Kit Lam and colleagues from UC Davis and other institutions have
created dynamic nanoparticles (NPs) that could provide an arsenal of
applications to diagnose and treat cancer. Built on an easy-to-make
polymer, these particles can be used as contrast agents to light up
tumors for MRI and PET scans or deliver chemo and other therapies to
destroy tumors. In addition, the particles are biocompatible and have
shown no toxicity. The study was published online today in Nature Communications.
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“These
are amazingly useful particles,” noted co-first author Yuanpei Li, a
research faculty member in the Lam laboratory. “As a contrast agent,
they make tumors easier to see on MRI and other scans. We can also use
them as vehicles to deliver chemotherapy directly to tumors; apply light
to make the nanoparticles release singlet oxygen (photodynamic therapy)
or use a laser to heat them (photothermal therapy) – all proven ways to
destroy tumors.”
Jessica Tucker, program director of Drug and Gene Delivery and Devices at the National
Institute of Biomedical Imaging and Bioengineering, which is part of
the National Institutes of Health, said the approach outlined in the
study has the ability to combine both imaging and therapeutic
applications in a single platform, which has been difficult to achieve,
especially in an organic, and therefore biocompatible, vehicle.
"This
is especially valuable in cancer treatment, where targeted treatment to
tumor cells, and the reduction of lethal effects in normal cells, is so
critical,” she added.
Though
not the first nanoparticles, these may be the most versatile. Other
particles are good at some tasks but not others. Non-organic particles,
such as quantum dots or gold-based materials, work well as diagnostic
tools but have safety issues. Organic probes are biocompatible and can
deliver drugs but lack imaging or phototherapy applications.
Built
on a porphyrin/cholic acid polymer, the nanoparticles are simple to
make and perform well in the body. Porphyrins are common organic
compounds. Cholic acid is produced by the liver. The basic nanoparticles
are 21 nanometers wide (a nanometer is one-billionth of a meter).
To
further stabilize the particles, the researchers added the amino acid
cysteine (creating CNPs), which prevents them from prematurely releasing
their therapeutic payload when exposed to blood proteins and other
barriers. At 32 nanometers, CNPs are ideally sized to penetrate tumors,
accumulating among cancer cells while sparing healthy tissue.
In the study, the team tested the nanoparticles, both in vitro and in vivo, for
a wide range of tasks. On the therapeutic side, CNPs effectively
transported anti-cancer drugs, such as doxorubicin. Even when kept in
blood for many hours, CNPs only released small amounts of the drug;
however, when exposed to light or agents such as glutathione, they
readily released their payloads. The ability to precisely control
chemotherapy release inside tumors could greatly reduce toxicity. CNPs
carrying doxorubicin provided excellent cancer control in animals, with
minimal side effects.
CNPs
also can be configured to respond to light, producing singlet oxygen,
reactive molecules that destroy tumor cells. They can also generate heat
when hit with laser light. Significantly, CNPs can perform either task
when exposed to a single wavelength of light.
CNPs
offer a number of advantages to enhance imaging. They readily chelate
imaging agents and can remain in the body for long periods. In animal
studies, CNPs congregated in tumors, making them easier to read on an
MRI. Because CNPs accumulated in tumors, and not so much in normal
tissue, they dramatically enhanced tumor contrast for MRI and may also
be promising for PET-MRI scans.
This versatility provides multiple options for clinicians, as they mix and match applications.
“These
particles can combine imaging and therapeutics,” said Li. “We could
potentially use them to simultaneously deliver treatment and monitor
treatment efficacy.”
“These
particles can also be used as optical probes for image-guided surgery,”
said Lam. “In addition, they can be used as highly potent
photosensitizing agents for intraoperative phototherapy.”
While
early results are promising, there is still a long way to go before
CNPs can enter the clinic. The Lam lab and its collaborators will pursue
preclinical studies and, if all goes well, proceed to human trials. In
the meantime, the team is excited about these capabilities.
“This
is the first nanoparticle to perform so many different jobs,” said Li.
“From delivering chemo, photodynamic and photothermal therapies to
enhancing diagnostic imaging, it’s the complete package.”
Other
researchers included Tzu-yin Lin, Yan Luo, Qiangqiang Liu, Wenwu Xiao,
Wenchang Gu1, Diana Lac, Hongyong Zhang, Caihong Feng, Sebastian
Wachsmann-Hogiu, Jeffrey H. Walton, Simon R. Cherry, Douglas J. Rowland,
David Kukis and Chongxian Pan.
This
research was funded by the National Cancer Institute (grants
R01CA115483 and R01CA140449), National Institute of Biomedical Imaging
and Bioengineering (grant R01EB012569), the Department of Defense (grant
W81XWH-12-1-008), the Prostate Cancer Foundation, the Veterans
Administration and the California Institute for Regenerative Medicine.
source : UC Davis Comprehensive Cancer Center
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