An international group of scientists led by Gang Han, PhD, at the University of Massachusetts Medical School, has combined a new type of nanoparticle with an FDA-approved photodynamic therapy to effectively kill deep-set cancer cells in vivo with minimal damage to surrounding tissue and fewer side effects than chemotherapy. This promising new treatment strategy could expand the current use of photodynamic therapies to access deep-set cancer tumors.
“We are very excited at the potential for clinical practice using our enhanced red-emission nanoparticles combined with FDA-approved photodynamic drug therapy to kill malignant cells in deeper tumors,” said Dr. Han, lead author of the study and assistant professor of biochemistry and molecular pharmacology at UMMS. “We have been able to do this with biocompatible low-power, deep-tissue-penetrating 980-nm near-infrared light.”
In photodynamic therapy, also known as PDT, the patient is given a non-toxic light-sensitive drug, which is absorbed by all the body’s cells, including the cancerous ones. Red laser lights specifically tuned to the drug molecules are then selectively turned on the tumor area. When the red light interacts with the photosensitive drug, it produces a highly reactive form of oxygen (singlet oxygen) that kills the malignant cancer cells while leaving most neighboring cells unharmed.
Because of the limited ability of the red light to penetrate tissue, however, current photodynamic therapies are only used for skin cancer or lesions in very shallow tissue. The ability to reach deeper set cancer cells could extend the use of photodynamic therapies.
In research published online by the journal ACS Nano of the American Chemical Society, Han and colleagues describe a novel strategy that makes use of a new class of upconverting nanoparticles (UCNPs), a billionth of a meter in size, which can act as a kind of relay station. These UCNPs are administered along with the photodynamic drug and convert deep penetrating near-infrared light into the visible red light that is needed in photodynamic therapies to activate the cancer-killing drug.
To achieve this light conversion, Han and colleagues engineered a UCNP to have better emissions in the red part of the spectrum by coating the nanoparticles with calcium fluoride and increasing the doping of the nanoparticles with ytterbium.
In their experiments, the researchers used the low-cost, FDA-approved photosensitizer drug aminolevulinic acid and combined it with the augmented red-emission UCNPs they had developed. Near-infrared light was then turned on the tumor location. Han and colleagues showed that the UCNPs successfully converted the near-infrared light into red light and activated the photodynamic drug at levels deeper than can be currently achieved with photodynamic therapy methods. Performed in both in vitro and with animal models, the combination therapy showed an improved destruction of the cancerous tumor using lower laser power.
Yong Zhang, PhD, chair professor of National University of Singapore and a leader in the development and application of upconversion nanoparticles, who was not involved in the study, said that by successfully engineering amplified red emissions in these nanoparticles, the research team has created the deepest-ever photodynamic therapy using an FDA-approved drug.
“This therapy has great promise as a noninvasive killer for malignant tumors that are beyond 1 cm in depth—breast cancer, lung cancer, and colon cancer, for example—without the side-effects of chemotherapy,” Zhang said.
Han said, “This approach is an exciting new development for cancer treatment that is both effective and nontoxic, and it also opens up new opportunities for using the augmented red-emission nanoparticles in other photonic and biophotonic applications.”
Targeted nanoparticles that combine imaging with two different therapies could attack cancer, other conditions
Nanosystems that are ‘theranostic’—they combine both therapeutic and diagnostic functions—present an exciting new opportunity for delivering drugs to specific cells and identifying sites of disease. Bin Liu of the A*STAR Institute of Materials Research and Engineering, and colleagues at the National University of Singapore, have created nanoparticles with two distinct anticancer functions and an imaging function, all stimulated on demand by a single light source. The nanoparticles also include the cell-targeting property essential for treating and imaging in the correct locations.
The system is built around a polyethylene-glycol-based polymer that carries a small peptide component that allows it to bind preferentially to specific cell types. The polymer itself serves as a photosensitizer that can be stimulated by light to release reactive oxygen species (ROS). It also carries the chemotherapy drug doxorubicin in a prodrug form.
The natural fluorescence of the polymer assists with diagnosis and monitoring of therapy as it shows where nanoparticles have accumulated. The ROS generated by light stimulation have a direct ‘photodynamic’ therapeutic activity, which destroys the targeted cells. The ROS additionally break the link between the polymer and the doxorubicin. Thus, cancer cells can be subjected to a two-pronged attack from the ROS therapy and the chemotherapy drug that is released within them (see image).
“This is the first nanoplatform that can offer on-demand and imaging-guided photodynamic therapy and chemotherapy withtriggered drug release through one light switch,” explains Liu, emphasizing the significance of the system.
The researchers demonstrated the power of their platform by applying it to a mixture of cultured cancer cells, some of which overexpressed a surface protein that could bind to the targeting peptide on the nanoparticles. Fluorescence imaging indicated that the nanoparticles were taken up by the target cells and that ROS and doxorubicin were released within these cells—all at significantly higher levels than in cells used as controls. The doxorubicin that was released in the cell cytoplasm readily entered the nucleus—its site of activity. Crucially, the combined therapy had a greater cytotoxic effect than any one therapy alone.
“The white light used in this work does not penetrate tissue sufficiently for in vivo applications,” Liu explains, “but we are now attempting to use near-infrared laser light to improve the tissue penetration and move toward on-demand cancer therapy.” She also suggests that with a few modifications, the system may be suitable for the diagnosis and treatment of other pathological processes including inflammation and HIV infection.
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American Chemical Society – ACS Nano is a monthly, peer-reviewed, scientific journal, first published in August 2007 by the American Chemical Society. The current editor in chief is Paul S. Weiss (University of California, Los Angeles). The journal publishes original research articles, reviews, perspectives, interviews with distinguished researchers, views on the future of nanoscience and nanotechnology. According to the Journal Citation Reports, ACS Nano has a 2010 impact factor of 9.855. The focus of ACS Nano is synthesis, assembly, characterization, theory, and simulation of nanostructures, nanotechnology, nanofabrication, self assembly, nanoscience methodology, and nanotechnology methodology. The focus also includes nanoscience and nanotechnology research – the scope of which is chemistry, biology, materials science, physics, and engineering. ACS Nano is indexed in the following databases
John Wiley & Sons Wiley-VCH – Angewandte Chemie International Edition is a weekly peer-reviewed scientific journal that covers all aspects of chemistry. Its impact factor was 12.730 in 2010, the highest value for a chemistry-specific journal that publishes original research. It is a journal of the German Chemical Society and is published by Wiley-VCH.