New light-controlled therapies could be a next step in treatment for retinal diseases. Image source: Paul Morris
New research published within Scientific Reports details an especially compelling breakthrough within the field of drug delivery: light-activated self-assembling microvesicles.1 All biologists are familiar with vesicle-based transport and drug delivery, but this research’s vesicles come with an important twist: light-activated cargo dispersal. Utilizing light as a trigger for drug delivery is uncharted ground within biotechnology. By linking drug release to light, a new era of retinal therapeutics is nigh. Future research seeking to use the principle of light-activated drug delivery will require powerful software tools which can handle the cutting edge.
The vesicles described by the new research can use light as a method of dose control and timed drug release in environments where measured release over time has been challenging to perfect. Many people may be skeptical, correctly identifying that light activated drug delivery is useless for most therapeutic indications. Most drugs are agnostic to light exposure because they aim to operate in the dark environment of the body’s internal organs. There are organs that are consistently exposed to light, however. The retinas, for example. Light activated microvesicles are a quantum leap forward in drug delivery because they can function in the notoriously difficult environment of the retina.2
Retinal drug delivery is extremely challenging due to the blood-retinal-barrier, inconsistent surface moisture, and the difficulties of transfusion at the retinal surface. Under the best of conditions, simulating the pharmacokinetics of drugs delivered to the retina is difficult, and requires a sophisticated software suite which can handle all of the many physical and biological variables involved.
Microvesicles have been an area of great interest for their potential applications in drug delivery for some time now.3 Though microvesicles themselves are still an area of active research, they have a number of properties which makes them a desirable jumping off point for drug delivery research. The largest advantages of microvesicles is that they are physiologically common and quite simple to generate ex vivo as well as in vitro, as noted by the authors of the newly published research.
Microvesicles perform a variety of functions within cells, and are created intracellularly by budding off of plasma membranes.4 This means that microvesicles are unlikely to stimulate an immune response which would lead to undesirable inflammation or premature degradation. As a further benefit, microvesicles are easily targetable by antibodies, meaning that it’s easy to confirm their localization to the proper area of the targeted tissue.
Finally, microvesicles are suitable for use in the retina because they are impermeable to water soluble molecules as well as most ions. The retinal environment is accustomed to encountering lipids from tears, and astute observers will note that many commercial eye care products are in fact proprietary lipid mixtures.5 Microvesicles will require an extensive safety testing period in silico, in vitro, and in vivo before making it into a clinical regimen where they can deliver a drug.
Flipping the Light Switch to Deliver Drugs
The new research’s primary innovation builds off of previous research on self-assembling artificial vesicles. The prior research found that the dynamic surface tension of cationic vesicles was decreased when exposed to ultraviolet radiation and visible light.6 This property was explored further, and found to be a result of reversible trans- to cis- isomerization—the same mechanism which enables the microvesicles’ self-assembly. Researchers interested in utilizing light-switchable microvesicles will need to model the biochemistry of the vesicle to ensure that the drug product is reliably disbursed.
During each isomerization, some of the microvesicle’s cargo escapes through the membrane due to its temporarily reduced surface tension; and voila, the drug has been delivered successfully. The light driven isomerization of microvesicles occurs at a stochastically predictable rate contingent on the intensity of light, allowing for the drug product to be delivered smoothly over a long period of time. Accurately modeling the actual rate of drug release and pharmacokinetic effect of the drug product on target tissues will require an additional layer of sophistication due to the features of the microvesicle, however.
Making a Microvesicle with a Light Switch
Microvesicles are unique in that they can be formed via simple chemical techniques or via careful engineering and production in small batches of transgenic cells. While the creators of the light-sensitive microvesicles opted for the simpler chemical technique, it won’t be sufficient for downstream clinical applications because chemical assemblies lack a way to fine tune microvesicle structure and formation. Researchers have opted to simulate microvesicles in the past for the purposes of membrane engineering, and will continue to do so when developing therapies using the “light switch” equipped microvesicles.7
The assembly and use of microvesicles will require simulating a few levels of organization:
- The small molecule drug product itself to be encapsulated
- The microvesicle’s phospholipid bilayer raft self-assembly
- The drug product’s initial encapsulation into the microvesicle
- The phospholipid bilayer’s resting and excited energy states in both isomerization conditions
- The phospholipid bilayer’s isomerization shift and resultant membrane surface tension disruption
- The drug product’s electrostatic interactions with the phospholipid bilayer in each isomerization state
- The microvesicle’s membrane interactions or fusing with the membrane of the target cells within the retina
- The microvesicle’s membrane interaction and integrity in the context of the aqueous retinal microenvironment
- The drug product’s ability to squeak through areas of the microvesicle’s membrane undergoing an isomerization shift into the target cell and through its membrane
Light-activated Microvesicles Enable New Drug Products
These informatics issues are only the beginning. Biochemical simulations of the drug’s delivery via the light-triggered isomerization shift don’t prove anything about the actual efficacy of the drug product itself. Given that the retina has been somewhat inaccessible to researchers and clinicians until recently, it’s likely that microvesicle-based drug delivery will spur research into new retinal small molecule therapies. A next generation informatics suite will be instrumental in integrating the unique biochemical modeling challenges of developing light-triggered microvesicles with the traditional drug testing and development cycle.
Designed to Cure can handle the complex world of light-triggered microvesicles intended for use as drug delivery vehicles. Using Designed to Cure, managing the planning, production, evaluation, and iteration of microvesicle constructs is in stride. Contact us today to find out how we can help you break open the field of light-triggered retinal therapies.
- “A Light-Responsive Self-Assembly Formed by a Cationic Azobenzene Derivative and SDS as a Drug Delivery System.” January 2017, http://www.nature.com/articles/srep39202 ↩
- “Novel approaches to retinal drug delivery.” August 2007, http://www.tandfonline.com/doi/abs/10.1517/17425247.4.4.371 ↩
- “Microvesicles and exosomes: Opportunities for cell-derived membrane vesicles in drug delivery.” November 2011, http://www.sciencedirect.com/science/article/pii/S0168365911010741 ↩
- “Membrane Microparticles: Two Sides of the Coin.” January 2005, http://physiologyonline.physiology.org/content/20/1/22.long ↩
- “Comparison of novel lipid-based eye drops with aqueous eye drops for dry eye: a multicenter, randomized controlled trial.” September 2014, https://www.dovepress.com/comparison-of-novel-lipid-based-eye-drops-with-aqueous-eye-drops-for-d-peer-reviewed-article-OPTH ↩
- “Self-assembly of light-sensitive surfactants.” 2005, http://pubs.rsc.org/en/Content/ArticleLanding/2005/SM/b510877m ↩
- “Molecular Dynamics Simulation of the Formation, Structure, and Dynamics of Small Phospholipid Vesicles.” 2003, http://pubs.acs.org/doi/abs/10.1021/ja0352092 ↩