查看完整版本: Nano.Cancer.Gov News - OCTOBER 2007

Nano.Cancer.Gov News - OCTOBER 2007

*  Remote Magnetic Field Triggers Nanoparticle Drug Release
    * Tracking Targeted siRNA Nanoparticles With In Vivo Imaging
    * Implantable Microfluidic Device Could Detect Cancer Markers
    * Mining Tiny Diamonds for Drug Delivery
    * Oligonucleotides Create Versatile Coating for Nanoscale Imaging Agents
    * Nanoparticle Images and Treats Cancer, Reports on Drug Delivery


Remote Magnetic Field Triggers Nanoparticle Drug Release

[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31a.asp[/url]

Magnetic nanoparticles heated by a remote magnetic field have the potential to release multiple anticancer drugs on demand at the site of a tumor, according to a study published in the journal Advanced Materials. Moreover, say the investigators who conducted this research, these same nanoparticles can do double duty as tumor imaging agents.

Two investigators from the Alliance for Nanotechnology in Cancer—Sangeeta Bhatia, Ph.D., Massachusetts Institute of Technology, and Erkki Ruoslahti, M.D., Ph.D., Burnham Institute—led this research effort, which has the ultimate goal of developing a targeted, multifunctional nanoparticle capable of providing time-tailored drug release into tumors. To create such a platform, the investigators started with dextran-coated iron oxide nanoparticles similar to the ones now under development as magnetic resonance imaging contrast agents. When stimulated by an oscillating magnetic field, these nanoparticles absorb energy and become warm, a property that the researchers capitalized on to create triggered drug release.

To these particles the researchers added a short piece of DNA to act as a tether for one or more anticancer drugs linked to pieces of DNA complementary to the particle-bound tether. At body temperature, the complementary strands of DNA form the famous double helix, creating a stable link between drug molecule and nanoparticle. But when the nanoparticle becomes warm as a result of an applied oscillating magnetic field, the bonds holding the two strands of DNA together become progressively weaker until the local temperature hits a critical value, at which point the double helix unwinds and the drug molecule diffuses away from the nanoparticle. The researchers also showed that when they applied the magnetic field in pulses of 5 minutes duration every 40 minutes, drug release occured in bursts, too.

Since this “melting temperature” depends on the length of the double helix, the investigators reasoned that they could use tethers of different lengths to produce one nanoparticle capable of releasing two or more drugs in sequence. Indeed, when the researchers attached two different model drug compounds to the nanoparticle using tethers of two different lengths, they were able to trigger release of the drug attached via the shorter tether and follow that with release of the second drug, attached with the longer tether, by increasing the power of the oscillating magnetic field.

This work, which was funded by the NCI’s Alliance for Nanotechnology in Cancer, is detailed in the paper “Remotely triggered release from magnetic nanoparticles.” Investigators from the University of California, San Diego, also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is not yet available.

[[i] 本帖最后由 nanoflower 于 2007-11-08 22:15 编辑 [/i]]

Tracking Targeted siRNA Nanoparticles With In Vivo Imaging

Tracking Targeted siRNA Nanoparticles With In Vivo Imaging
[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31b.asp[/url]

Using nanoparticles tagged with both a fluorescent label and a radioactive isotope of the element copper, a team of investigators at the California Institute of Technology (Caltech) has shown that targeting siRNA-containing nanoparticles to tumors increases tumor uptake rather than tumor localization. The methods that these investigators developed should be broadly applicable to studying nanoparticle biodistribution as part of the preclinical development process.

Reporting its work in the Proceedings of the National Academy of Sciences of the United States of America, a team led by Mark E. Davis, Ph.D., an investigator in the Nanosystems Biology Cancer Center at Caltech, described the multimodal imaging methods it used to measure biodistribution parameters for siRNA-loaded cyclodextrin-based nanoparticles. Davis’ collaborators at Calando Pharmaceuticals, Inc., are preparing to begin a Phase I clinical trial with this siRNA-loaded nanoparticle. Small interfering RNA (siRNA) triggers a naturally occurring mechanism within cells that can silence and regulate targeted genes.

In this study, the investigators used positron emission tomography (PET) to quantify biodistribution of the nanoparticles and imaging to measure siRNA function in a mouse model of human cancer. Some of the nanoparticles were targeted with transferrin, an iron-ferrying protein that binds to a receptor overexpressed by many types of tumors. Although PET data showed that both targeted and untargeted nanoparticles accumulated to a similar extent in tumors, targeted particles reduced the bioluminescent imaging signal by 50 percent compared with nontargeted particles. These nanoparticles were designed so that bioluminescent signal reduction would occur only if the siRNA agent was successfully delivered into cells and reduced expression of its targeted gene. These results show, therefore, that the advantages of targeted nanoparticles appear to be associated with uptake into tumor cells and not with overall tumor localization.

“This work reveals that the primary advantage of targeted nanoparticles for tumor-specific delivery of siRNA is the enhanced uptake in tumor cells rather than altered biodistribution,” said Davis. “The conclusions should be applicable to nanoparticle delivery systems in general, and they emphasize why targeted particles should show greater efficacy than nontargeted particles.”

This work, which was funded by the NCI’s Alliance for Nanotechnology in Cancer, is detailed in the paper “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging.” Investigators from the University of California, Los Angeles, and the University of Freiburg in Germany also participated in this study. This paper is available online at no cost through PubMed Central.

Implantable Microfluidic Device Could Detect Cancer Markers

Implantable Microfluidic Device Could Detect Cancer Markers
[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31c.asp[/url]
A tiny implant now being developed at the Massachusetts Institute of Technology (MIT) could one day help doctors rapidly monitor the growth of tumors and the progress of chemotherapy in cancer patients. The implant, developed by Michael Cima, Ph.D., and Robert Langer, Ph.D., both investigators at the MIT-Harvard Center of Cancer Nanotechnology Excellence, contains nanoparticles that can be designed to test for different substances, including cancer markers and metabolites such as glucose and oxygen, which are associated with tumor growth. The device can also track the effects of cancer drugs: Once inside a patient, the implant could reveal how much of a certain cancer drug has reached the tumor, helping doctors determine whether a treatment is working in a particular patient.

Although such nanoparticles have been used before, this study, which was published in the journal Lab on a Chip, demonstrates that encasing the nanoparticles in a silicone delivery device would allow them to remain in patients’ bodies for an extended period of time. The device can be implanted directly into a tumor, allowing researchers to get a more direct look at what is happening in the tumor over time.

The new technique, known as implanted magnetic sensing, makes use of detection nanoparticles composed of dextran-coated iron oxide. Antibodies specific to a target molecule—in this case, the investigators used antibodies that recognize the soluble cancer biomarker human chorionic gonadotrophin-β—are attached to the surface of the particles. When the target molecules are present, they bind to the particles and cause them to clump together. That clumping can be detected by magnetic resonance imaging.

The nanoparticles are trapped inside the silicone device, which is sealed off by a porous membrane. The membrane allows molecules smaller than 10 nm to get in, but the detection particles are too big to get out. The device can be engineered to test for many different biomarkers simultaneously and to monitor the presence of chemotherapy drugs. In addition, the device could also be used to check whether a tumor is growing or shrinking, or whether it has spread to other locations, by sensing the amount and location of tumor markers.

This work, which was funded by the NCI’s Alliance for Nanotechnology in Cancer, is detailed in the paper “Multi-reservoir device for detecting a soluble cancer biomarker.” An abstract of this paper is available through PubMed.
View abstract

Mining Tiny Diamonds for Drug Delivery

Mining Tiny Diamonds for Drug Delivery
[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31d.asp[/url]
Northwestern University researchers have shown that nanodiamonds are effective at delivering chemotherapy drugs to cells without the negative effects associated with current drug delivery agents. Their study, published in the journal Nano Letters, is the first to demonstrate the use of nanodiamonds, a new class of nanomaterials, in biomedicine. In addition to delivering cancer drugs, the model could be used for other applications, such as fighting tuberculosis or viral infections, say the researchers.

Nanodiamonds promise to play a significant role in improving cancer treatment by limiting uncontrolled exposure of toxic drugs to the body. The research team, headed by Dean Ho, Ph.D., reports that aggregated clusters of nanodiamonds were shown to be ideal for carrying a chemotherapy drug and shielding it from normal cells so as not to kill them, releasing the drug slowly only after it reached its cellular target.

Another advantage of the material, confirmed by a series of genetic studies also reported in the paper, is that nanodiamonds do not cause cell inflammation once the drug has been released, and only bare diamonds are left. “There are a lot of materials that can deliver drugs well, but we need to look at what happens after drug delivery,” said Ho. “How do cells react to an artificial material left in the body? Nanodiamonds are highly ordered structures, which cells like. If they didn’t, cells would become inflamed. From a patient’s perspective, this is very important.”

To make the material effective, Ho and his colleagues manipulated single nanodiamonds, each only 2 nanometers in diameter, to form aggregated clusters of nanodiamonds, ranging from 50 to 100 nanometers in diameter. The drug, loaded onto the surface of the individual diamonds, is not active when the nanodiamonds are aggregated; it only becomes active when the cluster reaches its target, breaks apart, and slowly releases the drug. Because of the large amount of available surface area, the clusters can carry a large amount of drug, nearly five times the amount of drug carried by conventional materials. Nanodiamonds are also soluble in water, an important property for any potential drug delivery vehicle.

For their study, Ho and his team used living murine macrophage cells, human colorectal carcinoma cells, and doxorubicin hydrochloride, a widely used chemotherapy drug. The drug was successfully loaded onto the nanodiamond clusters, which efficiently ferried the drug inside the cells. Once inside, the clusters broke up and slowly released the drug.

In the genetic studies, the researchers exposed cells to the bare nanodiamonds (no drug was present) and analyzed three genes associated with inflammation and one gene for apoptosis (cell death) to see how the cells reacted to the foreign material. Looking into the circuitry of the cell, they found no long-term toxicity or inflammation and no cell death. In fact, the cells grew well in the presence of the nanodiamond material.

This work is detailed in the paper “Active nanodiamond hydrogels for chemotherapeutic delivery.” An investigator from NanoCarbon Research Institute, Ltd., also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is available through PubMed.

Oligonucleotides Create Versatile Coating for Nanoscale Imaging Agents
[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31e.asp[/url]
Nanoparticles made of metals such as gold or iron oxide show tremendous promise as contrast agents for molecular imaging, but turning promise into clinical utility requires adding tumor targeting molecules to the surfaces of these nanoparticles. A new coating technique that uses oligonucleotides to tether targeting molecules securely to a nanoparticle’s surface could provide a versatile method for creating such targeted nanoparticles.

Reporting their work in the journal Bioconjugate Chemistry, Rebecca Richards-Kortum, Ph.D., and colleagues describe a method for using sulfur-containing derivatives of DNA that bind tightly to the surface of gold nanoparticles. The researchers then use a complementary DNA sequence to link the DNA-coated nanoparticle to a targeting ligand. The resulting oligonucleotide-linked nanoparticles are much smaller than similar imaging agents constructed by absorbing targeting proteins directly onto the surfaces of gold nanoparticles. The oligonucleotide tethers also produce a construct that is more stable under physiological conditions.

Using their new methodology, the investigators created imaging agents designed to detect the epidermal growth factor receptor (EGF) using either an EGF peptide or an antibody that binds to the receptor. The researchers also created a contrast agent designed to recognize the folate receptor that is overexpressed in many tumors, as well as a contrast agent that also contains a fluorescent marker that allows for multimodal imaging using both confocal reflectance imaging and standard fluoresence imaging. In each case, the contrast agents provided a significant signal boost that was detected easily using the appropriate imaging technique.

This work is detailed in the paper “Oligonucleotide-coated metallic nanoparticles as a flexible platform for molecular imaging agents.” This paper was published online in advance of print publication. An abstract of this paper is available through PubMed.

Nanoparticle Images and Treats Cancer, Reports on Drug Delivery

Nanoparticle Images and Treats Cancer, Reports on Drug Delivery
[url]http://nano.cancer.gov/news_center/2007/oct/nanotech_news_2007-10-31f.asp[/url]
Using a quantum dot plus an aptamer that doubles as a tether for the anticancer drug doxorubicin, a team of investigators at the Massachusetts Institute of Technology (MIT)-Harvard Center of Cancer Nanotechnology Excellence has developed a multifunctional nanoparticle that not only treats cancer but also images those tumors that have received drug therapy. The researchers report their work in the journal Nano Letters.

Omid Farokhzad, M.D., Harvard University, and Robert Langer, Ph.D., MIT, led the team of investigators that developed this multifunctional construct. The researchers built this construct by first coating a quantum dot with an RNA aptamer designed to recognize and bind tightly to prostate specific membrane antigen (PMSA), a surface marker found on prostate tumors. They then incubated this coated quantum dot with doxorubicin, which integrates, or intercalates, itself within the highly folded structure of the aptamer. The investigators showed that doxorubicin intercalation had no effect on the ability of the aptamer to bind to PMSA.

Quantum dots are well known for their ability to emit light of well-defined color. In this experiment, the investigators chose a quantum dot with light in the range of 470 to 530 nanometers (nm). Doxorubicin, aside from being a potent anticancer agent, also absorbs blue light efficiently, with maximal absorption at a wavelength of 480 nm, and then emits light that spans the green-to-orange portion (520-640 nm) of the visible light spectrum.

When the quantum dot and a doxorubicin molecule are close to one another, as they are in this construct, the two optically active systems interfere with one another, greatly suppressing any light emission from either of them. Indeed, when the investigators incubated the quantum dot-aptamer-doxorubicin construct with PMSA-expressing prostate cancer cells, they were able to detect only minimal light emission. However, 90 minutes later, the investigators detected bright optical signals from both the quantum dot and doxorubicin, resulting from the fact that the construct had released doxorubicin into the treated cells.

This work, which was funded by the NCI’s Alliance for Nanotechnology in Cancer, is detailed in the paper “Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on bi-fluorescence resonance energy transfer.” Investigators at the Gwangju Institute of Science and Technology in South Korea also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is available through PubMed.