Mark E. Byrne

Molecular imprinting within hydrogels

Hydrogels have been used primarily in the pharmaceutical field as carriers for delivery of various drugs, peptides and proteins. These systems have included stimuli-responsive gels that exhibit reversible swelling behavior and hence can show modulated release in response to external stimuli such as pH, temperature, ionic strength, electric field, or specific analyte concentration gradients. The focus of this article is to review molecular imprinting within hydrogels and discuss recent efforts on analyte-responsive intelligent gels, specifically suggesting the possibility of utilizing molecular imprinting strategies to impart analyte specificity and responsiveness within these systems. Molecular imprinting is an emerging field that produces precise chemical architecture that can bind analytes and differentiate between similar molecules with enantiomeric resolution. On the forefront of imprinting gel systems are intelligent, stimuli-sensitive imprinted gels that modify their swelling behavior and in turn modulate their analyte binding abilities. We discuss the challenges creating an imprinting effect in hydrogels and the possibilities of using molecularly imprinted mechanisms within controlled release gels.

Therapeutic RNA aptamers in clinical trials

RNA aptamers can fold into complex structures and bind with high affinity and selectivity to various macromolecules, viruses, and cells. They are isolated from a large pool of nucleic acids by a conceptually straightforward iterative selection process called SELEX. Aptamers have enormous potential as therapeutics due to their ability to bind to proteins and specifically inhibit their functions with minimal or no harmful side-effects. The first aptamer therapeutic was FDA approved in 2005 and a number of novel aptamer-based therapeutics are currently undergoing clinical trials for treating diseases such as macular degeneration, choroidal neovascularization, intravascular thrombus, acute coronary syndrome, von Willebrand factor related disorders, von Hippel-Lindau syndrome (VHL), angiomas, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer, thrombotic thrombocytopenic purpura, and several others. In this review, we present aptamers in on-going, completed, and terminated clinical studies highlighting their mechanism of action as well as the inherent challenges of aptamer production and use.

Molecular imprinting within hydrogels II : Progress and analysis of the field

In the past decade, there has been an exponential increase in the number of papers describing molecular imprinting in hydrogels, a technique which creates memory for template molecules within a flexible macromolecular structure. Macromolecular memory or structural plasticity of polymer chains is a superior description of weakly crosslinked imprinted networks since significant flexibility can occur within the polymer chains. The focus of this article is to review and highlight work in the field describing the imprinting strategy within hydrogels and associated challenges, characterization methods of imprinted gels, current and potential translational applications, and future strategies and directions. This paper also describes ways to improve binding parameter efficacy and presents significant areas of opportunity to further describe, characterize, and understand imprinted gels. An analysis of the literature indicates that imprinting in hydrogels leads to significant improvements in template affinity, capacity, and selectivity over non-templated hydrogels for a number of templates such as ions, small and moderate molecular weight molecules, proteins, viruses, DNA, and cells. However, the influence of imprinting on the transport of template is much more complex, with little attention of most studies to structural analysis or discussion of the gel porosity/tortuosity in the control of template transport. Responsive, intelligent imprinted hydrogels are also highlighted that exhibit reversibly modulated template binding and transport. It is clear that this field has transitioned from infancy and is leading to breakthroughs in a number of areas such as controlled and modulated drug delivery, diagnostic sensors, and separation. For example in drug delivery, imprinting can lead to delayed transport and provides further control of therapeutic transport through the macromolecular structure as well as optimizes the number of therapeutic molecules to polymer chains.

Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses.

Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 μg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 μg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses.

Injectable nanomaterials for drug delivery: Carriers, targeting moieties, and therapeutics

Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed.

Sustained in vivo release from imprinted therapeutic contact lenses.

In this paper, we demonstrate the successful in vivo extended release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug is maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. Poly(HEMA-co-AA-co-AM-co-NVP-co-PEG200DMA) soft contact lenses were prepared (100±5 μm thickness, diameter 11.8 mm, power zero), and a constant tear film concentration of 170±30 μg/mL was measured for up to 26 hrs in a New Zealand white rabbit model. The results showed a dramatic increase in ketotifen mean residence time (MRT) and bioavailability compared to topical drop therapy and drug soaked lenses. The MRT for imprinted lenses was 12.47±3.99 hrs, ~4 and 50 fold greater than non-imprinted lenses and 0.035% eye drops (Zaditor®), respectively. Furthermore, AUC(0-26 hrs) was 9 and 94 fold greater for imprinted lenses than non-imprinted lenses and eye drops, respectively. The results indicate that molecular imprinting provides an exciting rational engineering strategy for sustained release. It is clear that imprinted lenses are very promising combination devices and are much more effective and efficient delivery devices than eye drops.

Molecularly imprinted therapeutic contact lenses

Importance of the field: There exists a considerable unmet need for more efficacious delivery of ocular therapeutics. Contact lenses have been developed with high loading and controllable sustained release to overcome limited patient compliance and significant ocular transport limitations. This can best be achieved by extending and controlling the residence time of drugs on the eye surface and thereby limiting drug loss by lacrimation, drainage and non-productive absorption. Areas covered in the review: Within hydrogels, molecular imprinting can be used to create memory for template molecules embedded within a flexible macromolecular network. Control in therapeutic loading and delay of release have been demonstrated with careful attention to the functional monomer/template ratio, the diversity of functional monomers, and the polymer backbone and network structure. Experimental work has also confirmed that macromolecular memory and not structural differences or phenomena are responsible for delayed drug release kinetics compared with non-imprinted systems. A therapeutically relevant amount of drug can be loaded for release to occur over multiple days, which allows the technique to be applied to daily-wear and extended-wear contact lenses. What the reader will gain: The focus of this article is to review the emerging field of molecularly imprinted contact lenses and highlight significant accomplishments, trends, as well as future strategies and directions. Take home message: In the past 8 years, molecular imprinting has been used to produce therapeutic contact lenses with enhanced loading and delayed release. Progress in the field has mostly included low-molecular-weight therapeutics such as anti-glaucoma, antihistamine, antibiotic and anti-inflammatory therapeutics used to treat anterior eye disorders. Recently, high molecular weight comfort molecules have also been successfully demonstrated. Current methods can produce lenses of suitable thickness, water content, and mechanical and optical properties compared with commercial lenses on the market today.

In vitro controlled release of an anti-inflammatory from daily disposable therapeutic contact lenses under physiological ocular tear flow

Novel molecularly imprinted, therapeutic contact lenses capable of controlled release of the non-steroidal anti-inflammatory (NSAID) diclofenac sodium were synthesized, exploiting ionic non-covalent interactions. Poly(HEMA-co-DEAEM-co-PEG200DMA) soft contact lenses were prepared (105±5 μm thickness, diameter 15.0±0.2mm, base curve of 8.6±0.2mm) with different monomer to template ratios and dynamic release studies were conducted in artificial lacrimal solution using two different in vitro methods. Under infinite sink conditions, imprinted contact lenses demonstrated concentration dependent release kinetics. Under physiological flow rates, by increasing the M/T ratio from 1 to 10.5, the release rate decreased from 11.72 μg/h to 6.75 μg/h during the first 48 h. The release rate was more constant, moving toward zero-order release. To use these lenses as daily disposable lenses, the first 24h of release was studied and found to be linear with a rate of 17.27, 11.99, and 8.74 μg/h for M/T ratios of 1, 3.5, and 10.5, respectively. Furthermore, the lenses prepared with a M/T ratio of 10.5 released diclofenac at a rate close to the maximum dose delivered by commercial eye drops, making them ideal for use as daily disposable lenses, and potentially leading to better patient benefit with substantially increased efficacy.

Controlled drug release from contact lenses: a comprehensive review from 1965-present

This review covers the progress within the field of drug releasing contact lenses since 1965. It highlights the enormous potential of controlled release mechanisms and offers a comprehensive, comparative review of lenses, drugs, methods, drug loading, drug delivery rate, and release duration. Methods have included molecular imprinting as well various forms of mediated release via carriers, surfactants, inclusion complexes, and molecular barriers. Drug-soaked lens were the earliest releasing lenses, but they offer very little control over the release profile with low drug loading, are characterized by decaying, Fickian release rates, and typically reach completion in a very short amount of time. Molecular imprinting is consistently one of the most promising and versatile methods of enhanced drug loading and extended release with tailorable control over release rate when factors are balanced such as lens thickness, material, and release media and conditions.

Challenges and solutions in topical ocular drug-delivery systems

Vision significantly affects quality of life and the treatment of ocular disease poses a number of unique challenges. This review presents the major challenges faced during topical ocular drug administration and highlights strategies used to overcome the natural transport barriers of the eye. The circulation of tear fluid and aqueous humor decrease the residence time of topically delivered drugs, while ocular barriers in the corneal and conjuctival epithelia and the retinal pigment epithelium limit transport. Successful treatment strategies increase the residence time of drugs in the eye and/or enhance the ability of the drug to penetrate the ocular barriers and reach the target tissue. In this review, we discuss several drug-delivery strategies that have achieved clinical success or demonstrate high potential. We also draw attention to a number of excellent reviews that explore various ocular drug-delivery techniques in depth. Finally, we highlight cutting-edge drug-delivery technologies that improve the efficacy of current drug-delivery methods or use proven techniques to deliver novel therapeutics.