Below, find all the information on articles and publications from the ORBITAL Early Stage Researchers.

  • Ocular Disorders and Associated Drug Development Challenges: The Current Scenario
    D. Mishra, S. Gade, T. R. R. Singh, Ocular Disorders and Associated Drug Development Challenges: The Current Scenario (2020).

    • Vision is one of the most important human sense and hence eye diseases leading to impairment of vision have been the hot topic for drug delivery research lately. Diseases like glaucoma, cataract, age-related macular degeneration, diabetic retinopathy and trachomatous trichiasis have been known for their potential of visual impairment as well as blindness. A vast amount of research has been done in understanding the pathophysiology, risk factors and drug development and drug delivery challenges associated with these diseases, but the clinical success achieved so far is very sparse. This leading to the requirements for the better understanding of the ocular diseases which can be translated to better drug delivery systems. The current review is formulated with the aims to provide a concise summary of these ocular disorders and to address the challenges in their drug development research.
  • Therapeutic Ophthalmic Lenses: A Review
    Toffoletto, N.; Saramago, B.; Serro, A.P. Therapeutic Ophthalmic Lenses: A Review. Pharmaceutics 2021, 13, 36.

    • An increasing incidence of eye diseases has been registered in the last decades in developed countries due to the ageing of population, changes in lifestyle, environmental factors, and the presence of concomitant medical conditions. The increase of public awareness on ocular conditions leads to an early diagnosis and treatment, as well as an increased demand for more effective and minimally invasive solutions for the treatment of both the anterior and posterior segments of the eye. Despite being the most common route of ophthalmic drug administration, eye drops are associated with compliance issues, drug wastage by lacrimation, and low bioavailability due to the ocular barriers. In order to overcome these problems, the design of drug-eluting ophthalmic lenses constitutes a non-invasive and patient-friendly approach for the sustained drug delivery to the eye. Several examples of therapeutic contact lenses and intraocular lenses have been developed, by means of different strategies of drug loading, leading to promising results. This review aims to report the recent advances in the development of therapeutic ophthalmic lenses for the treatment and/or prophylaxis of eye pathologies (i.e., glaucoma, cataract, corneal diseases, or posterior segment diseases) and it gives an overview of the future perspectives and challenges in the field.
  • Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review
    Thareja, A.; Hughes, H.; Alvarez-Lorenzo, C.; Hakkarainen, J.J.; Ahmed, Z. Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review. Pharmaceutics 2021, 13, 276. https://doi.org/10.3390/pharmaceutics13020276

    • There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy.
  • Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation
    González-Fernández, F.M.; Bianchera, A.; Gasco, P.; Nicoli, S.; Pescina, S. Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics 2021, 13, 447. https://doi.org/10.3390/pharmaceutics13040447

    • Nanotherapeutics based on biocompatible lipid matrices allow for enhanced solubility of poorly soluble compounds in the treatment of ophthalmic diseases, overcoming the anatomical and physiological barriers present in the eye, which, despite the ease of access, remains strongly protected. Micro-/nanoemulsions, solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) combine liquid and/or solid lipids with surfactants, improving drug stability and ocular bioavailability. Current research and development approaches based on try-and-error methodologies are unable to easily fine-tune nanoparticle populations in order to overcome the numerous constraints of ocular administration routes, which is believed to hamper easy approval from regulatory agencies for these systems. The predictable quality and specifications of the product can be achieved through quality-by-design (QbD) implementation in both research and industrial environments, in contrast to the current quality-by-testing (QbT) framework. Mathematical modelling of the expected final nanoparticle characteristics by variation of operator-controllable variables of the process can be achieved through adequate statistical design-of-experiments (DoE) application. This multivariate approach allows for optimisation of drug delivery platforms, reducing research costs and time, while maximising the understanding of the production process. This review aims to highlight the latest efforts in implementing the design of experiments to produce optimised lipid-based nanocarriers intended for ophthalmic administration. A useful background and an overview of the different possible approaches are presented, serving as a starting point to introduce the design of experiments in current nanoparticle research.
  • Microneedle array systems for long-acting drug delivery
    Lalit K. Vora, Kurtis Moffatt, Ismaiel A. Tekko, Alejandro J. Paredes, Fabiana Volpe-Zanutto, Deepakkumar Mishra, Ke Peng, Raghu Raj Singh Thakur, Ryan F. Donnelly, Microneedle array systems for long-acting drug delivery, European Journal of Pharmaceutics and Biopharmaceutics, Volume 159, 2021, Pages 44-76, ISSN 0939-6411,
    https://doi.org/10.1016/j.ejpb.2020.12.006.

    • The development of microneedles (MNs) assisted drug delivery technologies have been highly active for more than two decades. The minimally invasive and self-administered MN technology bypasses many challenges associated with injectable drug delivery systems, by delivering the therapeutic materials directly into the dermal and ocular space and allowing the release of the active ingredient in a sustained or controlled manner. Different types of MNs (biodegradable solid/dissolving MNs and nanoparticle loaded/coated polymeric MNs or delivery by hollow MNs) have been envisioned for long-acting sustained delivery of therapeutic payloads, with the aim of reducing the side effects and administration frequency to improve the patient compliance. In this review, we covered the different types of MNs loaded with different nano/biotherapeutics for long-acting delivery for a wide range of potential clinical applications. We also outlined the future development scenario of such long-acting MN delivery systems for different disease conditions to achieve improved clinical benefit. Finally, we discussed the challenges lie ahead to realize the full potential of sustained-release long-acting MNs in the clinic.
  • Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release
    Pereira-da-Mota, A.F.; Vivero-Lopez, M.; Topete, A.; Serro, A.P.; Concheiro, A.; Alvarez-Lorenzo, C. Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release. Pharmaceutics 2021, 13, 606. https://doi.org/10.3390/pharmaceutics13050606

    • Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; KN/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseases.
  • Asymmetry in Drug Permeability through the Cornea
    Toffoletto, N.; Chauhan, A.; Alvarez-Lorenzo, C.; Saramago, B.; Serro, A.P. Asymmetry in Drug Permeability through the Cornea. Pharmaceutics 2021, 13, 694. https://doi.org/10.3390/pharmaceutics13050694

    • The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.
  • Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease
    Kumari, S.; Dandamudi, M.; Rani, S.; Behaeghel, E.; Behl, G.; Kent, D.; O’Reilly, N.J.; O’Donovan, O.; McLoughlin, P.; Fitzhenry, L. Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease. Pharmaceutics 2021, 13, 905. https://doi.org/10.3390/pharmaceutics13060905

    • Dry eye disease (DED) or keratoconjunctivitis sicca is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction. Symptoms include dryness, irritation, discomfort and visual disturbance, and standard treatment includes the use of lubricants and topical steroids. Secondary inflammation plays a prominent role in the development and propagation of this debilitating condition. To address this we have investigated the pilot scale development of an innovative drug delivery system using a dexamethasone-encapsulated cholesterol-Labrafac™ lipophile nanostructured lipid carrier (NLC)-based ophthalmic formulation, which could be developed as an eye drop to treat DED and any associated acute exacerbations. After rapid screening of a range of laboratory scale pre-formulations, the chosen formulation was prepared at pilot scale with a particle size of 19.51 ± 0.5 nm, an encapsulation efficiency of 99.6 ± 0.5%, a PDI of 0.08, and an extended stability of 6 months at 4 °C. This potential ophthalmic formulation was observed to have high tolerability and internalization capacity for human corneal epithelial cells, with similar behavior demonstrated on ex vivo porcine cornea studies, suggesting suitable distribution on the ocular surface. Further, ELISA was used to study the impact of the pilot scale formulation on a range of inflammatory biomarkers. The most successful dexamethasone-loaded NLC showed a 5-fold reduction of TNF-α production over dexamethasone solution alone, with comparable results for MMP-9 and IL-6. The ease of formulation, scalability, performance and biomarker assays suggest that this NLC formulation could be a viable option for the topical treatment of DED.
  • Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema
    Toffoletto, N.; Salema-Oom, M.; Anguiano Igea, S.; Alvarez-Lorenzo, C.; Saramago, B.; Serro, A.P. Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema. Pharmaceutics 2021, 13, 976. https://doi.org/10.3390/pharmaceutics13070976

    • Pseudophakic cystoid macular edema (PCME), caused by chronic inflammation, is the most common cause of visual impairment in the medium-term after cataract surgery. Therefore, the prophylactic topical administration of combined steroidal and non-steroidal anti-inflammatory drugs is commonly done. Drug-eluting intraocular lenses (IOLs) gained interest as an efficient way to overcome the compliance issues related to the use of ocular drops without the need for additional surgical steps. The incorporation of functional monomers and molecular imprinting were herein applied to design hydrogels suitable as IOLs and able to co-deliver steroidal (dexamethasone sodium phosphate) and non-steroidal (bromfenac sodium) drugs. The incorporation of N-(2-aminopropyl) methacrylamide (APMA) increased the drug uptake and improved the in vitro release kinetics. Imprinting with bromfenac resulted in a decreased drug release due to permanent drug bonding, while imprinting with dexamethasone increased the amount of dexamethasone released after dual-drug loading. The application of a mathematical model to predict the in vivo drug release behavior suggests the feasibility of achieving therapeutic drug concentrations of bromfenac and dexamethasone in the aqueous humor for about 2 and 8 weeks, respectively, which is compatible with the current topical prophylaxis after cataract surgery.
  • Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells
    Natalia Carballo-Pedrares, Axel Kattar, Angel Concheiro, Carmen Alvarez-Lorenzo, Ana Rey-Rico, Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells, Materials Science and Engineering: C, Volume 128, 2021, 112307, ISSN 0928-4931, https://doi.org/10.1016/j.msec.2021.112307.

    • Gene transfer to mesenchymal stem cells (MSCs) has arisen as a powerful approach to increase the therapeutic potential of this effective cell population. Over recent years, niosomes have emerged as self-assembled carriers with promising performance for gene delivery. The aim of our work was to develop effective niosomes-based DNA delivery platforms for targeting MSCs. Niosomes based on 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA; 0, 7 or 15%) as cationic lipid, cholesterol as helper lipid, and polysorbate 60 as non-ionic surfactant, were prepared using a reverse phase evaporation technique. Niosomes dispersions (filtered or not) and their corresponding nioplexes with a lacZ plasmid were characterized in terms of size, charge, protection, and complexation abilities. DOTMA concentration had a large influence on the physicochemical properties of resulting nioplexes. Transfection efficiency and cytotoxic profiles were assessed in two immortalized cell lines of MSCs. Niosomes formulated with 15% DOTMA provided the highest values of β-galactosidase activity, being similar to those achieved with Lipofectamine®, but showed less cytotoxicity. Filtration of niosomes dispersions before adding to the cells resulted in a loss of their biological activities. Storage of niosomes formulations (for 30 days at room temperature) caused minor modification of their physicochemical properties but also attenuated the transfection capability of the nioplexes. Differently, addition of the lysosomotropic agent sucrose into the culture medium during transfection or to the formulation itself improved the transfection performance of non-filtered niosomes. Indeed, steam heat-sterilized niosomes prepared in sucrose medium demonstrated transfection capability.
  • Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment
    Axel Kattar, Angel Concheiro & Carmen Alvarez-Lorenzo (2021) Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment, Expert Opinion on Drug Delivery, DOI: 10.1080/17425247.2021.1953466

    • Introduction: Diabetes is a pandemic disease that causes relevant ocular pathologies. Diabetic retinopathy, macular edema, cataracts, glaucoma, or keratopathy strongly impact the quality of life of the patients. In addition to glycemic control, intense research is devoted to finding more efficient ocular drugs and improved delivery systems that can overcome eye barriers. Areas covered: The aim of this review is to revisit first the role of diabetes in the development of chronic eye diseases. Then, commercially available drugs and new candidates in clinical trials are tackled together with the pros and cons of their administration routes. Subsequent sections deal with self-assembled drug carriers suitable for eye instillation combining patient-friendly administration with high ocular bioavailability. Performance of topically administered polymeric micelles, liposomes, and niosomes for the management of diabetic eye diseases is analyzed in the light of ex vivo and in vivo results and outcomes of clinical trials. Expert opinion: Self-assembled carriers are being shown useful for efficient delivery of not only a variety of small drugs but also macromolecules (e.g. antibodies) and genes. Successful design of drug carriers may offer alternatives to intraocular injections and improve the treatment of both anterior and posterior segments diabetic eye diseases.
  • From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment
    Dammak, Azza, Fernando Huete-Toral, Carlos Carpena-Torres, Alba Martin-Gil, Cristina Pastrana, and Gonzalo Carracedo. 2021. “From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment” Pharmaceutics 13, no. 9: 1376. https://doi.org/10.3390/pharmaceutics13091376

    • Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies.

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