Graphic representation of a 3-D atomic resolution screw dislocation in a platinum nanoparticle. Credit: Chien-Chun Chen and I-Sheng Chou, UCLA

Researchers from UCLA’s California NanoSystems Institute and Northwestern University have combined multiple imaging techniques to produce high quality 3D images of platinum nanoparticles, allowing advanced visualization of atomic-scale structural defects (an important advancement over X-ray crystallography).

The original 2012 work, published in Nature and posted by Jim Lewis here, used electron tomography to study 10-nm gold particles and was described at Phys.org:

…
“This is the first experiment where we can directly see local structures in three dimensions at atomic-scale resolution — that’s never been done before,” said Jianwei (John) Miao, a professor of physics and astronomy and a researcher with the California NanoSystems Institute (CNSI) at UCLA.
…
X-ray crystallography is a powerful technique for revealing the structure of perfect crystals, which are materials with an unbroken honeycomb of perfectly spaced atoms lined up as neatly as books on a shelf. Yet most structures existing in nature are non-crystalline, with structures far less ordered than their crystalline counterparts — picture a rock concert mosh pit rather than soldiers on parade.
…
Miao and his colleagues used a scanning transmission electron microscope to sweep a narrow beam of high-energy electrons over a tiny gold particle only 10 nanometers in diameter (almost 1,000 times smaller than a red blood cell). The nanoparticle contained tens of thousands of individual gold atoms, each about a million times smaller than the width of a human hair. These atoms interact with the electrons passing through the sample, casting shadows that hold information about the nanoparticle’s interior structure onto a detector below the microscope.

Miao’s team discovered that by taking measurements at 69 different angles, they could combine the data gleaned from each individual shadow into a 3-D reconstruction of the interior of the nanoparticle. Using this method, which is known as electron tomography, Miao’s team was able to directly see individual atoms and how they were positioned inside the specific gold nanoparticle.
…

The new study, using multiple imaging techniques, will be published in an upcoming issue of Nature, and includes a video showing three-dimensional volume renderings (available for viewing at Phys.org:

The authors describe being able to see how the atoms of a platinum nanoparticle—only 10 namometers in diameter—are arranged in three dimensions. They also identify how the atoms are arranged around defects in the platinum nanoparticle.
…
This novel method is a combination of three techniques: scanning transmission electron microscopy, equally sloped tomography (EST) and three-dimensional Fourier filtering. Compared to conventional CT, the combined method produces much higher quality 3-D images and allows the direct visualization of atoms inside the platinum nanoparticle in three dimensions.
…
“This is the first instance where the three-dimensional structure of dislocations in nanoparticles has been directly revealed at atomic resolution,” Ajayan said. “The elegant work demonstrates the power of electron tomography and leads to possibilities of directly correlating the structure of nanoparticles to properties, all in full 3-D view.” Defects can influence many properties of materials, and a technique for visualizing these structures at atomic resolution could lead to new insights beneficial to researchers in a wide range of fields.

-Posted by Stephanie C

(credit: Mary Leonard, University of Pennsylvania Biomedical Art & Design)

Research into using nanotechnology for improved drug delivery continues to advance as current nanoparticle technology is combined with increasingly more sophisticated biotechnology. One major problem with using nanoparticles for targeted drug delivery is that the patient’s immune system often clears the particle before they can be effective. A new approach uses a peptide derived from an important immune system molecule to fool the immune system. A commentary accompanying the publication (abstract) of the research in Science describes how short peptides from a human protein called CD47, which tells important immune system cells that cells or particles bearing the protein are human, not foreign, were used as a “passport” to get nanoparticles past the immune system. Additional details are supplied in a University of Pennsylvania news release “Penn Researchers Develop Protein ‘Passport’ That Helps Nanoparticles Get Past Immune System“:

… The research was conducted by professor Dennis Discher, graduate students Pia Rodriguez, Takamasa Harada, David Christian and Richard K. Tsai and postdoctoral fellow Diego Pantano … “From your body’s perspective,” Rodriguez said, “an arrowhead a thousand years ago and a pacemaker today are treated the same — as a foreign invader.

“We’d really like things like pacemakers, sutures and drug-delivery vehicles to not cause an inflammatory response from the innate immune system.”

The innate immune system attacks foreign bodies in a general way. Unlike the learned response of the adaptive immune system, which includes the targeted antibodies that are formed after a vaccination, the innate immune system tries to destroy everything it doesn’t recognize as being part of the body.

This response has many cellular components, including macrophages — literally “big eaters” — that find, engulf and destroy invaders. Proteins in blood serum work in tandem with macrophages; they adhere to objects in the blood stream and draw macrophages’ attention. If the macrophage determines these proteins are stuck to a foreign invader, they will eat it or signal other macrophages to form a barrier around it.

Drug-delivery nanoparticles naturally trigger this response, so researchers’ earlier attempts to circumvent it involved coating the particles with polymer “brushes.” These brushes stick out from the nanoparticle and attempt to physically block various blood serum proteins from sticking to its surface.

However, these brushes only slow down the macrophage-signaling proteins, so Discher and colleagues tried a different approach: Convincing the macrophages that the nanoparticles were part of the body and shouldn’t be cleared.

In 2008, Discher’s group showed that the human protein CD47, found on almost all mammalian cell membranes, binds to a macrophage receptor known as SIRPa in humans. Like a patrolling border guard inspecting a passport, if a macrophage’s SIRPa binds to a cell’s CD47, it tells the macrophage that the cell isn’t an invader and should be allowed to proceed on.

“There may be other molecules that help quell the macrophage response,” Discher said. “But human CD47 is clearly one that says, ‘Don’t eat me’.”

Since the publication of that study, other researchers determined the combined structure of CD47 and SIRPa together. Using this information, Discher’s group was able to computationally design the smallest sequence of amino acids that would act like CD47. This “minimal peptide” would have to fold and fit well enough into the receptor of SIRPa to serve as a valid passport.

After chemically synthesizing this minimal peptide, Discher’s team attached it to conventional nanoparticles that could be used in a variety of experiments.

“Now, anyone can make the peptide and put it on whatever they want,” Rodriguez said.

The research team’s experiments used a mouse model to demonstrate better imaging of tumors and as well as improved efficacy of an anti-cancer drug-delivery particle.

As this minimal peptide might one day be attached to a wide range of drug-delivery vehicles, the researchers also attached antibodies of the type that could be used in targeting cancer cells or other kinds of diseased tissue. Beyond a proof of concept for therapeutics, these antibodies also served to attract the macrophages’ attention and ensure the minimal peptide’s passport was being checked and approved.

“We’re showing that the peptide actually does inhibit the macrophage’s response,” Discher said. “We force the interaction and then overwhelm it.”

The test of this minimal peptide’s efficacy was in mice that were genetically modified so their mac[r]ophages had SIRPa receptors similar to the human version. The researchers injected two kinds of nanoparticles — ones carrying the peptide passport and ones without — and then measured how fast the mice’s immune systems cleared them.

“We used different fluorescent dyes on the two kinds of nanoparticles, so we could take blood samples every 10 minutes and measure how many particles of each kind were left using flow cytometry,” Rodriguez said. “We injected the two particles in a 1-to-1 ratio and 20-30 minutes later, there were up to four times as many particles with the peptide left.”

Even giving therapeutic nanoparticles an additional half-hour before they are eaten by macrophages could be a major boon for treatments. Such nanoparticles might need to make a few trips through the macrophage-heavy spleen and liver to find their targets, but they shouldn’t stay in the body indefinitely. Other combinations of exterior proteins might be appropriate for more permanent devices, such as pacemaker leads, enabling them to hide from the immune system for longer periods of time.

While more research is necessary before such applications become a reality, reducing the peptide down to a sequence of only a few amino acids was a critical step. The relative simplicity of this passport molecule to be more easily synthesized makes it a more attractive component for future therapeutics. …

A very interesting feature of this work is the computational identification of a small structure, in this case a peptide, that can substitute for a crucial part of the function of a large biological system (phagocytic cells to recognize non-self). We should probably expect to see this strategy often as nanomedicine evolves from predominantly biotechnology toward more machine-like advanced nanotechnology.
—James Lewis, PhD

(credit: Comp. Cog. Neurosci Lab/ Olaf Sporns, Indiana Univ.)

A proposal alluded to by President Obama in his State of the Union address to construct a dynamic “functional connectome” Brain Activity Map (BAM) would leverage current progress in neuroscience, synthetic biology, and nanotechnology to develop a map of each firing of every neuron in the human brain—a hundred billion neurons sampled on millisecond time scales. Although not the intended goal of this effort, a project on this scale, if it is funded, should also indirectly advance efforts to develop artificial intelligence and atomically precise manufacturing. In his blog, Robert L. Blum provides an excellent overview and brief introduction. From “BAM: Brain Activity Map: Every Spike from Every Neuron“:

A recent research proposal called BAM for Brain Activity Map Project generated much excitement. (The BAM proposal, published in Neuron in June 2012 is online, and an earlier draft with far greater detail is also online.)

(Addendum: 18 Feb 2013: I started drafting this story in Nov, 2012. Today it was headline news when it was made public that THIS is the very proposal that President Obama alluded to in his recent State of the Union address. See John Markoff’s NY Times piece. NIH is drafting a 3 billion dollar, 10 year proposal to fund this project. Also see this 25 Feb 2013 NY Times follow-up by Markoff.) …

The essence of the BAM proposal is to create the technology over the coming decade to be able to record every spike from every neuron in the brain of a behaving organism. While this notion seems insanely ambitious, coming from a group of top investigators, the paper deserves scrutiny. At minimum it shows what might be achieved in the future by the combination of nanotechnology and neuroscience. …

The Neuron article cited by Blum argues that in addition to breakthroughs in basic science with large medical and economic benefits, the BAM project will advance technology in terms of important general capabilities.

Many technological breakthroughs are bound to arise from the BAM Project, as it is positioned at the convergence of biotechnology and nanotechnology. These new technologies could include optical techniques to image in 3D; sensitive, miniature, and intelligent nanosystems for fundamental investigations in the life sciences, medicine, engineering, and environmental applications; capabilities for storage and manipulation of massive data sets; and development of biologically inspired, computational devices.

I think the emphasis on nanosystems of nanodevices integrated to provide complex functions is very important, even if many or most of those devices will, in the beginning, not be atomically precise. The more detailed description of the BAM proposal cited by Blum above hints at how nanoparticle-based sensors could be developed to noninvasively provide micrometer-scale spatial resolution and millisecond-scale temporal resolution to groups of millions of neurons deep inside the brain of a living, active animal (or human). The mention combining semiconductor quantum dots and nanodiamonds with organic nanostructures to functionalize them, so that they may be directed to and embedded in neural membranes to monitor synapses. In addition, nanotubes or nanowires could be developed to deliver photons to specific locations, or collect or release specific chemicals. Further, they suggest developing graphene into membrane patches for detailed monitoring of neurons. Taken together, the requirements for this ambitious project entail the need to develop a variety of nanoparticles for specific applications, and then integrating multifunctional nanoprobes, nanoparticles, and nanodevices into large functional systems, and producing such nanosystems en masse.

In his NY Times report John Markoff notes the possible effect of this project on the development of artificial intelligence: “Moreover, the project holds the potential of paving the way for advances in artificial intelligence.” Indeed, the information to be provided by BAM about how circuits of thousands or millions of neurons work should advance Ray Kurzweil’s program of reverse engineering the human brain to develop artificial general intelligence, as described in his new book How to Create a Mind: The Secret of Human Thought Revealed.

The next best thing to large program to develop molecular manufacturing is a large program aimed at other worthy and useful goals that also makes heavy use of nanotechnology and may promote some of the same or similar enabling technologies that will lead toward productive nanosystems.
—James Lewis, PhD

Mesocosms. Credit: Benjamin Coleman

The advent of new technologies is typically followed by new government regulation, and in the absence of data, fear-based reactionism can have far too much influence on policy. Quality research studies on real risks and impacts of nanoscale technologies can help lead to legitimate scientific consensus and appropriate regulation.

Engineered nanoparticles draw particular attention, because the same unique properties that give rise to special utility may also give rise to special health and environmental risks.

To calibrate our responses to nanoparticle toxicology studies, it is important to note whether an experiment reasonably represents likely exposure scenarios and whether nanoscale size is in fact a contributing factor to observed effects.

Recently highlighted at Phys.org, researchers at Duke University are investigating environmental impacts of widely used silver nanoparticles by way of experiments that seek to represent real-world exposure levels.

Previous studies have involved high concentrations of the nanoparticles in a laboratory setting, which the researchers point out, doesn’t represent “real-world” conditions.

For their studies, the researchers created mesocosms, which are small, man-made structures containing different plants and microorganisms meant to represent the environment. They applied sludge with low doses of silver nanoparticles in some of the mesocosms, then compared plants and microorganisms from treated and untreated mesocosms after 50 days.

“We’re trying to come up with the data that can be used to help regulators determine the risks to the environment from silver nanoparticle exposures,” [said Benjamin Colman, a post-doctoral fellow in Duke's biology department and a member of the Center for the Environmental Implications of Nanotechnology (CEINT)].

“Our results show that silver nanoparticles in the biosolids, added at concentrations that would be expected, caused ecosystem-level impacts,” Colman said.

The researchers plan to continue to study longer-term effects of silver nanoparticles and to examine another ubiquitous nanoparticle – titanium dioxide.

Studies that do not elucidate the roles of different particle properties can still be of great benefit by drawing attention to studies that do, and by adding to the pool of reliable data. Most important is for researchers and the public alike to recognize the difference and to support policy that is sensible and appropriate.
-Posted by Stephanie C

(Credit: Courtesy of UCLA Engineering)

One of the most promising near-term applications of current nanotechnology is in targeted drug delivery to treat cancer. Despite the fact that a number of approaches based on very different areas of nanoscience have shown promise in delivering a wide variety of agents in different animal models of cancer, a number of challenges remain, principally involving the stability of the nanoparticles in the circulatory system, getting them into cancer cells, releasing the cargo to kill the cells, and the fact that cancer cells often have defenses against anti-cancer drugs. A core-shell nanoparticle has been cleverly adapted to deliver a particularly effective agent to where it is needed. A hat tip to ScienceDaily for reprinting this UCLA news release “Tiny capsule effectively kills cancer cells“:

Devising a method for more precise and less invasive treatment of cancer tumors, a team led by researchers from the UCLA Henry Samueli School of Engineering and Applied Science has developed a degradable nanoscale shell to carry proteins to cancer cells and stunt the growth of tumors without damaging healthy cells.

In a new study, published online Feb. 1 in the peer-reviewed journal Nano Today [abstract], a group led by Yi Tang, a professor of chemical and biomolecular engineering and a member of the California NanoSystems Institute at UCLA, reports developing tiny shells composed of a water-soluble polymer that safely deliver a protein complex to the nucleus of cancer cells to induce their death. The shells, which at about 100 nanometers are roughly half the size of the smallest bacterium, degrade harmlessly in non-cancerous cells.

The process does not present the risk of genetic mutation posed by gene therapies for cancer, or the risk to healthy cells caused by chemotherapy, which does not effectively discriminate between healthy and cancerous cells, Tang said.

“This approach is potentially a new way to treat cancer,” said Tang. “It is a difficult problem to deliver the protein if we don’t use this vehicle. This is a unique way to treat cancer cells and leave healthy cells untouched.”

The cell-destroying material, apoptin, is a protein complex derived from an anemia virus in birds. This protein cargo accumulates in the nucleus of cancer cells and signals to the cell to undergo programmed self-destruction.

The polymer shells are developed under mild physiological conditions so as not to alter the chemical structure of the proteins or cause them to clump, preserving their effectiveness on the cancer cells.

Tests done on human breast cancer cell lines in laboratory mice showed significant reduction in tumor growth.

“Delivering a large protein complex such as apoptin to the innermost compartment of tumor cells was a challenge, but the reversible polymer encapsulation strategy was very effective in protecting and escorting the cargo in its functional form,” said Muxun Zhao, lead author of the research and a graduate student in chemical and biomolecular engineering at UCLA.

Tang’s group continues to research ways of more precisely targeting tumors, prolonging the circulation time of the capsules and delivering other highly sought-after proteins to cancer cells.

There is nothing very interesting here from the standpoint of the eventual development of atomically precise manufacturing, but this work presents an excellent case for making the most of the current tools of nanotechnology and employing a deep knowledge of biotechnology and using imaging technology to see what happens inside of cells to develop a promising solution to a set of difficult and important problems.
—James Lewis, PhD

The principle of contraction and extension of a telescopic polymer chain based on the supramolecular association of thousands of nano-machines. (Credit: Wiley-VCH Verlag GmbH & Co.KGaA. and CNRS)

Biology uses various types of molecular machines to produce movement, all of which are candidates to be mimicked for use in nanotechnology. Muscles produce movement through the contraction of systems of polymers, powered by the release of chemical energy. Now scientists from France’s CNRS have developed an artificial muscle that produces micrometer-scale movement through the coordinated action of thousands of individual molecular machines each producing nanometer-scale movement. A hat tip to Gene Ostrovsky at MedGadget for a story on this CNRS press release “Assembly of nano-machines mimics human muscle“:

For the first time, an assembly of thousands of nano-machines capable of producing a coordinated contraction movement extending up to around ten micrometers, like the movements of muscular fibers, has been synthesized by a CNRS team from the Institut Charles Sadron. This innovative work, headed by Nicolas Giuseppone, professor at the Université de Strasbourg, and involving researchers from the Laboratoire de Matière et Systèmes Complexes (CNRS/Université Paris Diderot), provides an experimental validation of a biomimetic approach that has been conceptualized for some years in the field of nanosciences. This discovery opens up perspectives for a multitude of applications in robotics, in nanotechnology for the storage of information, in the medical field for the synthesis of artificial muscles or in the design of other materials incorporating nano-machines (endowed with novel mechanical properties). This work has been published in the on-line version of the journal Angewandte Chemie International Edition [abstract].

… Even though synthetic chemists have made dazzling progress over the last few years in the manufacture of artificial nano-machines (the mechanical properties of which are of increasing interest for research and industry), the coordination of several of these machines in space and in time hitherto remained an unresolved problem.

Not anymore: for the first time, Giuseppone’s team has succeeded in synthesizing long polymer chains incorporating, via supramolecular bonds (1), thousands of nano-machines each capable of producing linear telescopic motion of around one nanometer. Under the influence of pH, their simultaneous movements allow the whole polymer chain to contract or extend over about 10 micrometers, thereby amplifying the movement by a factor of 10,000, along the same principles as those used by muscular tissues.

… These results, obtained using a biomimetic approach, could lead to numerous applications for the design of artificial muscles, micro-robots or the development of new materials incorporating nano-machines endowed with novel multi-scale mechanical properties.

UT Dallas researchers have made artificial muscles from carbon nanotube yarns that have been infiltrated with paraffin wax and twisted until coils form along their length. (Credit: UT Dallas)

A different flavor of nanotechnology involving nanostructures that are not defined to atomic precision has produced a different type of artificial muscle that looks very robust in that it does not require changing solutions of electrolytes, responds very quickly, and is far stronger than human muscles of the same size. These muscles are composed of a yarn of carbon nanotubes filled with wax. The research was published in Science [abstract]. A hat tip to KurzweilAI for reprinting this news release from UT Dallas “Wax-Filled Nanotech Yarn Behaves Like Super-Strong Muscle“:

New artificial muscles made from nanotech yarns and infused with paraffin wax can lift more than 100,000 times their own weight and generate 85 times more mechanical power than the same size natural muscle, according to scientists at The University of Texas at Dallas and their international team from Australia, China, South Korea, Canada and Brazil.

The artificial muscles are yarns constructed from carbon nanotubes, which are seamless, hollow cylinders made from the same type of graphite layers found in the core of ordinary pencils. Individual nanotubes can be 10,000 times smaller than the diameter of a human hair, yet pound-for-pound, can be 100 times stronger than steel.

“The artificial muscles that we’ve developed can provide large, ultrafast contractions to lift weights that are 200 times heavier than possible for a natural muscle of the same size,” said Dr. Ray Baughman, team leader, Robert A. Welch Professor of Chemistry and director of the Alan G. MacDiarmid NanoTech Institute at UT Dallas. “While we are excited about near-term applications possibilities, these artificial muscles are presently unsuitable for directly replacing muscles in the human body.”

Described in a study published in the Nov. 16 issue of the journal Science, the new artificial muscles are made by infiltrating a volume-changing “guest,” such as the paraffin wax used for candles, into twisted yarn made of carbon nanotubes. Heating the wax-filled yarn, either electrically or using a flash of light, causes the wax to expand, the yarn volume to increase, and the yarn length to contract.

The combination of yarn volume increase with yarn length decrease results from the helical structure produced by twisting the yarn. A child’s finger cuff toy, which is designed to trap a person’s fingers in both ends of a helically woven cylinder, has an analogous action. To escape, one must push the fingers together, which contracts the tube’s length and expands its volume and diameter.

“Because of their simplicity and high performance, these yarn muscles could be used for such diverse applications as robots, catheters for minimally invasive surgery, micromotors, mixers for microfluidic circuits, tunable optical systems, microvalves, positioners and even toys,” Baughman said.

Muscle contraction – also called actuation – can be ultrafast, occurring in 25-thousandths of a second. Including times for both actuation and reversal of actuation, the researchers demonstrated a contractile power density of 4.2 kW/kg, which is four times the power-to-weight ratio of common internal combustion engines. …

“The remarkable performance of our yarn muscle and our present ability to fabricate kilometer-length yarns suggest the feasibility of early commercialization as small actuators comprising centimeter-scale yarn length,” Baughman said. “The more difficult challenge is in upscaling our single-yarn actuators to large actuators in which hundreds or thousands of individual yarn muscles operate in parallel.”

Additional coverage, including a video of these micro-muscles in action, is included in Science News coverage by Sarah C. P. Williams “Wax-Filled Nanotubes Flex Their Muscles“. These two very different approaches to providing nanoscale motion that can scale to microscale or even macroscale robotic motion have different features that will probably suit them to different applications. It will be interesting to see if any applications are developed that will be relevant to nanoscale atomically precise manufacturing.
—James Lewis, PhD

In recent years, ball milling has become increasingly popular in the production of highly complex chemical structures. In such synthesis, steel balls are shaken with the reactants and catalysts in a rapidly vibrating jar. Chemical transformations take place at the sites of ball collision, where impact causes instant “hot spots” of localized heat and pressure. This is difficult to model and, without access to real time reaction monitoring, mechanochemistry remained poorly understood.
…
The team of scientists chose to study mechanochemical production of the metal-organic framework ZIF-8 from the simplest and non-toxic components. Materials such as ZIF-8 are rapidly gaining popularity for their ability to capture large amounts of CO2; if manufactured cheaply and sustainably, they could become widely used for carbon capture and storage, catalysis and even hydrogen storage.

“The team came to the ESRF because of our high-energy X-rays capable of penetrating 3 mm thick walls of a rapidly moving reaction jar made of steel, aluminium or plastic. The X-ray beam must get inside the jar to probe the mechanochemical formation of ZIF-8, and then out again to detect the changes as they happened”, says Simon Kimber, a scientist at the European Synchrotron Radiation Facility (ESRF) in Grenoble, who is a member of the team. This unprecedented methodology enabled the real-time observation of reaction kinetics, reaction intermediates and the development of their respective nanoparticles.

The work, published in Nature Chemistry (Abstract), allowed the research team to see differences in reaction pathways and kinetics relative to traditional solvent-phase processes.

An excellent introduction to mechanosynthesis and mechanochemistry (and their important distinctions) by Damian Allis of Syracuse University can be found in the Productive Nanosystems Technology Roadmap (see Part 3 Proceedings of the Roadmap Working Group, Atomically Precise Fabrication: 02 Mechanosynthesis).
-Posted by Stephanie C

Northwestern University researchers have broken a world record by creating two new synthetic materials with the greatest amount of surface areas reported to date.

Named NU-109 and NU-110, the materials belong to a class of crystalline nanostructure known as metal-organic frameworks (MOFs) that are promising vessels for natural-gas and hydrogen storage for vehicles, and for catalysts, chemical sensing, light harvesting, drug delivery, and other uses requiring a large surface area per unit weight.

The materials’ promise lies in their vast internal surface area. If the internal surface area of one NU-110 crystal the size of a grain of salt could be unfolded, the surface area would cover a desktop. …

MOFs are composed of organic linkers held together by metal atoms, resulting in a molecular cage-like structure. The researchers believe they may be able to more than double the surface area of the materials by using less bulky linker units in the materials’ design. …

Beyond their near-term practical applications, Eric Drexler has cited MOFs as potentially useful building blocks in the molecular machine path to molecular manufacturing. Near-term applications may drive the technology development to produce more choices for molecular machine system components.
—James Lewis, PhD

Shanta Dhar, right, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences, and doctoral student Sean Marrache have fabricated nanoparticles that boost the effectiveness of drugs by delivering them to the mitochondria of cells (credit: University of Georgia).

Targeted drug delivery is one of the most important contributions of current and near-term nanotechnology to medicine. New research shows that specifically targeting one component of the cell makes nanoparticle-mediated drug delivery much more effective for a variety of applications. A hat tip to KurzweilAI.net for reprinting this University of Georgia news release “UGA researchers boost efficacy of drugs by using nanoparticles to target ‘powerhouse of cells’“:

Nanoparticles have shown great promise in the targeted delivery of drugs to cells, but researchers at the University of Georgia have refined the drug delivery process further by using nanoparticles to deliver drugs to a specific organelle within cells.

By targeting mitochondria, often called “the powerhouse of cells,” the researchers increased the effectiveness of mitochondria-acting therapeutics used to treat cancer, Alzheimer’s disease and obesity in studies conducted with cultured cells.

“The mitochondrion is a complex organelle that is very difficult to reach, but these nanoparticles are engineered so that they do the right job in the right place,” said senior author Shanta Dhar, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences.

Dhar and her co-author, doctoral student Sean Marrache, used a biodegradable, FDA-approved polymer to fabricate their nanoparticles and then used the particles to encapsulate and test drugs that treat a variety of conditions. Their results were published this week in early edition of the journal Proceedings of the National Academy of Sciences [abstract].

To test the effectiveness of their drug targeting system against cancer, they encapsulated the drug lonidamine, which works by inhibiting energy production in the mitochondria, and, separately, a form of the antioxidant vitamin E. They then treated cultured cancer cells and found that mitochondrial targeting increased the effectiveness of the drugs by more than 100 times when compared to the drugs alone and by five times when compared to the delivery of drugs with nanoparticles that target the outside of cells.

Similarly, the compound curcumin has shown promise in inhibiting formation of the amyloid plaques that are a hallmark of Alzheimer’s disease, but it quickly degrades in the presence of light and is broken down rapidly by the body. By encapsulating curcumin in the mitochondria-targeting nanoparticles, however, the researchers were able to restore the ability of brain cells in culture to survive despite the presence of a compound that encourages plaque formation. Nearly 100 percent of the cells treated with the mitochondria-targeting nanoparticles survived in the presence of the plaque-inducing compound, compared to 67 percent of cells treated with free curcumin and 70 percent of cells treated with nanoparticles that target the outside of cells.

Finally, the researchers encapsulated the obesity drug 2,4-DNP—which works by making energy production in the mitochondria less efficient—in their nanoparticles and found that it reduced the production of fat by cultured cells known as preadipocytes by 67 percent compared to cells treated with the drug alone and by 61 percent of cells treated with nanoparticles that target the outside of cells.

“A lot of diseases are associated with dysfunctional mitochondria, but many of the drugs that act on the mitochondria can’t get there,” Marrache said. “Rather than try to alter the drugs, which can reduce their effectiveness, we encapsulate them in these nanoparticles and precisely deliver them to the mitochondria.”

Dhar said that getting drugs to the mitochondria is no simple feat. Upon entering cells, nanoparticles enter a sorting center known as the endosome. The first thing Dhar and Marrache had to demonstrate was that the nanoparticles escape from the endosome and don’t end up in the cells’ disposal center, the lysosome.

The mitochondria itself is protected by two membranes separated by an interstitial space. The outer membrane only permits molecules of a certain size to pass through, while the inner membrane only permits molecules of a given range of charges to pass. The researchers constructed a library of nanoparticles and tested them until they identified the optimum size range—64 to 80 nanometers, or approximately 1,000 times finer than the width of a human hair—and an optimum surface charge, plus 34 millivolts.

Dhar notes the components they used to create the nanoparticles are FDA approved and that their methods are highly reproducible and therefore have the potential to be translated into clinical settings. The researchers are currently testing their targeted delivery system in rodents and say that preliminary results are promising.

“Mitochondrial dysfunctions cause many disorders in humans,” Dhar said, ” so there are several potential applications for this delivery system.”

Subject to the usual caveat that these nanoparticles are still in an early stage of testing, having been tested only in cell culture, it is remarkable that such effective targeting to reach the matrix of the mitochondria was achieved by the relatively crude strategy of optimizing only particle size and surface charge through engineering polymer composition. So success was achieved through clever application of biological knowledge more than through sophisticated atomically precise construction. It will be fascinating to watch the evolution of this technology as ever more sophisticated construction leads to increasing effectiveness. While we are waiting, this targeting of drug delivery to mitochondria is likely to be especially helpful because so many pathologies seem rooted in imperfections and consequences of the symbiosis that led to eukaryotic cells, and all complex life on Earth, nearly two billion years ago.
—James Lewis, PhD