Nanoparticles refined for more accurate delivery of cancer drugs

A new class of nanoparticles, synthesized by a UC Davis research team to prevent premature drug release, holds promise for greater accuracy and effectiveness in delivering cancer drugs to tumors. The work is published in the current issue of Angewandte Chemie, a leading international chemistry journal.

In their paper, featured on the inside back cover of the journal, Kit Lam, professor and chair of the Department of Biochemistry and Molecular Medicine, and his team report on the synthesis of a novel class of micelles called dual-responsive boronate cross-linked micelles (BCMs) , which produce physicochemical changes in response to specific triggers.

A micelle is an aggregate of surfactant molecules dispersed in water-based liquid such as saline. Micelles are nano-sized, measuring about 25-50 nanometers (one nanometer is one billionth of a meter), and can function as nanocarriers for drug delivery.

BCMs are a unique type of micelle, which releases the payload quickly when triggered by the acidic micro-environment of the tumor or when exposed to an intravenously administered chemical compound such as mannitol, an FDA-approved sugar compound often used as a diuretic agent, which interferes with the cross-linked micelles.

"This use of reversibly cross-linked targeting micellar nanocarriers to deliver anti-cancer drugs helps prevent premature drug release during circulation and ensures delivery of high concentrations of drugs to the tumor site," said first author Yuanpei Li, a postdoctoral fellow in Lam's laboratory who created the novel nanoparticle with Lam. "It holds great promise for a significant improvement in cancer therapy."

Stimuli-responsive nanoparticles are gaining considerable attention in the field of drug delivery due to their ability to transform in response to specific triggers. Among these nanoparticles, stimuli-responsive cross-linked micelles (SCMs) represent a versatile nanocarrier system for tumor-targeting drug delivery.

Too often, nanoparticles release drugs prematurely and miss their target. SCMs can better retain the encapsulated drug and minimize its premature release while circulating in the blood pool. The introduction of environmentally sensitive cross-linkers makes these micelles responsive to the local environment of the tumor. In these instances, the payload drug is released primarily in the cancerous tissue.

The dual-responsive boronate cross-linked micelles that Lam's team has developed represent an even smarter second generation of SCMs able to respond to multiple stimuli as tools for accomplishing the multi-stage delivery of drugs to the complex in vivo tumor micro-environment. These BCMs deliver drugs based on the self-assembly of boronic acid-containing polymers and catechol-containing polymers, both of which make these micelles unusually sensitive to changes in the pH of the environment. The team has optimized the stability of the resulting boronate cross-linked micelles as well as their stimuli-response to acidic pH and mannitol.

This novel nano-carrier platform shows great promise for drug delivery that minimizes premature drug release and can release the drug on demand within the acidic tumor micro-environment or in the acidic cellular compartments when taken in by the target tumor cells. It also can be induced to release the drug through the intravenous administration of mannitol.

The study was funded by grants from the National Institutes of Health and a Department of Defense Breast Cancer Research Program Postdoctoral Award. Other authors are Wenwu Xiao, Kai Xiao, Lorenzo Berti, Harry P. Tseng, and Gabriel Fung of UC Davis; and Juntao Luo of SUNY Upstate Medical University, Syracuse, New York.

Story Source:

The above story is reprinted from materials provided by University of California - Davis Health System.

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Journal Reference:

Yuanpei Li, Wenwu Xiao, Kai Xiao, Lorenzo Berti, Juntao Luo, Harry P. Tseng, Gabriel Fung, Kit S. Lam. Well-Defined, Reversible Boronate Crosslinked Nanocarriers for Targeted Drug Delivery in Response to Acidic pH Values and cis-Diols. Angewandte Chemie International Edition, 2012; DOI: 10.1002/anie.201107144

Computer simulations revealing how methane and hydrogen pack into gas hydrates could enlighten alternative fuel production and carbon dioxide storage

For some time, researchers have explored flammable ice for low-carbon or alternative fuel or as a place to store carbon dioxide. Now, a computer analysis of the ice and gas compound, known as a gas hydrate, reveals key details of its structure. The results show that hydrates can hold hydrogen at an optimal capacity of 5 weight-percent, a value that meets the goal of a U.S. Department of Energy standard and makes gas hydrates practical and affordable.

The analysis is the first time researchers have accurately quantified the molecular-scale interactions between the gases -- either hydrogen or methane, aka natural gas -- and the water molecules that form cages around them. A team of researchers from the Department of Energy's Pacific Northwest National Laboratory published the results in Chemical Physics Letters online December 22, 2011.

The results could also provide insight into the process of replacing methane with carbon dioxide in the naturally abundant "water-based reservoirs," according to the lead author, PNNL chemist Sotiris Xantheas.

"Current thinking is that you need large amounts of energy to push the methane out, which destroys the scaffold in the process," said Xantheas. "But the computer modeling shows that there is an alternative low energy pathway. All you need to do is break a single hydrogen bond between water molecules forming the cage -- the methane comes out, and then the hydrate reseals itself."

Cagey Ice

Gas hydrates -- especially methane hydrates, which store natural gas -- look like ice but actually hold burnable fuel. Naturally found deep in the ocean, water and gas interweave in the hydrates, but little is known about their chemical structure and processes occurring at the molecular level. They have been known to cause problems for the petroleum industry because they tend to clog pipes and can explode. A methane hydrate produced the bubble of methane gas that contributed to 2010's Gulf of Mexico oil spill.

In previous work, Xantheas and colleagues used computer algorithms and models to examine the water-based, ice-like scaffold that holds the gas. Water molecules form individual cages made with 20 or 24 molecules. Multiple cages join together in large lattices. But those scaffolds were empty in the earlier analysis.

To find out how fuels can be accommodated inside the water cages, Xantheas and PNNL colleague Soohaeng Yoo Willow built computer models of the cages with either hydrogen gas -- in which two hydrogen atoms are bound together -- or methane gas, a small molecule made with one carbon and four hydrogen atoms.

In the hydrogen hydrates, which could potentially be used as materials for hydrogen fuel storage, a small hollow cage made from 20 water molecules could hold up to a maximum of five hydrogen molecules and a larger cage made from 24 water molecules could hold up to seven.

The maximum storage capacity equates to about 10 weight-percent, or the percentage of hydrogen by mass in the chunks of ice, although packing hydrogen in that tight puts undue strain on the system. The Department of Energy's goal for hydrogen storage -- to make the fuel practical -- is above 5.5 weight-percent.

Experimentally, hydrogen storage researchers typically measure much less storage capacities. The computer model showed them why: The hydrogen molecules tended to leak out of the cages, reducing the amount of hydrogen that could be stored.

The researchers found that adding a methane molecule to the larger cages in the pure hydrogen hydrate, however, prevented the hydrogen gas from leaking out. The computer model showed the researchers that they could store the hydrogen at high pressure and practical temperatures, and release it by reducing the pressure, which melts it.

Water Gates

Understanding how the gas interacts and moves through the cages can help chemists or engineers store gas and remove it at will. Willow and Xantheas' computer simulations showed that hydrogen molecules could migrate through the cages by passing between the figurative bars of the water cages. However, the cages also had gates: Sometimes a low-energy bond between two water molecules broke, causing a water molecule to swing open and let the hydrogen molecule drift out. The "gate" closed right after the molecule passed through to reform the lattice.

With methane hydrates, some fuel producers want to remove the gas safely to use it. Others see the emptied cages as potential storage sites for carbon dioxide, which could theoretically keep it out of the atmosphere and ocean, where it warms the earth and acidifies the sea. So, Willow and Xantheas tested how methane could migrate through the cages.

The water cages were only big enough to comfortably hold one methane molecule, so the chemists stuffed two methanes inside and watched what happened. Quickly, one of the water molecules forming the cage swung open like a gate, allowing one methane molecule to escape. The gate then slammed shut as the remaining methane scooted into the middle of the cage.

"This process is important because it can happen with natural gas. It shows how methane can move in the natural world," said Xantheas. "We hope this analysis will help with the technical issues that need to be addressed with gas hydrate research and development."

Xantheas said performing computer simulations with carbon dioxide instead of methane might help determine whether it's chemically feasible to store carbon dioxide in hydrates.

This work was supported by the Department of Energy Office of Science (BES). Computer resources used were at the National Energy Research Scientific Computing Center at DOE's Lawrence Berkeley National Laboratory in Berkeley, Calif.

Story Source:

The above story is reprinted from materials provided by Pacific Northwest National Laboratory.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Soohaeng Yoo Willow, Sotiris S. Xantheas. Enhancement of hydrogen storage capacity in hydrate lattices. Chemical Physics Letters, 2011; DOI: 10.1016/j.cplett.2011.12.036

Solar alchemy: Photocatalysts to clean water and recover chemicals

 Polluted water can be easily cleaned and treated to extract valuable chemicals, e.g., used in drug manufacturing. No factories or plants are needed, the sun and a "magic" powder are enough. The nearly alchemic transformation is accomplished due to photocatalysts studied by researchers from the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw.

In many places of the world water is highly polluted by organic chemicals from industrial wastes. The experiments carried out at the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS) in Warsaw prove that the biomass can be successfully transformed into useful chemicals and fuel. Due to appropriately selected photocatalysts, the transformation of polluted water into clean one and chemicals does not require specialized plants and takes place under conditions that are commonly met in nature.

Catalyst is a substance that participates in the chemical reaction, speeds its course and fully recovers after the reaction is completed. In typical catalytic processes the catalysts are activated at high temperatures, typically of several hundreds degrees centigrade, often at a significantly increased pressure.

"Photocatalysts studied by us differ in many respects from traditional catalysts. They are activated by light, and the temperature has no significant effect here," says Dr Juan Carlos Colmenares from the IPC PAS. The reactions with participation of photocatalysts occur at good exposure to sun rays, at temperature about 30 degrees centigrade and at normal atmospheric pressure -- so at conditions occurring naturally all year round in many equatorial countries.

The photocatalysts studied at the IPC PAS are solids based on titanium dioxide, TiO2. The catalysed reaction occurs in a liquid containing organic pollutants. After the reaction is completed, the catalyst can be isolated almost without losses and used again.

"My work resembles somewhat alchemy," jokes Colmenares. "I take a 'magic' powder, pour it into polluted water, stir and expose to the sun. After several hours, I get clean water plus chemicals that can be used to make useful things, for instance drugs."

The research on photochemical degradation of pollutants has been carried out in the world already in the late 1960's. By intensive UV irradiation chemical compounds with simple structures have been obtained at that time.

The research pursued at the IPC PAS aims at such a selection of photocatalysts and reaction conditions that the reaction can occur without using specialized equipment, and the degradation of biomass stops at a precisely defined stage. With titania-based photocatalysis the researchers managed to produce carboxylic acids used, e.g., in pharmaceutical and food industries. It is also possible to prepare a photocatalyst so as to have the reaction completed and yielding substances with the simplest structure, such as hydrogen or carbon dioxide. The latter compound is undesirable and would require disposal, hydrogen, however, has excellent prospects as the fuel of the future.

"In laboratory conditions, the reactions of the biomass with participation of photocatalysts are promising already now. In this year we are going to attempt the first tests in the pilot biochemical photoreactors at the University of Cordoba, Spain. The reactions will occur there in liquids with volumes measured in tens of litres," says Colmenares while making clear that still many tests and studies are to be carried out before the new technology gets disseminated.

The co-authors of the paper published in the Bioresource Technology journal, describing application of photocatalysts to glucose degradation and to production of valuable chemicals are Agnieszka Magdziarz and Dr Anna Bielejewska, who passed away late last year. The research has been financed from an international Marie Skłodowska-Curie reintegration grant under the 7th Framework Programme of the European Union.

Story Source:

The above story is reprinted from materials provided by Institute of Physical Chemistry of the Polish Academy of Sciences, via AlphaGalileo.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Juan C. Colmenares, Agnieszka Magdziarz, Anna Bielejewska. High-value chemicals obtained from selective photo-oxidation of glucose in the presence of nanostructured titanium photocatalysts. Bioresource Technology, 2011; 102 (24): 11254 DOI: 10.1016/j.biortech.2011.09.101

T-rays technology could help develop Star Trek-style hand-held medical scanners

 Scientists have developed a new way to create Terahertz waves (T-rays) that may one day lead to biomedical detective devices similar to the 'tricorder' scanner used in Star Trek

Scientists have developed a new way to create electromagnetic Terahertz (THz) waves or T-rays -- the technology behind full-body security scanners. The researchers behind the study, published recently in the journal Nature Photonics, say their new stronger and more efficient continuous wave T-rays could be used to make better medical scanning gadgets and may one day lead to innovations similar to the 'tricorder' scanner used in Star Trek.

In the study, researchers from the Institute of Materials Research and Engineering (IMRE), a research institute of the Agency for Science, Technology and Research (A*STAR) in Singapore, and Imperial College London in the UK have made T-rays into a much stronger directional beam than was previously thought possible, and have done so at room-temperature conditions. This is a breakthrough that should allow future T-ray systems to be smaller, more portable, easier to operate, and much cheaper than current devices.

The scientists say that the T-ray scanner and detector could provide part of the functionality of a Star Trek-like medical 'tricorder' -- a portable sensing, computing and data communications device -- since the waves are capable of detecting biological phenomena such as increased blood flow around tumorous growths. Future scanners could also perform fast wireless data communication to transfer a high volume of information on the measurements it makes.

T-rays are waves in the far infrared part of the electromagnetic spectrum that have a wavelength hundreds of times longer than those that make up visible light. Such waves are already in use in airport security scanners, prototype medical scanning devices and in spectroscopy systems for materials analysis. T-rays can sense molecules such as those present in cancerous tumours and living DNA, since every molecule has its unique signature in the THz range. They can also be used to detect explosives or drugs, for gas pollution monitoring or non-destructive testing of semiconductor integrated circuit chips.

Current T-ray imaging devices are very expensive and operate at only a low output power, since creating the waves consumes large amounts of energy and needs to take place at very low temperatures.

In the new technique, the researchers demonstrated that it is possible to produce a strong beam of T-rays by shining light of differing wavelengths on a pair of electrodes -- two pointed strips of metal separated by a 100 nanometre gap on top of a semiconductor wafer. The structure of the tip-to-tip nano-sized gap electrode greatly enhances the THz field and acts like a nano-antenna to amplify the wave generated. In this method, THz waves are produced by an interaction between the electromagnetic waves of the light pulses and a powerful current passing between the semiconductor electrodes. The scientists are able to tune the wavelength of the T-rays to create a beam that is useable in the scanning technology.

Lead author Dr Jing Hua Teng, from A*STAR's IMRE, said: "The secret behind the innovation lies in the new nano-antenna that we had developed and integrated into the semiconductor chip." Arrays of these nano-antennas create much stronger THz fields that generate a power output that is 100 times higher than the power output of commonly used THz sources that have conventional interdigitated antenna structures. A stronger T-ray source renders the T-ray imaging devices more power and higher resolution.

Research co-author Stefan Maier, a visiting scientist at A*STAR's IMRE and Professor in the Department of Physics at Imperial College London, said: "T-rays promise to revolutionise medical scanning to make it faster and more convenient, potentially relieving patients from the inconvenience of complicated diagnostic procedures and the stress of waiting for accurate results. Thanks to modern nanotechnology and nanofabrication, we have made a real breakthrough in the generation of T-rays that takes us a step closer to these new scanning devices. With the introduction of a gap of only 0.1 micrometers into the electrodes, we have been able to make amplified waves at the key wavelength of 1000 micrometers that can be used in such real world applications."

The research was led by scientists from A*STAR's IMRE and Imperial College London, and involved partners from A*STAR Institute for Infocomm Research (I2R) and the National University of Singapore. The research is funded under A*STAR's Metamaterials Programme and the THz Programme, as well as the Leverhume Trust and the Engineering and Physical Sciences Research Council (EPSRC) in the UK.

Story Source:

The above story is reprinted from materials provided by Imperial College London.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

H. Tanoto, J. H. Teng, Q. Y. Wu, M. Sun, Z. N. Chen, S. A. Maier, B. Wang, C. C. Chum, G. Y. Si, A. J. Danner, S. J. Chua. Greatly enhanced continuous-wave terahertz emission by nano-electrodes in a photoconductive photomixer. Nature Photonics, 2012; DOI: 10.1038/nphoton.2011.322

Breast cancer cells targeted, then burned, by gold-filled silicon wafers

 By shining infrared light on specially designed, gold-filled silicon wafers, scientists at The Methodist Hospital Research Institute have successfully targeted and burned breast cancer cells. If the technology is shown to work in human clinical trials, it could provide patients a non-invasive alternative to surgical ablation, and could be used in conjunction with traditional cancer treatments, such as chemotherapy, to make those treatments more effective.

The research is presented in the first issue of the new Advanced Healthcare Materials, a Wiley journal.

"Hollow gold nanoparticles can generate heat if they are hit with a near-infrared laser," said Research Institute Assistant Member Haifa Shen, M.D., Ph.D., the report's lead author. "Multiple investigators have tried to use gold nanoparticles for cancer treatment, but the efficiency has not been very good -- they'd need a lot of gold nanoparticles to treat a tumor."

Instead, Shen and his colleagues turned to a technology developed by the study's principal investigator, Mauro Ferrari, Ph.D., The Methodist Hospital Research Institute (TMHRI) president and CEO, to amplify the gold particles' response to infrared light.

"We developed a system based on Dr. Ferrari's multi-stage vector technology platform to treat cancers with heat," Shen said. "We found that heat generation was much more efficient when we loaded gold nanoparticles into porous silicon, the carrier of the multistage vectors."

Shen and his team found that in the presence of 808 nanometer light, the gold-filled silicon particles heated up a surrounding solution by about 20 deg C (35 deg F) in seven minutes. Water particles immediately around the particles were presumed to have been hotter. And experiments showed that tumor cell growth was lowest in the presence of gold-loaded silicon nanoparticles in three types of breast cancer cells -- MDA-MB-231 and SK-BR-3 (human), and 4T1 (mouse).

The silicon wafers the scientists are using are the result of painstaking work by Ferrari's group to design nanoparticles that preferentially bind to breast cancer cells, rather than, say, healthy liver or immune system cells. The shape and size of the silicon particles, as well as their surface chemistry, are all crucial, Ferrari's group found. Too big or the wrong shape, and the silicon nanoparticles bind to multiple cell types -- or none at all. Polyamine structures are attached to the wafers to improve their attraction to cancer cell surfaces and their solubility. The wafers are about one micrometer in diameter (one-thousandth of a millimeter). By contrast, the typical breast cancer cell is about 10 to 12 times that size.

Shen says the gold particles, too, must be designed with a specific use in mind, albeit for indirect reasons.

"The hollow gold particles we load into the porous silicon must be the right size and have the correct-sized space inside them to interact with the infrared light we are using," he said. "But the wavelength of infrared we use will have to change depending on where the tumor is. If it's close to the skin, we can use shorter wavelengths. Deeper inside the body, we have to use longer wavelengths of infrared to penetrate the tissue. The hollow space of the gold particles must be modified in response to that."

Both silicon and gold have low toxicity profiles in the human body, and are popular materials in current investigations using medical nanotechnology. Silicon is steadily broken down by physiological processes into an acid that is removed through the kidneys. And gold is chemically inert.

And infrared -- the type of light used by TV remote controls and garage door openers -- is also far less dangerous than light with shorter wavelengths, such as ultraviolet, which can cause DNA damage, and x-rays.

Understanding why hollow gold particles heat up in the presence of certain wavelengths of infrared is complex enough to require some background in physical chemistry. But the upshot is that the energy of certain wavelengths of light is largely absorbed by the particles, and that energy is released as vibrational (heat) energy. Absorption is influenced both by the diameter of the space within the hollow gold particles, and by the properties of gold itself.

Shen says he'd like to know whether the silicon-gold nanotechnology can be used to wipe out whole tumors, rather than just cancerous cells.

"We are planning pre-clinical studies to study the technology's impact on whole tissues, breast cancer cells and possibly pancreatic cancer cells," Shen said. "We would also like to see whether this approach makes chemotherapy more effective, meaning you could use less drugs to achieve the same degree of success in treating tumors. These investigations are next."

Coauthors of the Advanced Healthcare Materials paper were Jian You, whose contributions were equal to Shen's, Guodong Zhang, Arturas Ziemys, Qingpo Li, Litao Bai, Xiaoyong Deng, Donald R. Erm, Xuewu Liu, Chun Li, and Mauro Ferrari. The research was supported with grants to Ferrari from the Department of Defense and the National Institutes of Health.

Story Source:

The above story is reprinted from materials provided by Methodist Hospital, Houston.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Haifa Shen, Jian You, Guodong Zhang, Arturas Ziemys, Qingpo Li, Litao Bai, Xiaoyong Deng, Donald R. Erm, Xuewu Liu, Chun Li, Mauro Ferrari. Cooperative, Nanoparticle-Enabled Thermal Therapy of Breast Cancer. Advanced Healthcare Materials, 2012; 1 (1): 84 DOI: 10.1002/adhm.201100005