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.”

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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.

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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

University of Cambridge: A New Class of Biosensors Basis for New Drug Delivery Systems.

Nano Sensing id38606Researchers from the University of Cambridge have developed a new self-assembled material, which, by changing its shape, can amplify small variations in temperature and concentration of biomolecules, making them easier to detect. The material, which consists of synthetic spheres ‘glued’ together with short strands of DNA, could be used to underpin a new class of biosensors, or form the basis for new drug delivery systems.

The interplay between the lipid spheres, called giant vesicles, and the strands of DNA produces a unique response when the material is exposed to changes in temperature. Instead of expanding when heated – as is normally the case – the material contracts, a phenomenon known as negative thermal expansion. Details are published today (7 January) in the journal Nature Communications (“Thermal regulation of volume and porosity in lipid mesophases by coupling mobile ligands to soft membranes”).

Nano Sensing id38606

A lipid membrane functionalised with DNA-linkers. (Image: Lorenzo Di Michele)

In addition to its role as a carrier of genetic information, DNA is also useful for building advanced materials. Short strands of DNA, dubbed ‘sticky ends’, can be customised so that they will only bind to specific complementary sequences. This flexibility allows researchers to use DNA to drive the self-assembly of materials into specific shapes.

Basing self-assembled materials around vesicles – synthetic versions of the soft sacs which envelop living cells – allows for even more flexibility, since the vesicles are so easily deformable. Using short DNA tethers with a cholesterol ‘anchor’ at one end and an exposed sticky DNA sequence at the other, the vesicles can be stuck together. When assembled into a hybrid DNA-lipid network, the DNA tethers can diffuse and rearrange, resulting in massive vesicle shape changes.
Besides negative thermal expansion, the researchers also found that changes in temperature lead to a significant variation in the porosity of the material, which is therefore highly controllable. A similar response is expected by changing the concentration of the DNA tethers, which could also be replaced by other types of ligand-receptor pairs, such as antibodies.
“The characteristics of this material make it suitable for several different applications, ranging from filtration, to the encapsulation and triggered release of drugs, to biosensors,” said Dr Lorenzo Di Michele of the University’s Cavendish Laboratory, who led the research. “Having this kind of control over a material is like a ‘golden ticket’ of sensing.”
This research is part of the CAPITALS, a UK-wide programme funded by the Engineering and Physical Sciences Research Council (EPSRC). Cambridge Enterprise, the University’s commercialisation arm, is currently looking for commercial partners to help develop this material.
Source: Science China Press

Sopping up Proteins with Nano-Thermosponges: A Novel Nanoparticle Platform for Delivering Protein-Based Drugs

1-BYU 50348Abstract: A research team led by Brigham and Women’s Hospital (BWH) has developed and tested a novel nanoparticle platform that efficiently delivers clinically important proteins in vivo in initial proof-of-concept tests.

Nanoparticles, which are particles measuring nanometers in size, hold promise for a range of applications, including human therapeutics. The key advantage of the new platform, known as a thermosponge nanoparticle, is that it eliminates the need for harsh solvents, which can damage the very molecules the particles are designed to carry.

Boston, MA | Posted on October 22nd, 2014

The study is published online October 21 in Nano Letters.

1-BYU 50348

“A central challenge in applying nanoparticle technology to protein therapeutics is preserving proteins’ biological activity, which can be inactivated by the organic solvents used in nanoparticle engineering,” said Omid Farokhzad, MD, Director of the BWH Laboratory of Nanomedicine and Biomaterials. “Our research demonstrates that the thermosponge platform, which enables the solvent-free loading of proteins, is a promising approach for the delivery of a variety of proteins, including highly labile proteins such as IL-10.”

Protein-based therapeutics form an important class of drugs to treat a range of human diseases. However, significant challenges in their development have generally resulted in very slow development paths. To overcome these challenges, Farokhzad and his colleagues sought to create improved nanoparticle methods for delivering protein therapies.

The new thermosponge nanoparticles (TNPs) they developed are composed of biocompatible and biodegradable polymers. These polymers include a central, spherical core, made of the polymer poly(D,L-lactide), and an outer “thermosponge,” made of a polaxomer polymer. The core can be either positively or negatively charged, to allow for the delivery of negatively or positively charged proteins, respectively. Importantly, the thermosponge shell can expand or contract as temperatures change, which permits the solvent-free loading of proteins onto the TNP.

The researchers selected a range of different proteins for loading onto the TNPs, including positively-charged interleukin-10 (IL-10) and erythropoietin, and negatively-charged insulin and human growth hormone. The proteins showed similar patterns of sustained release for four days after loading, indicating that the TNPs are able to effectively deliver a variety of proteins.

Further tests showed that the proteins loaded onto the TNPs retained their bioactivity throughout both loading and release from the TNPs.

Importantly, in studies of pre-clinical models, loading of IL-10 or insulin onto the TNPs resulted in dramatic increases in systemic exposure to the proteins, reduced clearance, and increased circulating half-life of the proteins compared to the native protein without TNP.

“The TNPs have been designed and nanoengineered with protein bioactivity in mind, where we optimized a solvent-free nanotechnology that can entrap proteins of various size and charges based on temperature differences into the shell of the nanoparticles. This methodology is amenable for the delivery of a range of therapeutic proteins and can potentially lead to the facile clinical translation of nanoparticles for biologics delivery,” said Won IL Choi, Ph.D., a postdoctoral fellow in the BWH Laboratory of Nanomedicine and Biomaterials.

This research was supported by the Program of Excellence in Nanotechnology (PEN) Award, Contract #HHSN268201000045C, from the National Heart, Lung, and Blood Institute, National Institutes of Health (CA151884, and NIH R01 grant EB015419-01), and the David Koch-Prostate Cancer Foundation Award in Nanotherapeutics.