pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Current trends in pharmaceutical treatment of dry eye disease: A review.

Dry eye disease (DED), keratoconjunctivitis sicca or dysfunctional tear syndrome, is the most prevalent ophthalmic disease which affects a substantial segment of people worldwide with increasing frequency. It is considered a multifactorial disease of the ocular surface and tear film, characterized by a variation of signs and symptoms. The symptoms range from mild to severe itching, burning, irritation, eye fatigue, and ocular inflammation that may lead to potential damage to the cornea, conjunctiva and even vision loss. Correspondingly, depending on the different manifestations and pathophysiology, the treatment must be tailored specifically to each patient by targeting the specific mechanisms implicated in their disease. Currently, there are several medical products and techniques available or under investigation for the treatment of DED. The present article focused on the pathophysiology of DED, the new diagnostic approach and the recently developed drug delivery systems or devices reducing the progress of the disease and treating the causes.

Design, Characterization, and Application of a pH-Triggered In Situ Gel for Ocular Delivery of Vinpocetine.

We developed a pH-triggered in situ gel (ISG) for ocular delivery of vinpocetine to achieve systemic absorption and a brain-targeting effect in rats. Carbopol acted as a gelling agent combined with hydroxypropyl methylcellulose (HPMC) as a viscosity-enhancing agent. The concentration of Carbopol (0.2%, w/v) and HPMC (1.5%, w/v) was optimized for the ISG system. The optimized formulation was evaluated for studies on release in vitro, rheology, differential scanning calorimetry, ocular irritation, residence time, and in vivo pharmacokinetics. The vinpocetine ISG stayed longer in rabbit eyes than vinpocetine ointment. In vivo pharmacokinetics showed that compared with vinpocetine ointment, vinpocetine ISG attained a peak plasma concentration and area under the curve that was 1-2 folds greater in rat plasma. The Drug Targeting Index (DTI) was 1.06 and 1.26 for vinpocetine ointment and vinpocetine ISG, respectively, after ocular administration, showing that vinpocetine ISG had better distribution in rat brain. These results revealed that a pH-triggered ISG system via ocular administration could be an alternative approach compared with traditional ophthalmic formulations.

Synthesis and characterization of timolol maleate-loaded quaternized chitosan-based thermosensitive hydrogel: A transparent topical ocular delivery system for the treatment of glaucoma.

The chitosan-based thermosensitive hydrogel is one of the attractive in situ forming drug delivery systems that are suggested for ophthalmic applications. However, the use of this thermogel has been limited by non-transparency, relatively low solubility and prolonged gelation time. In this study, a convenient approach has been reported to develop transparent thermosensitive hydrogel with suitable cytocompatibility and gelation properties for glaucoma treatment. After obtaining the optimum quaternization conditions, the developed in-situ gelling formulation of quaternized chitosan was achieved by mixing sodium hydrogen carbonate with ß-glycerophosphate as a gelling agent. The formulation was a solution below or at room temperature and turned to a transparent hydrogel around ocular surface temperature within several minutes. The results of thermal and rheological evaluations demonstrated that adding sodium hydrogen carbonate has a synergic effect in enhancing the thermosensitivity of the hydrogel. Also, the prepared hydrogels based on quaternized chitosan presented obvious porous architectures, good swelling, and degradability. Hemolysis and cytotoxicity evaluations suggested that the developed hydrogels indicated good biocompatibility as a drug carrier. Finally, the in vitro release profile of timolol maleate as an anti-glaucoma model drug showed the initial burst release in the early hours and a steady linear release of drug from the hydrogel over 1 week. The obtained results confirmed that the developed hydrogel can be considered as an efficient drug delivery candidate for glaucoma therapy.

Nanomicelle-Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo.

Ocular inflammations are common diseases that may lead to serious vision-threatening obstacles. Eye drops for antiinflammation therapy need to be administered multiple times daily at a high dosage due to the rapid precorneal removal and low bioavailability of drugs. To overcome these problems, a cRGD-functionalized DSPE-PEG2000 nanomicelle (DSPE-PEG2000-cRGD) encapsulated with flurbiprofen is proposed. The tailored nanomicelles trigger specific binding to integrin receptors on the ocular surface, which leads to rapid and robust mucoadhesion, superior ocular surface retention, and transcorneal penetration behaviors of nanomicelles. Due to the enhanced drug delivery on ocular surface and in aqueous humor, the functionalized nanoformulation significantly improves ocular antiinflammation efficacy at a low dosage by blocking the synthesis of inflammatory mediators and cytokines. The present study demonstrates a promising strategy that uses a functional peptide combined with nanomicelles for targeted delivery to the eye in ophthalmologic applications.