Bitter-taste receptors in the lungs: implications for asthma treatment
Scientists at the University of Maryland (MD, USA) and Johns Hopkins university (MD, USA) have discovered that bitter-taste receptors (TAS2Rs), which are present on the tongue, are also expressed in the smooth muscle in the lungs. The research, presented in Nature Medicine, showed that in the presence of compounds that act on these receptors, such as the bitter tastant chloroquine, the smooth lung muscle relaxed and the airways dilated. This dilation was larger than that observed using current medications.
The research team exposed the airways and smooth muscle cells of humans and mice to bitter-tasting compounds. They found that some substances, known to activate TAS2Rs on the tongue, caused the airways to open up, behaving in the opposite way to that expected. Lead author, Stephen B Liggett, of the University of Maryland School of Medicine (MD, USA), said “It turns out that the bitter compounds worked the opposite way from what we thought. They all opened the airway more extensively than any known drug that we have for the treatment of asthma or chronic obstructive pulmonary disease”.
It was initially thought that the receptors would cause the airways to constrict in the presence of a bitter ‘taste‘, acting analogously to the bitter taste receptors on the tongue. These receptors transmit an unpleasant taste to the brain in the presence of certain compounds, a bodily mechanism thought to have evolved to prevent the ingestion of toxins.
As well as exposing bitter tastants to human and mouse smooth muscle cells, the respiratory systems of asthmatic mice were also exposed to the same compounds. It was observed that the airways dilated and obstruction decreased. Eating bitter-tasting foods would not have the desired effect warned Ligget. The best means of utilizing the observed effects in the treatment of asthma is thought to be incorporating compounds based on the chemical structure of natural bitter tastants into inhalable drug delivery systems. This approach could potentially revolutionize the treatment of asthma and obstructive lung disorders and enhance therapeutic uptake.
When an asthma sufferer has an attack, the airway muscle tightens up, which restricts airflow and results in the shortness of breath typically observed. A treatment causing the airways to open would counteract this response. Similarly, in obstructive lung disorders, medication that opened the airway would allow for more effective delivery of a therapeutic to the site of action.
Unlike those in the tongue, the receptors in the lungs have a nonclustered distribution and do not communicate the sensation of bitterness to the brain. Otherwise, they are identical and respond to agonists in the same way.
The existence of the receptors was discovered accidently by researchers during unrelated work on lung muscle. The scientists were looking into how the receptors in the muscle control the constriction and dilation of the airway, one of the principle means of oxygen delivery to cells. The discovery was unexpected and so counter-intuitive that the researchers were originally doubtful of their findings, “The detection of functioning taste receptors on smooth muscle of the bronchus in the lungs was so unexpected that we were at first quite skeptical ourselves”, explains Liggett.
This unlikely finding and the subsequent research exploring the response of taste receptors in the smooth lung muscle to bitter-tasting compounds could represent a real improvement in the treatment of asthma.
Sources: Deshpande DA, Wang WC, McIlmoyle EL et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine DOI: x10.1038/nm.2237 2010. 10.24 (2010) (Epub ahead of print); Bitter taste receptors in the lungs could revolutionize asthma treatment: www.medicalnewstoday.com/articles/205671.php
Ultrasound and the BBB: emerging implications for intravenous delivery
Research conducted by scientists at the Department of Biomedical Engineering, Columbia University (NY, USA) has shown that ultrasound can be used to temporarily relax the blood–brain barrier (BBB) in mice.
The BBB is the body‘s natural barrier between the circulatory system and the brain, and acts as a guard preventing potentially harmful compounds passing from the blood into the brain and causing neurological damage.
One of the main challenges in CNS therapy is the impenetrability of the BBB, which prevents many drugs from reaching the brain, and therefore the intended site of action. ‘Neurodegenerative diseases are under-treated because of the BBB‘, says lead researcher Elisa Konofogue of Columbia University.
This work presents a potential new direction for research into a drug delivery method to the CNS whereby the BBB of the recipient is relaxed by ultrasound and the therapeutic administered intravenously. Once the therapeutic is in the blood, it will come into contact with the brain via the circulatory system and cross over the relaxed BBB to the site of action.
Currently employed methods for facilitating the transport of CNS agents to the brain include carrier-mediated delivery, where the drug is conjugated to a carrier such as a protein or lipophilic molecule that can pass over the BBB, thus taking the drug with it. However, this approach can prove expensive and the proportion of drug that reaches the brain can vary widely.
Other approaches include direct injection of the drug into the brain, which requires specially trained medical professionals to carry out the invasive procedure and carries a high risk of infection.
While this new research has only been tested on mice so far, and is in the very early stages of development, it could provide a noninvasive, simple way of introducing drugs to the brain, presenting advantages over other more invasive or expensive techniques, and could be applied to the treatment of diseases such as Alzheimer‘s and Parkinson‘s.
Sources: Tung YS, Vlachos F, Choi JJ, Deffieux T, Selert K, Konofagou EE. In vivotranscranial cavitation threshold detection during ultrasound-induced blood–brain barrier opening in mice. Phys. Med. Biol. 55(20), 6141-6155 (2010); Groundbreaking ultrasound device being developed for Alzheimer's disease: www.dailymail.co.uk/health/article-1321460/Scientists-developing-groundbreaking-ultrasound-device-Alzheimers-disease.html#ixzz13O5K8VaN
Copper transfer through membrane proteins: implications for chemotherapy treatments
New research on membrane proteins by scientists at Tel Aviv University‘s Department of Biochemistry and Molecular Biology and Bogazici University (Istanbul, Turkey) has shed light on the mechanism for the transfer of copper ions throughout the body. This knowledge could be particularly relevant to the treatment of cancer by chemotherapy agents such as cisplatin, the mechanism of absorption for which could be similar to the way in which essential metal ions such as copper are transferred throughout the body.
Membrane proteins, the proteins present in the fine membrane enclosing a cell, are difficult to study compared with other proteins as they are destroyed in an aqueous environment. They are thought to be key in the mechanism regulating essential trace elements in the body such as copper. The mechanism is thought to be a combination of ‘chaperone molecules‘ and membrane proteins, whereby, the chaperone transports the copper ion to an ‘opening‘ in the cell membrane, through which it passes without the chaperone, only to be picked up by another one on the other side where it is transported to the required destination within the cell.
Nir Ben-Tal of Tel Aviv University suggests that this system allows for maximum control of copper ion concentration and transport by passing one copper ion at a time through the copper transporter protein “This way, there is no risk of bringing several copper ions into the protein at the same time, which ultimately prevents harmful chemical reactions between the ions and the abundant chemical reagents within the cell.”
This mechanism could also be responsible for the absorbtion and transfer throughout the body of the common chemotherapy drug cisplatin. Further study into the mechanism may allow scientists to better understand how cisplatin and other such medications are transferred in the body. As such, the delivery of the drug could be improved or a more effective drug developed, potentially enhancing cancer therapy.
Sources: Schushan M, Barkan Y, Haliloglu T, Ben-Tal N. C(α)-trace model of the transmembrane domain of human copper transporter 1, motion and functional implications. Proc. Natl Acad. Sci. USA 107(24), 10908–10913 (2010); With a chaperone, copper breaks through: research identifies features of copper transfer that may improve chemotherapy treatments: www.sciencedaily.com/releases/2010/10/101018121444.htm
Upconversion nanoparticles: targeted cancer cell imaging and therapy
Recent work by scientists at Soochow University (China), has explored the tandem use of upconversion nanoparticles (UCNPs), nanoparticles made with unique photoluminesence properties, and a chemotherapy agent, doxorubicin (DOX) to combine targeted cancer cell imaging with therapy. Speaking to Therapeutic Delivery lead scientist Zhuang Lui describes the potential application for UCNPs in cancer therapy “This would be useful for imaging-guided-therapy. The eventual aim is to do imaging during treatment, to reveal the therapeutic responses at the real time of treatment”.
Upconversion nanoparticles have been recently used as novel contrast agents to highlight cancer cells in biomedical imaging. Researchers at Soochow University modified UCNPs by adding a polyethylene glycol polymer. These newly functionalized UCNPs could then be loaded with the chemotherapy agent DOX via adsorbtion of the DOX to the polyethylene glycol groups, forming a supramolecular structure that acts as a nanocarrier, capable of intracellular delivery of the chemotherapy agent. The loading and releasing of DOX from these nanocarriers is shown to be pH-dependent, allowing for controlled drug release.
Further work involved conjugating the UCNPs with folic acid. This allowed for targeted drug-delivery, as folate receptors are overexpressed on various types of cancer cells.
This UCNP-based, non-covalent, drug-loading strategy shows potential for use with light-induced photodynamic therapy when the UCNPs are loaded with photosensitizer molecules. Lui regards the next stage of development in this research to be using UCNPs as combined therapy agents, delivering both chemotherapy and photosensitizer molecules.
These results highlight the potential for UCNPs to act as multi-functional, targeted cancer therapy and imaging agents.
Source: Wang C, Cheng L, Liu Z. Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy. Biomaterials DOI:10.1016/j.biomaterials.2010.09.069 (2010) (Epub ahead of print).
Novel extraction-resistant oral drug delivery systems for opioid medications
Highland Pharmaceuticals, the Missouri-based development and manufacturing company, has announced the availability of its latest product, an extraction-resistant formulation for opioid-based medications. This technology makes the recreational use of such prescription medications as fentanyl or oxymorphone a lot more difficult. Analytical tests undertaken by Highland Pharmaceuticals show that under 10% of the opioid was extracted using common alteration methods such as crushing or dissolving the medication for inhalation or injection, respectively, frustrating those seeking to misuse prescription drugs.
Bill Moskoff, CEO of Highland Pharmaceuticals, says of their novel technology, “Our delivery system frustrates the most well-known forms of opiate drug abuse. These methods include crushing tablets into a fine powder for inhalation or extracting with water or alcohol for injection – all for an enhanced high.”
In addition, the solid-dose tablets, which are manufactured using lipid-based technology, perform well when taken as instructed, dissolving efficiently in the gastrointestinal tract.
Opioid-based drugs are commonly prescribed by doctors for the relief of pain. These formulations can be used to gain an intense high by drug abusers through crushing or dissolving the medication for inhalation or injection, thus delivering a much more intense hit of the drug than the intended gastrointestinal absorption. This innovation in drug delivery technology is driven by increasing abuse of prescription medication, estimated by the NIH to cost US$484 billion per year in the USA alone.
On the relevance and potential impact of this technology, Moskoff says, “We are excited about this new formulation, as we see it as another step toward improving the security of delivering controlled pain medications and potentially reducing street drug abuse and misuse.”
Highland seeks to improve this technology further and is looking to pursue regulatory approval and market their pain-management products.
Sources: Highland Pharmaceuticals, LLC: www.highlandpharma.com; Highland Pharmaceuticals announces new extraction-resistant oral drug delivery system: www.prweb.com/releases/Highland/Pharmaceuticals/prweb4680124.htm