Tumor study reveals size limitations for new
drugs
A new
study shows that combining angiogenesis inhibitors and nanomedicines only
improves cancer treatment when the nanomedicines are at the small end of a size
range. Top panels show the control setups. Bottom panels show mammary tumor
tissue after normalization of blood vessels. Few of the large nanoparticles are
visible in the bottom left panel, while the smaller nanoparticles have
penetrated well, as seen in the bottom right panel.
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 Ph.D.
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-nanometer particles but not of 60- or 125-nanometer
particles.
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.
“A
variety of anti-cancer 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 nanometers in
size — we also need to investigate ways to improve delivery of the larger
nanomedicines that are currently in use.”
Additional
co-authors of the Nature Nanotechnology report are Triantafyllos
Stylianopoulos, John Martin, Walid Kamoun, and Dai Fukumura of MGH; and Zoran
Popovic, Ou Chen, and Moungi Bawendi of the Massachusetts
Institute of Technology (MIT).
The
work benefited from a long-term collaboration between Harvard, MGH, and MIT
that explores the use of quantum dots as a biocompatible fluorescent marker in
medical studies.
Support
for the study included grants from the National
Institutes of Healthand the Department
of Defense.
Adapted
from an earlier
release by Sue McGreevey, Massachusetts General Hospital.
No comments:
Post a Comment