery of larger nanotherapy molecules.
“We found that vascular normalization
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 tumor-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
tumors tend to be disorganized, 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 tumor, 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 normalization.
“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 normalization 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 tumor 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 tumors. 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-nm particles
but not of 60- or 125-nm particles.
They treated mice with implanted breast
tumors either with DC101 and Doxil, a 100-nm version of the chemotherapy drug
doxorubicin, or with DC101 and Abraxane, a 10-nm 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.
“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 nm in size—we also need to investigate
ways to improve delivery of the larger nanomedicines that are currently in
use.”