Tag Archives: lipids

Lungs: EU SmartNanoTox and Pneumo NP

I have three news bits about lungs one concerning relatively new techniques for testing the impact nanomaterials may have on lungs and two concerning developments at PneumoNP; the first regarding a new technique for getting antibiotics to a lung infected with pneumonia and the second, a new antibiotic.

Predicting nanotoxicity in the lungs

From a June 13, 2016 news item on Nanowerk,

Scientists at the Helmholtz Zentrum München [German Research Centre for Environmental Health] have received more than one million euros in the framework of the European Horizon 2020 Initiative [a major European Commission science funding initiative successor to the Framework Programme 7 initiative]. Dr. Tobias Stöger and Dr. Otmar Schmid from the Institute of Lung Biology and Disease and the Comprehensive Pneumology Center (CPC) will be using the funds to develop new tests to assess risks posed by nanomaterials in the airways. This could contribute to reducing the need for complex toxicity tests.

A June 13, 2016 Helmholtz Zentrum München (German Research Centre for Environmental Health) press release, which originated the news item, expands on the theme,

Nanoparticles are extremely small particles that can penetrate into remote parts of the body. While researchers are investigating various strategies for harvesting the potential of nanoparticles for medical applications, they could also pose inherent health risks*. Currently the hazard assessment of nanomaterials necessitates a complex and laborious procedure. In addition to complete material characterization, controlled exposure studies are needed for each nanomaterial in order to guarantee the toxicological safety.

As a part of the EU SmartNanoTox project, which has now been funded with a total of eight million euros, eleven European research partners, including the Helmholtz Zentrum München, want to develop a new concept for the toxicological assessment of nanomaterials.

Reference database for hazardous substances

Biologist Tobias Stöger and physicist Otmar Schmid, both research group heads at the Institute of Lung Biology and Disease, hope that the use of modern methods will help to advance the assessment procedure. “We hope to make more reliable nanotoxicity predictions by using modern approaches involving systems biology, computer modelling, and appropriate statistical methods,” states Stöger.

The lung experts are concentrating primarily on the respiratory tract. The approach involves defining a representative selection of toxic nanomaterials and conducting an in-depth examination of their structure and the various molecular modes of action that lead to their toxicity. These data are then digitalized and transferred to a reference database for new nanomaterials. Economical tests that are easy to conduct should then make it possible to assess the toxicological potential of these new nanomaterials by comparing the test results s with what is already known from the database. “This should make it possible to predict whether or not a newly developed nanomaterial poses a health risk,” Otmar Schmid says.

* Review: Schmid, O. and Stoeger, T. (2016). Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung. Journal of Aerosol Science, DOI:10.1016/j.jaerosci.2015.12.006

The SmartNanoTox webpage is here on the European Commission’s Cordis website.

Carrying antibiotics into lungs (PneumoNP)

I received this news from the European Commission’s PneumoNP project (I wrote about PneumoNP in a June 26, 2014 posting when it was first announced). This latest development is from a March 21, 2016 email (the original can be found here on the How to pack antibiotics in nanocarriers webpage on the PneumoNP website),

PneumoNP researchers work on a complex task: attach or encapsulate antibiotics with nanocarriers that are stable enough to be included in an aerosol formulation, to pass through respiratory tracts and finally deliver antibiotics on areas of lungs affected by pneumonia infections. The good news is that they finally identify two promising methods to generate nanocarriers.

So far, compacting polymer coils into single-chain nanoparticles in water and mild conditions was an unsolved issue. But in Spain, IK4-CIDETEC scientists developed a covalent-based method that produces nanocarriers with remarkable stability under those particular conditions. Cherry on the cake, the preparation is scalable for more industrial production. IK4-CIDETEC patented the process.

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

At the same time, another route to produce lipidic nanocarriers have been developed by researchers from Utrecht University. In particular, they optimized the method consisting in assembling lipids directly around a drug. As a result, generated lipidic nanocarriers show encouraging stability properties and are able to carry sufficient quantity of antibiotics.

Fig.: On presence of antibiotics, the lipidic layer (step 1) aggregates the the drug (step 2) until the lipids forms a capsule around the antibiotics (step 3).

Fig.: On presence of antibiotics, a lipidic layer (step 1) aggregates the drug (step 2) until the lipids forms a capsule around antibiotics (step 3).

Assays of both polymeric and lipidic nanocarriers are currently performed by ITEM Fraunhofer Institute in Germany, Ingeniatrics Tecnologias in Spain and Erasmus Medical Centre in the Netherlands. Part of these tests allows to make sure that the nanocarriers are not toxic to cells. Other tests are also done to verify that the efficiency of antibiotics on Klebsiella Pneumoniae bacteria when they are attached to nanocarriers.

A new antibiotic for pneumonia (PneumoNP)

A June 14, 2016 PneumoNP press release (received via email) announces work on a promising new approach to an antibiotic for pneumonia,

The antimicrobial peptide M33 may be the long-sought substitute to treat difficult lung infections, like multi-drug resistant pneumonia.

In 2013, the European Respiratory Society predicted 3 millions cases of pneumonia in Europe every year [1]. The standard treatment for pneumonia is an intravenous administration of a combination of drugs. This leads to the development of antibiotic resistance in the population. Gradually, doctors are running out of solutions to cure patients. An Italian company suggests a new option: the M33 peptide.

Few years ago, the Italian company SetLance SRL decided to investigate the M33 peptide. The antimicrobial peptide is an optimized version of an artificial peptide sequence selected for its efficacy and stability. So far, it showed encouraging in-vitro results against multidrug-resistant Gram-negative bacteria, including Klebsiella Pneumoniae. With the support of EU funding to the PneumoNP project, SetLance SRL had the opportunity to develop a new formulation of M33 that enhances its antimicrobial activity.

The new formulation of M33 fights Gram-negative bacteria in three steps. First of all, the M33 binds with the lipopolysaccharides (LPS) on the outer membrane of bacteria. Then, the molecule forms a helix and finally disrupts the membrane provoking cytoplasm leaking. The peptide enabled up to 80% of mices to survive Pseudomonas Aeruginosa-based lung infections. Beyond these encouraging results, toxicity to the new M33 formulation seems to be much lower than antimicrobial peptides currently used in clinical practice like colistin [2].

Lately, SetLance scaled-up the synthesis route and is now able to produce several hundred milligrams per batch. The molecule is robust enough for industrial production. We may expect this drug to go on clinical development and validation at the beginning of 2018.

[1] http://www.erswhitebook.org/chapters/acute-lower-respiratory-infections/pneumonia/
[2] Ceccherini et al., Antimicrobial activity of levofloxacin-M33 peptide conjugation or combination, Chem Med Comm. 2016; Brunetti et al., In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Scientific Reports 2016

I believe all the references are open access.

Brief final comment

The only element linking these news bits together is that they concern the lungs.

At the nanoscale, grapefruit swings from being medication danger to medication enhancer

It’s known that grapefruit, despite its health benefits, can inhibit (or even a pose danger) to a medication’s effectiveness. Most of us have been warned at one time or another to avoid grapefruit juice when downing a pill. So, the news from the University of Louisville (Kentucky; UofL) about grapefruit as part of a drug delivery system seems a little counter-intuitive (from the May 22, 2013 news item on Azonano),

Grapefruits have long been known for their health benefits, and the subtropical fruit may revolutionize how medical therapies like anti-cancer drugs are delivered to specific tumor cells.

University of Louisville researchers have uncovered how to create nanoparticles using natural lipids derived from grapefruit, and have discovered how to use them as drug delivery vehicles. UofL scientists Huang-Ge Zhang, D.V.M., Ph.D., Qilong Wang, Ph.D., and their team today (May 21, 2013), published their findings in Nature Communications.

The May 21, 2013 University of Louisville news release by Julie Heflin, which originated the news item, describes how the nanoparticles are derived and their advantages,

“These nanoparticles, which we’ve named grapefruit-derived nanovectors (GNVs), are derived from an edible plant, and we believe they are less toxic for patients, result in less biohazardous waste for the environment and are much cheaper to produce at large scale than nanoparticles made from synthetic materials,” said Zhang, who holds the Founders Chair in Cancer Research at the Brown Cancer Center.

The researchers demonstrated that GNVs can transport various therapeutic agents, including anti-cancer drugs, DNA/RNA and proteins such as antibodies. Treatment of animals with GNVs seemed to cause less adverse effects than treatment with drugs encapsulated in synthetic lipids.

“Our GNVs can be modified to target specific cells — we can use them like missiles to carry a variety of therapeutic agents for the purpose of destroying diseased cells,” he said. “Furthermore, we can do this at an affordable price.”

The therapeutic potential of grapefruit derived nanoparticles was further validated through a Phase 1 clinical trial for treatment of colon cancer patients. So far, researchers have observed no toxicity in the patients who orally took the anti-inflammatory agent curcumin encapsulated in grapefruit nanoparticles.

The UofL scientists also plan to test whether this technology can be applied in the treatment of inflammation related autoimmune diseases like rheumatoid arthritis.

Here’s a link to and a citation for the researchers’ paper,

Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids by Qilong Wang, Xiaoying Zhuang, Jingyao Mu, Zhong-Bin Deng, Hong Jiang, Xiaoyu Xiang, Baomei Wang, Jun Yan, Donald Miller, & Huang-Ge Zhang. Nature Communications 4, 1867 doi:10.1038/ncomms2886 Published 21 May 2013

This paper is behind a paywall.

As for the dangers of grapefruit-medication interactions, ABC (American Broadcasting Corporation) has a Nov. 26, 2012 news item featuring then new research suggesting that even more medications are affected by grapefruit/grapefruit juice than had previously been believed,

It has long been known that grapefruit juice can pose dangerous — and even deadly — risks when taken along with certain medications. Now, experts warn the list of medications that can result in these interactions is longer than many may have believed.

In a new report released Monday in the Canadian Medical Association Journal [CMAJ], researchers at the University of Western Ontario said that while 17 drugs were identified in 2008 as having the potential to cause serious problems when taken with grapefruit, this number has now grown to 43.

So how does a common breakfast fruit cause these problems? Grapefruits contain chemicals called furanocoumarins that interfere with how your body breaks down drugs before they enter the bloodstream. By preventing this normal breakdown of a drug, these chemicals in grapefruit can effectively cause a drug overdose and more severe side-effects.

Among the side effects sometimes seen with grapefruit-induced overdoses are heart rhythm problems, kidney failure, muscle breakdown, difficulty with breathing and blood clots. …

ABC provides a list of drugs that are affected by grapefruit here.

For interested parties, here’s a link to and a citation for the research on grapefruit-medication interactions,

Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? by David G. Bailey, George Dresser, and J. Malcolm O. Arnold. CMAJ March 5, 2013 185:309-316; published ahead of print November 26, 2012,

This paper is behind a paywall.

I have a couple of final comments. (1) It would seem that the grapefruit’s characteristics at the macroscale are not echoed at the nanoscale. (2) Interestingly, the grapefruit nanoparticles (grapefruit nanovectors [GNVs]) are being used to encapsulate curcumin (a constituent of turmeric). I wrote about turmeric and its healing properties in a Dec. 26, 2011 posting, which features a number of links to research in this area.