Light-responsive systems for ocular drug delivery

Among the various routes of administration, ophthalmic drug delivery is particularly challenging regardless of the relatively simple accessibility of the eyes. Drug delivery to the posterior segment of the eye through periocular and intravitreal injections involve a high risk of complications e.g. inflammation, infection, and haemorrhage. Consequently, researchers have developed a variety of delivery systems to overcome these limitations. Stimuli responsive polymers are the focus of increasing attention as they undergo physical or chemical change in response to external or internal stimuli. Light is an attractive trigger for drug release because it can offer both spatial and temporal control based on parameters that can be adjusted with ease e.g. irradiation intensity, wavelength, and exposure duration, potentially via non/minimally invasive methods. Photo-cleavage can be accomplished either by UV, visible or NIR light, resulting in fast degradation of molecule structures and allowing on demand release of payloads. Photocleavable moieties enhance drug targeting abilities as the drug will remain inactive until reaching the site of action and irradiation of the correct wavelength will release the free active form of it. However, exploiting these valuable materials in the ocular delivery field has still not been fully accomplished. Accordingly, the purpose of the current work is to develop a platform for controlled drug delivery to intraocular tissues using light triggered DDS that exploits drug conjugates with immobilized photocleavable linkages e.g. o-nitrobenzyl (o-NB) derivative to polymer matrix. Here we report the synthesis of both light-responsive conjugates and investigation of drug release profiles. Complementary DDSs were designed to immobilize drug conjugates to polymers that would enable preparation of materials capable of targeting the intraocular compartment and triggering drug release with suitable light sources. Learning objective: Synthesis of Photocleavable moieties/drug moieties and light triggered release of payloads & application of in silico toxicity screening to polymer design

Poly(2-Hydroxyethyl Methacrylate) Hydrogel-Based Microneedles for Bioactive Release

Microneedle arrays are minimally invasive devices that have been extensively investigated for the transdermal/intradermal delivery of drugs/bioactives. Here, we demonstrate the release of bioactive molecules (estradiol, melatonin and meropenem) from poly(2-hydroxyethyl methacrylate), pHEMA, hydrogel-based microneedle patches in vitro. The pHEMA hydrogel microneedles had mechanical properties that were sufficiently robust to penetrate soft tissues (exemplified here by phantom tissues). The bioactive release from the pHEMA hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application in the transdermal delivery of bioactives (exemplified here by estradiol, melatonin and meropenem) for the treatment of various conditions

Phenolic Polymers as Model Melanins

Melanins are a class of conjugated biopolymers with varying compositions and functions, which have a variety of potential medical and technical applications. Here we examine the conjugated polymers derived from a variety of phenolic monomers (catechol (CAT), levodopa (DOPA) and homogentisic acid (HGA)), using a selection of different analytical chemistry techniques to compare their properties with a view to understanding structure-function relations. The polymers displayed measurable conductivity, with electronic properties tuned by the functional groups pendant on the polymer backbones (which served as dopants) suggesting their potential for application in electronic devices

Polymer hydrogel-based microneedles for metformin release

Drug delivery devices ensure the effective delivery of a broad range of therapeutics to millions of patients worldwide on a daily basis.1 Microneedles are a class of drug delivery device that provide pain free transdermal delivery with improved patient compliance.2-4 The release of metformin, a drug used in the treatment of cancer and diabetes, from polymer hydrogel-based microneedle patches was demonstrated in vitro. Tuning the composition of the polymer hydrogels enabled preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ca. 40 N). Swelling experiments conducted at 20°C, 35°C and 60°C show temperature dependent degrees of swelling and kinetics (Fickian diffusion). Drug release from the hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order, Korsmeyer-Peppas, Peppas-Sahlins), observing the best fit for the zero-order model. Such microneedles have potential application for transdermal delivery of metformin for the treatment of cancer and diabetes

Poly(2-Hydroxyethyl Methacrylate) Hydrogel-Based Microneedles for Metformin Release

The release of metformin, a drug used in the treatment of cancer and diabetes, from poly(2-hydroxyethyl methacrylate), pHEMA, hydrogel-based microneedle patches is demonstrated in vitro. Tuning the composition of the pHEMA hydrogels enables preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ≈40 N). Swelling experiments conducted at 20, 35, and 60 °C show temperature-dependent degrees of swelling and diffusion kinetics. Drug release from the pHEMA hydrogel-based microneedles is fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application for transdermal delivery of metformin for the treatment of aging, cancer, diabetes, etc

Stimuli-responsive biomaterials for drug delivery

Corneal neovascularization is one of the most severe ocular diseases. Current therapy is limited to repeated intraocular injections of antiangiogenic drugs, associated with significant side effects including infection, bleeding and retinal detachment. The work presented herein attempts to address these issues through the development of degradable and cytocompatible light responsive drug delivery systems. These biomaterials facilitate the delivery of therapeutic drugs and nucleic acids, with tuneable, on demand qualities, which highlights their potential for treating a variety of conditions. The translucency of eyes and advances in laser technology in ophthalmology make light-responsive delivery of drugs feasible. Importantly, light can be applied in a non-invasive fashion; therefore, light-triggered drug delivery systems have great potential for clinical application. Novel methacrylate-based photo-responsive polymers are reported here, demonstrating the ability to process them into spherical nanogels. The nanogels comprising an immobilized metformin photocage were shown to release a consistent amount of drug with temporal control when stimulated with light. These nanogels were optimized to release metformin with tailored profiles based on their chemical characteristics. In order to explore the potential for co-delivery of different drugs independently, synthesis of photocleavable drug cage with bathochromic shift was successfully accomplished and incorporated into nanogels. The resulted particles were shown to exhibit sequential wavelength dependent release profiles of ciprofloxacin and metformin in line with their irradiation with infrared light. Methacrylate nanogels suffer from compromised degradability due to the reduced labile groups in their polymer backbone. Therefore, our approach was to modify them via co-polymerization with cyclic ketene acetals via ring opening mechanism. The formulated nanogels displayed improved degradation potential with enzymatic treatment. This should diminish the prospects for inflammatory conditions, thus reducing possible impacts on the patient and the healthcare system. The prepared nanogels in these studies have been shown to generate cytocompatible and degradable polymers that can be processed into drug delivery system suitable for triggered release of payloads. These polymers demonstrated marked ability to suppress the formation of new blood vessels in an in vitro cell model for corneal neovascularization. This project encompasses novel materials utilising photocleavable units to enable stimuli-responsive drug delivery. A range of polymeric nanogels have demonstrated the ability to consistently release controlled amounts of loaded drugs in response to light triggering, which may enable suppression of neovascularization. We anticipate these nanogels will perform well in vivo by selecting the site of ocular administration and non-invasive irradiation with light and thereby improve patient compliance, which will be the subject of future studies

Light-responsive biomaterials for ocular drug delivery

Light-responsive biomaterials can be used for the delivery of therapeutic drugs and nucleic acids, where the tunable/precise delivery of payload highlights the potential of such biomaterials for treating a variety of conditions. The translucency of eyes and advances of laser technology in ophthalmology make light-responsive delivery of drugs feasible. Importantly, light can be applied in a non-invasive fashion; therefore, light-triggered drug delivery systems have great potential for clinical impact. This review will examine various types of light-responsive polymers and the chemistry that underpins their application as ophthalmic drug delivery systems

Poly(2-Hydroxyethyl Methacrylate) Hydrogel-Based Microneedles for Bioactive Release

Microneedle arrays are minimally invasive devices that have been extensively investigated for the transdermal/intradermal delivery of drugs/bioactives. Here, we demonstrate the release of bioactive molecules (estradiol, melatonin and meropenem) from poly(2-hydroxyethyl methacrylate), pHEMA, hydrogel-based microneedle patches in vitro. The pHEMA hydrogel microneedles had mechanical properties that were sufficiently robust to penetrate soft tissues (exemplified here by phantom tissues). The bioactive release from the pHEMA hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order). Such pHEMA microneedles have potential application in the transdermal delivery of bioactives (exemplified here by estradiol, melatonin and meropenem) for the treatment of various conditions

In Vitro and Randomized Controlled Clinical Study of Natural Constituents’ Anti-HPV Potential for Treatment of Plantar Warts Supported with In Silico Studies and Network Analysis

The aim of this study is to evaluate the anti-HPV potential of a Moringa olifera Lam seed, Nigella sativa L. seed, and Musa Acuminata peel herbal mixture in the form of polymer film-forming systems. A clinical trial conducted in outpatient clinics showed that the most significant outcome was wart size and quantity. Compared to the placebo group, the intervention group’s size and number of warts were considerably better according to the results. Chemical profiling assisted by LC-HRMS led to the dereplication of 49 metabolites. Furthermore, network pharmacology was established for the mixture of three plants; each plant was studied separately to find out the annotated target genes, and then, we combined all annotated genes of all plants and filtered the genes to specify the genes related to human papilloma virus. In a backward step, the 24 configured genes related to HPV were used to specify only 30 compounds involved in HPV infection based on target genes. CA2 and EGFR were the top identified genes with 16 and 12 edges followed by PTGS2, CA9, and MMP9 genes with 11 edges each. A molecular docking study for the top active identified compounds of each species was conducted in the top target HPV genes, CA2 and EGFR, to investigate the mode of interaction between these compounds and the targets’ active sites

Antiulcer Potential of <i>Psidium guajava</i> Seed Extract Supported by Metabolic Profiling and Molecular Docking

One of the most severe human health problems is gastric ulceration. The main aim of our study is to explore the gastroprotective effect of the Psidium guajava seeds extract (PGE). Metabolic profiling based on LC-HRMS for the extract led to the dereplication of 23 compounds (1–23). We carried out a gastric ulcer model induced by indomethacin in male albino rats in vivo and the extract of PGE was investigated at a dose of 300 mg/kg in comparison to cimetidine (100 mg/kg). Furthermore, the assessment of gastric mucosal lesions and histopathology investigation of gastric tissue was done. It has been proved that Psidium guajava seeds significantly decreased the ulcer index and protected the mucosa from lesions. The antiulcer effect of Psidium guajava seed extract, which has the power of reducing the ensuing inflammatory reactions, can counteract the inflammation induced by indomethacin by the downregulation of relative genes expression (IL-1β, IL-6, and TNF-α). Moreover, PGE significantly downregulated the increased COX-2, TGF-β, and IGF-1 relative genes expression, confirming its beneficial effect in ulcer healing. Moreover, the possible PGE antioxidant potential was determined by in vitro assays using hydrogen peroxide and superoxide radical scavenging and revealed high antioxidant potential. Additionally, on the putatively annotated metabolites, an in silico study was conducted, which emphasized the extract’s antiulcer properties might be attributed to several sterols such as stigmasterol and campesterol. The present study provided evidence of Psidium guajava seeds considered as a potential natural gastroprotective agent