Researchers at CUNY create guidelines for morphable nanomaterials to diagnose, target and effectively treat Life-Threatening Illness such as Cancer, Cardiovascular and Autoimmune diseases

Sensing Nanomaterials newpaperprov

Peptides spontaneously form spherical or worm-like nanostructures that can be morphed or broken down by enzymes overexpressed in cancer cells. By controlling the shape and charge of the nanostructures, scientists can predict the rate of …more

Scientists have long sought to develop drug therapies that can more precisely diagnose, target and effectively treat life-threatening illness such as cancer, cardiovascular and autoimmune diseases.

One promising approach is the design of morphable nanomaterials that can circulate through the body and provide diagnostic information or release precisely targeted drugs in response to disease-marker enzymes. Thanks to a newly published paper from researchers at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York, Brooklyn College, and Hunter College, scientists now have design guidance that could rapidly advance development of such nanomaterials.

In the paper, which appears online in the journal ACS Nano, researchers detail broadly applicable findings from their work to characterize a  that can predictably, specifically and safely respond when it senses overexpression of the enzyme matrix metalloproteinase-9 (MMP-9). MMP-9 helps the body breakdown unneeded extracellular materials, but when levels are too high, it plays a role in the development of cancer and several other diseases.

“Right now, there are no clear rules on how to optimize the nanomaterials to be responsive to MMP-9 in predictable ways,” said Jiye Son, the study’s lead author and a Graduate Center Ph.D. student working in one of the ASRC Nanoscience Initiative labs. “Our work outlines an approach using short peptides to create enzyme-responsive nanostructures that can be customized to take on specific therapeutic actions, like only targeting  and turning on drug release in close proximity of these cells.”

Researchers designed a modular peptide that spontaneously assembles into nanostructures, and predictably and reliably morphs or breaks down into  when they come in contact with the MMP-9 enzyme. The designed components include a charged segment of the nanostructure to facilitate its sensing and engagement with the enzyme; a cleavable segment of the structure so that it can lock onto the enzyme and determine how to respond; and a hydrophobic segment of the structure to facilitate self-assembly of the therapeutic response.

“This work is a critical step toward creating new smart-drug delivery vehicles and diagnostic methods with precisely tunable properties that could change the face of disease treatment and management,” said ASRC Nanoscience Initiative Director Rein Ulijn, whose lab is leading the work. “While we specifically focused on creating nanomaterials that could sense and respond to MMP-9, the components of our design guidance can facilitate development of nanomaterials that sense and respond to other cellular stimuli.”

Among other advances, the research team’s work builds on their previous findings, which showed that amino acid peptides can encapsulate and transform into fibrous drug depots upon interaction with MMP-9. The group is collaborating with scientists at Memorial Sloan Kettering and Brooklyn College to use their findings to create a novel cancer therapy.

 Explore further: Scientists create nanomaterials that reconfigure in response to biochemical signals

More information: Jiye Son et al, Customizing Morphology, Size, and Response Kinetics of Matrix Metalloproteinase-Responsive Nanostructures by Systematic Peptide Design, ACS Nano (2019). DOI: 10.1021/acsnano.8b07401



NIST Research Suggests Graphene Can Stretch to be a Tunable Ion Filter – Applications for nanoscale sensors, drug delivery and water purification



Researchers at the National Institute of Standards and Technology (NIST) have conducted simulations suggesting that graphene, in addition to its many other useful features, can be modified with special pores to act as a tunable filter or strainer for ions (charged atoms) in a liquid.

The concept, which may also work with other membrane materials, could have applications such as nanoscale mechanical sensors, drug delivery, water purification and sieves or pumps for ion mixtures similar to biological ion channels, which are critical to the function of living cells. The research is described in the November 26 issue of Nature Materials.

“Imagine something like a fine-mesh kitchen strainer with sugar flowing through it,” project leader Alex Smolyanitsky said. “You stretch that strainer in such a way that every hole in the mesh becomes 1-2 percent larger. You’d expect that the flow through that mesh will be increased by roughly the same amount. Well, here it actually increases 1,000 percent. I think that’s pretty cool, with tons of applications.”

If it can be achieved experimentally, this graphene sieve would be the first artificial ion channel offering an exponential increase in ion flow when stretched, offering possibilities for fast ion separations or pumps or precise salinity control. Collaborators plan laboratory studies of these systems, Smolyanitsky said.

Graphene is a layer of carbon atoms arranged in hexagons, similar in shape to chicken wire, that conducts electricity. The NIST molecular dynamics simulations focused on a graphene sheet 5.5 by 6.4 nanometers (nm) in size and featuring small holes lined with oxygen atoms. These pores are crown ethers—electrically neutral circular molecules known to trap metal ions. A previous NIST simulation study showed this type of graphene membrane might be used for nanofluidic computing.

In the simulations, the graphene was suspended in water containing potassium chloride, a salt that splits into potassium and chlorine ions. The crown ether pores can trap potassium ions, which have a positive charge. The trapping and release rates can be controlled electrically. An electric field of various strengths was applied to drive the ion current flowing through the membrane.

Researchers then simulated tugging on the membrane with various degrees of force to stretch and dilate the pores, greatly increasing the flow of potassium ions through the membrane. Stretching in all directions had the biggest effect, but even tugging in just one direction had a partial effect.

Researchers found that the unexpectedly large increase in ion flow was due to a subtle interplay of a number of factors, including the thinness of graphene; interactions between ions and the surrounding liquid; and the ion-pore interactions, which weaken when pores are slightly stretched. There is a very sensitive balance between ions and their surroundings, Smolyanitsky said.

The research was funded by the Materials Genome Initiative.

Paper: A. Fang, K. Kroenlein, D. Riccardi and A. Smolyanitsky. Highly mechanosensitive ion channels from graphene-embedded crown ethers. Nature Materials. Published online November 26, 2018. DOI: 10.1038/s41563-018-0220-4

Dengue fever vaccine delivered with nanotechnology targets all four virus serotypes – University of North Carolina Research

denguefeverCredit: CC0 Public Domain

The latest in a series of studies led by the Aravinda de Silva Lab at the UNC School of Medicine shows continued promise in a dengue virus vaccine delivered using nanoparticle technology.


Each year, an estimated 25,000 people die from dengue infections and millions more are infected. Scientists have been trying to create a  for many years, but creating an effective  is challenging due to the four different serotypes of the virus. For a person to be fully protected against dengue, they need to be vaccinated against all four serotypes at once – something current vaccines do not achieve. In their paper published in PLOS Neglected Tropical Diseases, Aravinda de Silva, Ph.D., professor of microbiology and immunology, and UNC research associate Stefan Metz, Ph.D., detail how their nanoparticle delivery platform is producing a more balanced immune  versus other vaccine delivery platforms.

To deliver the vaccine, the de Silva lab is using a nanoparticle platform produced with PRINT (Particle Replication in Non-wetting Templates) technology, which was developed by Joseph DeSimone, Ph.D., the Chancellor’s Eminent Professor of Chemistry at UNC-Chapel Hill, with an appointment in the department of pharmacology. Rather than using a killed or attenuated virus to develop a vaccine for , researchers are focusing on expressing the E protein and attaching it to  to induce good immune responses. In previous studies of monovalent vaccines, they have shown that the platform can induce protective immune response in individual serotypes. Their latest study of a tetravalent vaccine shows the response in all four serotypes at the same time.

“We are also seeing a more balanced immune response for each of the serotypes, which means the quality of neutralizing antibodies created is leading to a better overall protective reaction for the patient,” said Metz, the paper’s lead author.

The de Silva lab performed the experiments on their Dengue vaccine in close collaboration with co-author Shaomin Tian, Ph.D., research assistant professor in the department of microbiology and immunology. The proteins used in the experiments were produced by the UNC Protein Expression and Purification (PEP) core.

The de Silva lab’s next steps include optimizing the technique they use to attach the E protein to the nanoparticle. This work will be extremely important when trying to create a vaccine that induces consistently strong protective immune responses.

 Explore further: Nanoparticle vaccinates mice against dengue fever

More information: Stefan W. Metz et al. Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype, PLOS Neglected Tropical Diseases (2018). DOI: 10.1371/journal.pntd.0006793

Graphene applications for bioelectronics and neuroprosthetics – Graphene BioElectronics

Graphene Bioelectrics id50987_1

The term bioelectronics, or bionics for short, describes a research field that is concerned with the integration of biological components with electronics; specifically, the application of biological materials and processes in electronics, and the use of electronic devices in living systems.
One day, bionics research could result in neural prostheses that augment or restore damaged or lost functions of the nervous system – restore vision, healing spinal cord injuries, and ameliorate neurodegenerative diseases such as Parkinson’s.
Bioelectronics has benefited greatly from the miniaturization offered by nanotechnology materials such as carbon nanotubes graphene (see for instance our previous Nanowerk Spotlights Eavesdropping on cells with graphene transistors or Nanotechnology to repair the brain.
Graphene bioelectronics has become a ground-breaking field that offers exciting opportunities for developing new kinds of sensors capable of establishing outstanding interfaces with soft tissue (see for instance: Light-driven bioelectronic implants without batteries). Graphene-based transistors, as well as electrode arrays, have emerged as a special group of biosensors with their own peculiarities, advantages and drawbacks.
Design of graphene-based in vivo neuronal probes
Design of graphene-based in vivo neuronal probes. (a-d) the simple monolayer graphene based GMEAs based on parylene-C substrates (© Springer Nature). (e-f) the porous graphene based GMEAs built on polyimide substrates. Open access. (g-h) schematics of the parylene-C based GMEAs (Image: Open access). (i) shows the optical images of the same parylene-C based GMEA µECoG devices (© Springer Nature). (click on image to enlarge)
Reviewing the progress of the field from single device measurements to in vivo neuroprosthetic devices, researchers from the Institute of Bioelectronics at Forschungszentrum Jülich in Germany, have published a review paper about graphene bioelectronics in 2D Materials (“Graphene & two-dimensional devices for bioelectronics and neuroprosthetics”).
The authors, Dmitry Kireev and Prof. Andreas Offenhaeusser, present a comprehensive overview of the use of graphene for bioelectronics applications; specifically they focus on interfacing graphene-based devices with electrogenic cells, such as cardiac and neuronal cells.
“Graphene possesses a number of important properties that may make it a game changer for future bioelectronics,” Kireev, the review’s first author, tells Nanowerk. “Above all and important for neuroscience, it was found to be biocompatible and completely stable in liquids and electrolytes. Excellent conductivity as well as transistor amplification properties allow graphene to be used for active parts of biosensors with extremely large sensitivities.”
In their review, the authors focus on a special kind of device that utilizes graphene as its active sensor material for extracellular signal detection. Starting with a short explanation of graphene-based devices, they then discuss in detail the reasons for the importance of graphene for future bioelectronics.
The paper provides a detailed description the working principle of two main graphene-based electronic devices that are currently used in bioelectronics applications: graphene field effect transistors (GFETs) and graphene multielectrode arrays (GMEAs). The authors discuss in detail the advantages and drawbacks of these devices.
The authors in-depth discussion includes past developments in order to provide a profound understanding of fundamental problems that have already been solved in order to guide future research.
Useful for researchers in the field, the paper provides a detailed time line of the development of GFETs and GMEAs, complete with key benchmarking properties.
The authors end their review with a structured perspective on future developments expected in the field.
“Basic research on graphene’s properties and proof-of-concept applications/devices is now concluding or at least declining,” notes Kireev. “We believe that research is now in the phase of optimizing these devices and searching for novel designs and approaches to utilize the given advantages of graphene and at the same time neutralize its drawbacks.”
The authors believe that the most intriguing outcome of the discovery of graphene has been the formation of a new research field: 2D materials science. Surprisingly, it appears that a myriad of standard bulk materials, such as silicon, germanium, and MoS2, whose properties have been known and studied for a long time, change their properties dramatically when thinned down to one or several monolayers. Some materials become semiconducting, some become fluorescent, and others become superconducting or create specific surface bonds. Other materials, such as 2D Ti3C2-MXenes, are suddenly sensitive to neurotransmitters, such as dopamine, creating an ultimately interesting device for neuroelectronics.
“The example of graphene and its usage for bioelectronics, which is exceptionally interesting, paves the way for further original research and exploration yet to come, possibly utilizing other 2D materials or graphene in standard forms (GFETs & GMEAs) or in the form of completely new devices,” Kireev concludes.

Re-Posted from Michael Berger/ Nanowerk

‘DNA-based’ nanocomposite hydrogel as a potent injectable drug delivery platform – A base matrix to form tissue engineering scaffolds and drug delivery platforms – U of Kansas

Injectable Nano Gel id51136_1

DNA is the carrier of genetic information of all living beings on earth. The nitrogenous base sequences along the DNA chain are responsible for the encoding and transmission of genetic information.

DNA downloadRead More: Understanding DNA

Besides being a genetic material, DNA can also be considered as a chemical entity and hence can be exploited as a base matrix to form tissue engineering scaffolds and drug delivery platforms.
From a chemical perspective, DNA is a long chain polymer consisting of monomeric repeat units. Each repeat unit consists of a deoxyribose sugar molecule linked to a phosphate group. Every monomeric unit is also connected to one of the four nitrogenous bases.
The base pairing interactions between the DNA strands are highly specific. Together with the binding of other substances to the backbone, this can be exploited to construct three-dimensionally interconnected hydrogel networks.
Sayantani Basu, a PhD student from the lab of Professor Arghya Paul (BioIntel Research Group) at the University of Kansas, Lawrence, has been working on the utilization of DNA as a high molecular weight polymeric chain in order to form hydrogel networks for tissue regeneration and drug delivery applications.
They have designed shear thinning hydrogels, which can be passed through a 22-gauge syringe by taking advantage of the native chemical structure of DNA and its specific base pairing interactions.
“As a bio and nano-materials engineering lab we are constantly trying to explore the structural properties of different polymers and nanoparticles to design smart materials for diverse biomedical applications including regenerative medicine,” says Dr. Arghya Paul.
Previous studies from Paul’s BioIntel Research Group at the University of Kansas have shown the use of two-dimensional nanosilicates to form injectable hydrogels (Acta Biomaterialia“Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue”)..
In their recent study (ACS Nano“Harnessing the Noncovalent Interactions of DNA Backbone with 2D Silicate Nanodisks To Fabricate Injectable Therapeutic Hydrogels”), the group has investigated the potential of DNA to form self-assembled injectable hydrogels via physical crosslinking with silicate nanodisks.


DNA-based physically crosslinked hydrogels
DNA-based physically crosslinked hydrogels. (Reprinted with permission by American Chemical Society) (click on image to enlarge)

The DNA-nanosilicate hydrogel is formed by a combination of non-covalent network points without the need of any toxic chemical crosslinkers. DNA denaturation and rehybridization mechanism as well as attractive electrostatic interactions of nanosilicates with the DNA backbone are utilized to generate an interconnected network via a two-step gelation process.

Basu has also shown a sustained release of a model osteogenic drug dexamethasone from the nanoengineered hydrogels and confirmed the bioactivity of the released drugs under lab and preclinical settings to promote bone regeneration.
The animal work was done in collaboration with Professor Jinxi Wang, who directs the Harrington Laboratory for Molecular Orthopedics at University of Kansas Medical Center.
Future work from the research group will focus on the feasibility of the DNA based hydrogels for other more potent drug (small molecules, nucleic acids, growth factors) delivery, and cell delivery applications.
Provided by the University of Kansas as a Nanowerk exclusive.

Drug combination delivered by nanoparticles may help in melanoma treatment

Melenoma 170314140859_1_540x360Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute, works with associates in the Melanoma Center.
Credit: Penn State College of Medicine

Summary: The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

CelePlum-777 combines a special ratio of the drugs Celecoxib, an anti-inflammatory, and Plumbagin, a toxin. By combining the drugs, the cells have difficulty overcoming the effect of having more than one active ingredient.

Celecoxib and Plumbagin work together to kill melanoma cells when used in a specific ratio. Researchers used microscopic particles called nanoparticles to deliver the drugs directly to the cancer cells. These particles are several hundred times smaller than the width of a hair and can be loaded with medications.

“Loading multiple drugs into nanoparticles is one innovative approach to deliver multiple cancer drugs to a particular site where they need to act and have them released at that optimal cancer cell killing ratio,” said Raghavendra Gowda, assistant professor of pharmacology, who is the lead author on the study. “Another advantage is that by combining the drugs, lower concentrations of each that are more effective and less toxic can be used.”

Celecoxib and Plumbagin cannot be taken by mouth because the drugs do not enter the body well this way and cannot be used together in the ratio needed because of toxicity.

CelePlum-777 can be injected intravenously without toxicity. Because of its small size, it also accumulates inside the tumors where it then releases the drugs to kill the cancer cells. Researchers report their results in the journals Molecular Cancer Therapeutics and Cancer Letters.

“This drug is the first of a new class, loaded with multiple agents to more effectively kill melanoma cells, that has potential to reduce the possibility of resistance development,” said senior author Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute. “There is no drug like it in the clinic today and it is likely that the next breakthrough in melanoma treatment will come from a drug like this one.”

The researchers showed the results of CelePlum-777 on killing cancer cells growing in culture dishes and in tumors growing in mice following intravenous injection. The drug prevented tumor development in mice with no detectable side effects and also prevented proteins from enabling uncontrolled cancer cell growth.

More research is required by the Food and Drug Administration before CelePlum-777 can be tested in humans through clinical trials. Penn State has patented this discovery and licensed it to Cipher Pharmaceuticals, which will perform the next series of FDA-required tests.

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Materials provided by Penn State College of Medicine. Note: Content may be edited for style and length.

Florida State University Researchers take big step forward in nanotech-based drugs

Nanoparticle drug delivery F3.large

Florida State University Summary:New research takes a step forward in the understanding of nanoparticles and how they can best be used to deliver drugs.

Nanotechnology has become a growing part of medical research in recent years, with scientists feverishly working to see if tiny particles could revolutionize the world of drug delivery.

But many questions remain about how to effectively transport those particles and associated drugs to cells.

In an article published in Scientific Reports, FSU Associate Professor of Biological Science Steven Lenhert takes a step forward in the understanding of nanoparticles and how they can best be used to deliver drugs.

After conducting a series of experiments, Lenhert and his colleagues found that it may be possible to boost the efficacy of medicine entering target cells via a nanoparticle.

“We can enhance how cells take them up and make more drugs more potent,” Lenhert said.

Initially, Lenhert and his colleagues from the University of Toronto and the Karlsruhe Institute of Technology wanted to see what happened when they encapsulated silicon nanoparticles in liposomes — or small spherical sacs of molecules — and delivered them to HeLa cells, a standard cancer cell model.

The initial goal was to test the toxicity of silicon-based nanoparticles and get a better understanding of its biological activity.

Silicon is a non-toxic substance and has well-known optical properties that allow their nanostructures to appear fluorescent under an infrared camera, where tissue would be nearly transparent. Scientists believe it has enormous potential as a delivery agent for drugs as well as in medical imaging.

But there are still questions about how silicon behaves at such a small size.

“Nanoparticles change properties as they get smaller, so scientists want to understand the biological activity,” Lenhert said. “For example, how does shape and size affect toxicity?”

Scientists found that 10 out of 18 types of the particles, ranging from 1.5 nanometers to 6 nanometers, were significantly more toxic than crude mixtures of the material.

At first, scientists believed this could be a setback, but they then discovered the reason for the toxicity levels. The more toxic fragments also had enhanced cellular uptake. That information is more valuable long term, Lenhert said, because it means they could potentially alter nanoparticles to enhance the potency of a given therapeutic.

The work also paves the way for researchers to screen libraries of nanoparticles to see how cells react.

“This is an essential step toward the discovery of novel nanotechnology based therapeutics,” Lenhert said. “There’s big potential here for new therapeutics, but we need to be able to test everything first.”

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Materials provided by Florida State University. Original written by Kathleen Haughney. Note: Content may be edited for style and length.

Journal Reference:

  1. Aubrey E. Kusi-Appiah, Melanie L. Mastronardi, Chenxi Qian, Kenneth K. Chen, Lida Ghazanfari, Plengchart Prommapan, Christian Kübel, Geoffrey A. Ozin, Steven Lenhert. Enhanced cellular uptake of size-separated lipophilic silicon nanoparticles. Scientific Reports, 2017; 7: 43731 DOI: 10.1038/srep43731


U Penn: Computer modeling for designing drug-delivery nanocarriers

Drug Carriers 080516 160804141256_1_540x360Previous work by some of the researchers uncovered a counter-intuitive relationship that suggested that adding more targeting molecules on the nanocarrier’s surface is not always better, as increases in stability may come with decreases in targeting specificity. Understanding the role the fluttering of the target cell’s surface plays in this equation is necessary for better design of nanocarriers.
Credit: University of Pennsylvania

A team of University of Pennsylvania researchers has developed a computer model that will aid in the design of nanocarriers, microscopic structures used to guide drugs to their targets in the body. The model better accounts for how the surfaces of different types of cells undulate due to thermal fluctuations, informing features of the nanocarriers that will help them stick to cells long enough to deliver their payloads.

The study was led by Ravi Radhakrishnan, a professor in the departments of bioengineering and chemical and biomolecular engineering in Penn’s School of Engineering and Applied Science, and Ramakrishnan Natesan, a member of his lab.

Also contributing to the study were Richard Tourdot, a Radhakrishnan lab member; David Eckmann, the Horatio C. Wood Professor of Anesthesiology and Critical Care in Penn’s Perelman School of Medicine; Portonovo Ayyaswamy, the Asa Whitney Professor of Mechanical Engineering and Applied Mechanics in Penn Engineering; and Vladimir Muzykantov, a professor of pharmacology in Penn Medicine.

It was published in the journal Royal Society Open Science.

Nanocarriers can be designed with molecules on their exteriors that only bind to biomarkers found on a certain type of cell. This type of targeting could reduce side effects, such as when chemotherapy drugs destroy healthy cells instead of cancerous ones, but the biomechanics of this binding process are complex.

Previous work by some of the researchers uncovered a counter-intuitive relationship that suggested that adding more targeting molecules on the nanocarrier’s surface is not always better.

A nanocarrier with more of those targeting molecules might find and bind to many of the corresponding biomarkers at once. While such a configuration is stable, it can decrease the nanocarrier’s ability to distinguish between healthy and diseased tissues. Having fewer targeting molecules makes the nanocarrier more selective, as it will have a harder time binding to healthy tissue where the corresponding biomarkers are not over-expressed.

The team’s new study adds new dimensions to the model of the interplay between the cellular surface and the nanocarrier.

“The cell surface itself is like a caravan tent on a windy day on a desert,” Radhakrishnan said. “The more excess in the cloth, the more the flutter of the tent. Similarly, the more excess cell membrane area on the ‘tent poles,’ the cytoskeleton of the cell, the more the flutter of the membrane due to thermal motion.”

The Penn team found that different cell types have differing amounts of this excess membrane area and that this mechanical parameter governs how well nanocarriers can bind to the cell. Accounting for the fluttering of the membrane in their computer models, in addition to the quantity of targeting molecules on the nanocarrier and biomarkers on the cell surface, has highlighted the importance of these mechanical aspects in how efficiently nanocarriers can deliver their payloads.

“These design criteria,” Radhakrishnan said, “can be utilized in custom designing nanocarriers for a given patient or patient-cohort, hence showing an important way forward for custom nanocarrier design in the era of personalized medicine.”

The research was supported by the National Science Foundation through grants DMR-1120901, CBET-1236514 and MCB060006, and the National Institutes of Health through grants U01EB016027, 1R01EB006818-05, HL125462 and HL087936.

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The above post is reprinted from materials provided byUniversity of Pennsylvania. Note: Materials may be edited for content and length.

UC San Diego: Targeted Drug Delivery with Nanoparticles = More Effective Medicines

Targeted Drug Delivery 150916162906_1_540x360Nanoparticles disguised as human platelets could greatly enhance the healing power of drug treatments for cardiovascular disease and systemic bacterial infections. These platelet-mimicking nanoparticles, developed by engineers at the University of California, San Diego, are capable of delivering drugs to targeted sites in the body — particularly injured blood vessels, as well as organs infected by harmful bacteria. Engineers demonstrated that by delivering the drugs just to the areas where the drugs were needed, these platelet copycats greatly increased the therapeutic effects of drugs that were administered to diseased rats and mice.

The research, led by nanoengineers at the UC San Diego Jacobs School of Engineering, was published online Sept. 16 in Nature.

“This work addresses a major challenge in the field of nanomedicine: targeted drug delivery with nanoparticles,” said Liangfang Zhang, a nanoengineering professor at UC San Diego and the senior author of the study. “Because of their targeting ability, platelet-mimicking nanoparticles can directly provide a much higher dose of medication specifically to diseased areas without saturating the entire body with drugs.”

Targeted Drug Delivery 150916162906_1_540x360

Pseudocolored scanning electron microscope images of platelet-membrane-coated nanoparticles (orange) binding to the lining of a damaged artery (left) and to MRSA bacteria (right). Each nanoparticle is approximately 100 nanometers in diameter, which is one thousand times thinner than an average sheet of paper.
Credit: Zhang Research Group, UC San Diego Jacobs School of Engineering.

The study is an excellent example of using engineering principles and technology to achieve “precision medicine,” said Shu Chien, a professor of bioengineering and medicine, director of the Institute of Engineering in Medicine at UC San Diego, and a corresponding author on the study. “While this proof of principle study demonstrates specific delivery of therapeutic agents to treat cardiovascular disease and bacterial infections, it also has broad implications for targeted therapy for other diseases such as cancer and neurological disorders,” said Chien.

The ins and outs of the platelet copycats

On the outside, platelet-mimicking nanoparticles are cloaked with human platelet membranes, which enable the nanoparticles to circulate throughout the bloodstream without being attacked by the immune system. The platelet membrane coating has another beneficial feature: it preferentially binds to damaged blood vessels and certain pathogens such as MRSA bacteria, allowing the nanoparticles to deliver and release their drug payloads specifically to these sites in the body.

Enclosed within the platelet membranes are nanoparticle cores made of a biodegradable polymer that can be safely metabolized by the body. The nanoparticles can be packed with many small drug molecules that diffuse out of the polymer core and through the platelet membrane onto their targets.

To make the platelet-membrane-coated nanoparticles, engineers first separated platelets from whole blood samples using a centrifuge. The platelets were then processed to isolate the platelet membranes from the platelet cells. Next, the platelet membranes were broken up into much smaller pieces and fused to the surface of nanoparticle cores. The resulting platelet-membrane-coated nanoparticles are approximately 100 nanometers in diameter, which is one thousand times thinner than an average sheet of paper.

This cloaking technology is based on the strategy that Zhang’s research group had developed to cloak nanoparticles in red blood cell membranes. The researchers previously demonstrated that nanoparticles disguised as red blood cells are capable of removing dangerous pore-forming toxins produced by MRSA, poisonous snake bites and bee stings from the bloodstream.

By using the body’s own platelet membranes, the researchers were able to produce platelet mimics that contain the complete set of surface receptors, antigens and proteins naturally present on platelet membranes. This is unlike other efforts, which synthesize platelet mimics that replicate one or two surface proteins of the platelet membrane.

“Our technique takes advantage of the unique natural properties of human platelet membranes, which have a natural preference to bind to certain tissues and organisms in the body,” said Zhang. This targeting ability, which red blood cell membranes do not have, makes platelet membranes extremely useful for targeted drug delivery, researchers said.

Platelet copycats at work

In one part of this study, researchers packed platelet-mimicking nanoparticles with docetaxel, a drug used to prevent scar tissue formation in the lining of damaged blood vessels, and administered them to rats afflicted with injured arteries. Researchers observed that the docetaxel-containing nanoparticles selectively collected onto the damaged sites of arteries and healed them.

When packed with a small dose of antibiotics, platelet-mimicking nanoparticles can also greatly minimize bacterial infections that have entered the bloodstream and spread to various organs in the body. Researchers injected nanoparticles containing just one-sixth the clinical dose of the antibiotic vancomycin into one of group of mice systemically infected with MRSA bacteria. The organs of these mice ended up with bacterial counts up to one thousand times lower than mice treated with the clinical dose of vancomycin alone.

“Our platelet-mimicking nanoparticles can increase the therapeutic efficacy of antibiotics because they can focus treatment on the bacteria locally without spreading drugs to healthy tissues and organs throughout the rest of the body,” said Zhang. “We hope to develop platelet-mimicking nanoparticles into new treatments for systemic bacterial infections and cardiovascular disease.”

Story Source:

The above post is reprinted from materials provided by University of California – San Diego. The original item was written by Liezel Labios. Note: Materials may be edited for content and length.

Journal Reference:

  1. Che-Ming J. Hu, Ronnie H. Fang, Kuei-Chun Wang, Brian T. Luk, Soracha Thamphiwatana, Diana Dehaini, Phu Nguyen, Pavimol Angsantikul, Cindy H. Wen, Ashley V. Kroll, Cody Carpenter, Manikantan Ramesh, Vivian Qu, Sherrina H. Patel, Jie Zhu, William Shi, Florence M. Hofman, Thomas C. Chen, Weiwei Gao, Kang Zhang, Shu Chien, Liangfang Zhang. Nanoparticle biointerfacing by platelet membrane cloaking. Nature, 2015; DOI: 10.1038/nature15373

‘Super-Cool’ way to Deliver Drugs

Super Cooled Drug 050815 asupercoolwaWater, when cooled below 32°F, eventually freezes — it’s science known even to pre-schoolers. But some substances, when they undergo a process called “rapid-freezing” or “supercooling,” remain in liquid form — even at below-freezing temperatures.

The supercooling phenomenon has been studied for its possible applications in a wide spectrum of fields. A new Tel Aviv University study published in Scientific Reports is the first to break down the rules governing the complex process of crystallization through rapid-cooling. According to the research, membranes can be engineered to crystallize at a specific time. In other words, it is indeed possible to control what was once considered a wild and unpredictable process — and it may revolutionize the delivery of drugs in the human body, providing a way to “freeze” the drugs at the exact time and biological location in the body necessary.

The study was led jointly by Dr. Roy Beck of the Department of Physics at TAU’s School of Physics and Astronomy and Prof. Dan Peer of the Department of Cell Research and Immunology at TAU’s Faculty of Life Sciences, and conducted by TAU graduate students Guy Jacoby, Keren Cohen, and Kobi Barkai.

Controlling a metastable process

“We describe a supercooled material as ‘metastable,’ meaning it is very sensitive to any external perturbation that may transform it back to its stable low-temperature state,” Dr. Beck said. “We discovered in our study that it is possible to control the process and harness the advantages of the fluid/not-fluid transition to design a precise and effective nanoscale drug encapsulating system.”

For the purpose of the study, the researchers conducted experiments on nanoscale drug vesicles (fluid-filled sacs that deliver drugs to their targets) to determine the precise dynamics of crystallization. The researchers used a state-of-the-art X-ray scattering system sensitive to nanoscale structures.

“One key challenge in designing new nano-vesicles for drug delivery is their stability,” said Dr. Beck. “On the one hand, you need a stable vesicle that will entrap your drug until it reaches the specific diseased cell. But on the other, if the vesicle is too stable, the payload may not be released upon arrival at its target.”

“Supercooled material is a suitable candidate since the transition between liquid and crystal states is very drastic and the liquid membrane explodes to rearrange as crystals. Therefore this new physical insight can be used to release entrapped drugs at the target and not elsewhere in the body’s microenvironment. This is a novel mechanism for timely drug release.”

All in the timing

The researchers found that the membranes were able to remain stable for tens of hours before collectively crystallizing at a predetermined time.

“What was amazing was our ability to reproduce the results over and over again without any complicated techniques,” said Dr. Beck. “We showed that the delayed crystallization was not sensitive to minor imperfection or external perturbation. Moreover, we found multiple alternative ways to ‘tweak the clock’ and start the crystallization process.”

The researchers are investigating an appropriate new nano-capsule capable of releasing medication at a specific time and place in the body. “The challenge now is to find the right drugs to exploit our insights for the medical benefit of patients,” said Dr. Beck.

Story Source:

The above story is based on materials provided by American Friends of Tel Aviv University. Note: Materials may be edited for content and length.

Journal Reference:

  1. Guy Jacoby, Keren Cohen, Kobi Barkan, Yeshayahu Talmon, Dan Peer, Roy Beck. Metastability in lipid based particles exhibits temporally deterministic and controllable behavior. Scientific Reports, 2015; 5: 9481 DOI: 10.1038/srep09481