Breaking News
September 20, 2018 - Potential drugs to treat neurodegenerative diseases garner $3 million grant
September 20, 2018 - Processing speed important to higher order cognitive function in multiple sclerosis patients
September 20, 2018 - Helping a patient survive a hurricane
September 20, 2018 - Tafamidis Treats Transthyretin Amyloid Cardiomyopathy
September 20, 2018 - Low academic achievement can lead to drug abuse decades later, research finds
September 20, 2018 - Study identifies stem cell that gives rise to new bone, cartilage in humans | News Center
September 20, 2018 - Celltrion and Emory University sign ‘Incubation’ agreement to develop new drug candidates for atherosclerosis
September 20, 2018 - TGen and PNOC take part in launch of NIH-supported Kids First Data Resource Portal
September 20, 2018 - Could Household Cleaners Make Your Kid Fat?
September 20, 2018 - Addiction nonprofit makes searching for services simple
September 20, 2018 - We are bombarded by thousands of diverse species and chemicals | News Center
September 20, 2018 - Experts to Present Prostate Cancer Advances at Patient Summit
September 20, 2018 - Alector announces initiation of Phase 1 trial of AL001 for treating frontotemporal dementia
September 20, 2018 - Pfizer’s 20vPnC vaccine receives Breakthrough Therapy designation from FDA
September 20, 2018 - Study could allow doctors to screen patients at risk from Aspergillus
September 20, 2018 - Emergex signs MoU with Brazil’s Fiocruz for development of viral vaccines
September 20, 2018 - The ‘real you’ is a myth – we constantly create false memories to achieve the identity we want
September 20, 2018 - Researchers describe cell mechanism that optimizes proteins production in stressful situations
September 20, 2018 - Cell Medica successfully doses first patient with CMD-501 targeting pediatric neuroblastoma
September 20, 2018 - Senators unveil legislation to protect patients against surprise medical bills
September 20, 2018 - Study provides insights into development of special-purpose cosmetic products
September 20, 2018 - Research shows enlarged genotype-phenotype correlation for three-base pair deletion in NF1
September 20, 2018 - 91% of people around the world believe medical research will result in dementia cure
September 20, 2018 - DePuy Synthes introduces CONCORDE LIFT Expandable Interbody Device at EUROSPINE 2018
September 20, 2018 - Manx Telecom unveils MT clearSound that improves clarity of mobile phone calls
September 20, 2018 - Mediterranean-style diet appears to reduce stroke risk in women
September 20, 2018 - AbbVie Announces Patient-Reported Outcomes Data from Three Pivotal Phase 3 Studies of Risankizumab, Showing Significant Improvements in Health-Related Quality of Life for Patients with Psoriasis
September 20, 2018 - Characterization of pregnancy microbiome reveals variations in bacterial diversity
September 20, 2018 - New guidance for treatment of bone loss in hematologic stem cell transplant Recipients
September 20, 2018 - Experts to present research on prevention, management of dysphagia at international conference
September 20, 2018 - New study focuses on two-way gene switches controlling gene activity
September 20, 2018 - Zika virus could become a weapon against brain cancer
September 20, 2018 - Home-based video game exercises can reduce chronic low back pain in older people, study finds
September 20, 2018 - Investigators find that bile acids reduce cocaine reward
September 20, 2018 - Cannabinoid drugs reduce perceived unpleasantness of painful stimuli and increase tolerance
September 20, 2018 - Health care companies’ data could enable more accurate flu season forecasts
September 20, 2018 - Geroscience takes center stage in Journal of the American Medical Association
September 20, 2018 - Ambient Particulate Matter Linked to Emergency Asthma Care
September 20, 2018 - Patient satisfaction with plastic surgery—it’s the surgeon, not the practice
September 20, 2018 - Medicine is a team sport – and that’s exactly how it should be
September 20, 2018 - Logos Biosystems releases new electrophoretic tissue clearing system with twice the features in half the space
September 20, 2018 - Novel micro-platform reveals never-before-seen behaviors of cancer cells
September 20, 2018 - PAREXEL partners with Datavant to enhance clinical study design and generate real-world evidence
September 20, 2018 - Robert Koch Institute publishes new data on allergies, mental health problems, and accident injuries
September 20, 2018 - Study finds higher readmission rates in for-profit hospitals
September 20, 2018 - Encouraging youth to do strength-based exercises could help tackle child obesity
September 20, 2018 - Sleep apnea, congenital heart disease in hospitalized infants strongly associated with death
September 20, 2018 - Researchers find way to map mysterious content of non-coding RNA
September 20, 2018 - Air Pollutants Reach Placenta, Might Harm Fetus: Study
September 20, 2018 - Sleep apnea, congenital heart disease may be deadly mix for hospitalized infants
September 20, 2018 - My relative has cancer, should I worry? Encouraging cascade genetic testing
September 20, 2018 - Investigators determine specific treatable traits that can predict future asthma attacks
September 20, 2018 - More doctor visits can lower risk of suicide attempts in fibromyalgia patients
September 20, 2018 - Computer avatars play role in diagnosis of dementia
September 20, 2018 - Addition of CTLA4 targeted therapy to PD-1 targeted therapy may benefit patients with ovarian cancer
September 20, 2018 - ASPREE trial explores whether low dose aspirin can prolong good health in elderly people
September 20, 2018 - ATS publishes new guideline focused on weight loss strategies for sleep apnea patients
September 20, 2018 - The Current issue of “The view from here” is concerned with Drug Delivery
September 19, 2018 - Sleep apnea could favour tumor growth at young ages
September 19, 2018 - Stealth vaping fad hidden from parents, teachers
September 19, 2018 - Witnessing school violence linked to later risk of psycho-social and academic impairment
September 19, 2018 - Common household cleaners could make children overweight by changing gut microbiota
September 19, 2018 - Salk research in yeast leads to serendipitous finding about hypomyelinating leukodystrophy
September 19, 2018 - Study: Overweight or obese women may have increased risk of urinary incontinence
September 19, 2018 - Study shows how cellular waste disposal processes also promote inflammation
September 19, 2018 - New multidisciplinary microsurgery microscope, PROVIDO, introduced by Leica
September 19, 2018 - Phase 2b STORM Data Evaluating Selinexor in Patients with Penta-Refractory Multiple Myeloma Presented at the Society of Hematologic Oncology 2018 Annual Meeting
September 19, 2018 - Decisions recruiting gut feelings seen as reflection of true self, more assuredly held, study says
September 19, 2018 - How AI can improve end-of-life care
September 19, 2018 - UNIST and Ulsan initiate research collaboration to develop human organs-on-chips
September 19, 2018 - Study highlights key role of migrating shoals of fish in sustaining deep-ocean microorganisms
September 19, 2018 - Disagreeable individuals can benefit most from behaving more compassionately, finds study
September 19, 2018 - Janssen Submits New Drug Application to U.S. FDA Seeking Approval of Erdafitinib for the Treatment of Metastatic Urothelial Cancer
September 19, 2018 - Neuroplasticity is increased but dysregulated in the aging brain, study finds
September 19, 2018 - Suicide: A public health crisis
September 19, 2018 - Infants using popular anti-reflux medicines are not at increased risk of lung infections
September 19, 2018 - Stanford team will participate in NIH-funded study of tobacco policies | News Center
September 19, 2018 - Women with high levels of anti-Müllerian hormone more likely to develop breast cancer
September 19, 2018 - Researchers use larval zebrafish model to reveal role of locus coeruleus in anesthesia
September 19, 2018 - Effects of prematurity found to be more severe for the brains of males than females
Producing Super-Swelled Lyotropic Crystals for Drug Development

Producing Super-Swelled Lyotropic Crystals for Drug Development

image_pdfDownload PDFimage_print

What are lyotropic liquid crystals? How are they used in drug development?

Liquid crystals are state of matter that have properties of liquids and crystals. There are several types of liquid crystal materials. There are some that change their properties as a response to temperature, called thermotropic liquid crystals, and others that change in response to a solvent. These are called lyotropic liquid crystals and in most cases the solvent is water.

Liposomes. Credit: RomanenkoAlexey/Shutterstock.com

Lyotropic liquid crystals are used in drug development because they are liquids, however, they do have some crystalline properties. There useful in drug development as they can be organized into structures that are ideal to encapsulate drugs and other bioactive molecules.

Lyotropic liquid crystals are used because they remain stable in water, which makes up a large percentage of the human body. Aqueous structures are essential for drug delivery in vivo, which is why lyotropic liquid crystals are so useful.

What methodologies have been used to produce lyotropic liquid crystals for drug development in the past?

Liposomes are the most used lyotropic liquid crystal for drug development. They are characterized by a membrane sphere with water and the target drug inside. The way drugs are developed using this method is complex.

You start with a lyotropic liquid crystal, which is a bilayer, or lamellar phase, that looks very much like sheets of a cell membrane. Then, you apply a technique to make little particles come out of the crystal. Following this, you add water and agitate the membrane. This causes the crystal to close-up into spheres with water on the inside; where the drug will go.

However, there are alternative methods. One example is bicontinuous cubic phases, which are three-dimensional objects that have lots of pores. The discovery of bicontinuous cubic phases got scientists thinking, “Well instead of just making liposomes, we can make other types of particles with other types of structures, and that might be beneficial”.

Due to their highly porous nature, these structures can, in theory, hold a larger amount of cargo than liposomes, making them superior structures for drug delivery. But to this day, liposomes are still the leading lyotropic liquid crystal used in drug delivery. This is because bicontinuous cubic phases are difficult to process and their pores are too small.

What are the limitations of the current methods used to produce lyotropic liquid crystals? Why is it important that new methods are developed?

Liposomes are great and very useful, but there are certain drugs that can crystallize inside them. If you have a method that uses a perforated membrane like bicontinuous cubic phases, larger, more complex drugs can be delivered, as the structure has an increased surface to volume ratio.

Another limitation of liposomes is that the drugs need to be soluble. This is a problem for hydrophobic drugs that won’t go into the water domain. They will want to go into the hydrophobic core of the membrane.

In liposomes you only have one membrane that encloses the drug. If you have other phases, like bicontinuous cubic phases, where the particle is made up of perforated membranes that allow the water to enter pores, you have a particle that is a continuum of water and fat everywhere.

If a liposome is, say, 200 nanometers, then those 200 nanometers are mostly made up of water. With bicontinuous cubic phases, you have tons of membranes that are continuous in both polar and hydrophobic domains. This means you can encapsulate drugs that are both water soluble and not water insoluble.

Then there are other advantages. For example, bicontinuous cubic phases are known to have a preferential interaction with cell membranes, allowing easier delivery of drugs into cells of the body.

Please outline your recent research involving lyotropic liquid crystals.

Traditionally, lyotropic liquid crystals had pores that are really small, only about three nanometers. So, there was a limit of what kind of drugs or proteins you could encapsulate within them. Our recent findings describe a new processing technique that allowed us to expand those pores to five times larger than previous methods, so they are now around 15 nanometers in size.

Dr. Cecilia Leal holding a 3D printed model of a super-swelled bicontinuous cubic phase monocrystal

Why are super-swelled lyotropic monocrystals such an advancement?

The first advancement was that we could make these materials with larger pores than ever before. The second was that the materials that we had generated were extremely stable for months. This is because, instead of existing as a collection of membranes, the liquid crystals had formed a monocrystal with extremely large pores.

Typically, if you do anything with membranes, or soft materials in general, you have these small unit cells or these small crystals or micro crystallites that appear. They are the size of a micron and are randomly oriented in all directions in solution.

We’ve found that if you let these highly porous membranes rest for a few months, they develop into a single crystal that is more than one cubic millimeter. It’s no longer micrometer size, its macro size; you can see it with the human eye.

What’s surprising to us is that, the crystal is still able to hold a lot of water. It’s 90% water, and is still soft but is also a crystalline shape like a diamond. That was very surprising to us. Not only that it is super swollen, but that it was also incredibly well-organized.

Whilst this might not be useful for drug development, it may be useful for protein crystallization. This has actually been used in a recent paper for Nature Communications. The researchers used our method to encapsulate the Gloeobacter ligand-gated ion channel protein (GLIC) when they crystallized it.

How did you find out that fast chloroform removal was crucial for producing lyotropic monocrystals?

If you want to develop a material using a mixture of liposomes or any form of lipid molecules, they first need to be solubilized in an organic solvent. The most commonly used solvent is chloroform, which is removed slowly and completely, creating the lyotropic liquid crystal. The addition of water turns the crystal into a liposome or bicontinuous cubic phase.

My student was working with some of these lipid mixtures, and was in a rush to move to the next step. This meant he removed the chloroform really fast. He then added the water and saw these super swollen phases develop.

He told me he’d messed up but when we looked, the solvent had been completely removed, so it was only the speed that differed, as it is usually done very slowly. He then started working on this method, comparing the size of the phases that develop from a slow, medium and fast speed of chloroform extraction.

He found that when you add water then the size of the pores that develop are a function of the speed at which the solvent is removed.  If you do this slowly you get the regular size, and if you do fast you get these super swollen phases.

We assumed it was a kinetic effect that wouldn’t be stable. But, it was stable, not thermodynamically, but it was stable. We let it sit for six months and found that not only was it still stable, it was actually more organized.  

In fact, liposomes are not thermodynamically stable either. They are formed via kinetic traps that are stable when you need to apply them but not thermodynamically, therefore this is not a limitation of our discovery. It’s been a year since we first discovered this method and our sample is still in the lab today.

What applications are there for super-swelled lyotropic monocrystals? What impact will the new methodology have on research?

I think the major applications of our research will be in protein crystallization. This is important because this is at the forefront of research, with the development of useful technologies such as Cryo-EM and imaging techniques to determine protein structure.

The leading technology to determine protein structure is crystallography. The limitations of current techniques are that most proteins are difficult to crystallize. Before our discovery, the number of proteins that you could crystallize was very limited. This was because the pores were so small that are only a handful of proteins could be crystallized.

In the future, do you think super-swelled lyotropic monocrystals will be routinely used in research and drug development?

Yes, I hope so. The good thing about the method is that it is a relatively easy processing technique, meaning it is accessible to many scientists. It is also a reliable technique as the materials themselves are highly flexible. For example, let’s say you want to use a cocktail of three different lipids that target a specific cell type, with this method, you could use any lipid as long as you removed the solvent fast.

I think that it will have a big impact. However, the widespread use of new techniques take time. People are very used to working with liposomes and they are more familiar than other more complicated structures.

Where can readers find more information?

  • Dr. Cecilia Leal’s profile for The University of Illinois
  • The Leal Research group
  • Zabara, A., Chong, J., Martiel, I., Stark, L., Cromer, B., Speziale, C., Drummond, C. and Mezzenga, R. (2018). Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains. Nature Communications.

About Dr. Cecília Leal

Cecília Leal is an Assistant Professor in the Department of Materials Science and Engineering and the Frederick Seitz Materials Research Laboratory at the University of Illinois, Urbana-Champaign. She graduated in Industrial Chemistry from Coimbra University in Portugal before moving to Sweden to do a PhD in physical chemistry at Lund University, supervised by Professor Wennerström.

After working for a year in the Norwegian Radium Hospital, she joined Professor Safinya’s Lab at the University of California, Santa Barbara, as a postdoctoral fellow.

Her research interests focus on the characterization and functionalization of lipid materials for cellular delivery. She is the recipient of the National Institutes of Health New Innovator award (2016), the National Science Foundation CAREER award (2016), and the University of Illinois Dean’s Award of Excellence in Research (2018).

Tagged with:

About author

Related Articles