An injectable thermosensitive hydrogel for dual delivery of diclofenac and Avastin® to effectively suppress inflammatory corneal neovascularization.

Corneal neovascularization (CNV) is a sequela of anterior segment inflammation, which could lead to vision impairment and even blindness. In the present study, the dual delivery of anti-inflammatory agent (i.e., diclofenac; DIC) and anti-VEGF antibody (i.e., Avastin®; Ava) by the thermosensitive hydrogel (Poly(dl-lactide)-poly(ethylene glycol)-poly(dl-lactide); PDLLA-PEG-PDLLA) is expected to effectively inhibit CNV via their synergistic effects. The optimal DIC micelles were formulated and then mixed with Ava and PDLLA-PEG-PDLLA aqueous solution to generate various DIC@Ava-loaded hydrogels. The co-encapsulation of DIC micelles and Ava did not influence the gelling behavior of the system, and the resulting DIC@Ava-loaded hydrogel provided sustained drug release of both DIC and Ava without compromising their pharmacological activity over 19 days. As indicated by in vitro cytotoxicity and in vivo ocular biocompatibility test, the proposed PDLLA-PEG-PDLLA hydrogel caused minimal cytotoxicity against all tested cell lines at a polymeric concentration ranging from 0.05 mg/mL to 0.8 mg/mL and demonstrated good ocular biocompatibility after a single subconjunctival injection. Using the rabbit CNV model, we documented the superior anti-angiogenic effects of the DIC@Ava-loaded hydrogel over Ava alone medication (treatment with Ava solution and Ava-loaded hydrogel) due to synergistic effects of anti-VEGF and anti-inflammatory action. Overall, the proposed DIC@Ava-loaded hydrogel might be a powerful strategy to reduce CNV.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

Single subcutaneous injection of the minocycline nanocomposite-loaded thermosensitive hydrogel for the effective attenuation of experimental autoimmune uveitis.

Autoimmune uveitis induces a serious pathological and inflammatory response in the retina/choroid and results in vision impairment and blindness. Here, we report a minocycline (Mino) nanocomposite-loaded hydrogel offering a high drug payload and sustained drug release for the effective control of ocular inflammation via a single subcutaneous injection. In the presence of divalent cations (i.e., Ca2+), Mino was found to co-assemble with a phosphorylated peptide (i.e., NapGFFpY) via electrostatic interaction and consequently generating Mino nanocomposite. The drug entrapment efficiency (EE) of the Mino nanocomposite varied from 29.93 ± 0.76% to 67.90 ± 6.57%, depending on different component concentrations. After incorporation into 30 wt% poly (D,L-lactide)-b-poly (ethylene glycol)-b-poly (D,L-lactide) (PDLLA-PEG-PDLLA) thermosensitive hydrogel, the resulting Mino nanocomposite-loaded hydrogel provided a sustained drug release over 21 days. In the experimental autoimmune uveitis (EAU) rat model, a single subcutaneous injection of the Mino nanocomposite-loaded hydrogel effectively alleviated ocular inflammation in a dose-dependent manner. As indicated by optical coherence tomography (OCT) and electroretinogram (ERG) measurements, the Mino nanocomposite-loaded hydrogel treatment not only remarkably reduced destruction of the retina by EAU, but also greatly rescued retinal functions. Moreover, the proposed Mino nanocomposite-loaded hydrogel exerted its therapeutic effect on EAU primarily through a significant reduction of the influx of leukocytes and Th17 cells as well as suppression of microglia activation and apoptosis in the retina. Overall, the proposed Mino nanocomposite-loaded hydrogel might be a promising strategy for the clinical management of EAU.

Ganciclovir attenuates the onset and progression of experimental autoimmune uveitis by inhibiting infiltration of Th17 and inflammatory cells into the retina.

Noninfectious (autoimmune and immune-mediated) uveitis is one of the primary diseases leading to blindness in the world. Due to the limitation of current first-line drugs for clinical uveitis, novel drugs and targets against uveitis are urgently needed. Ganciclovir (GCV), an FDA-approved antiviral drug, is often used to treat cytomegalovirus-induced retinitis in clinical patients. Recently, GCV was found to suppress neuroinflammation via targeting STING signaling because the STING pathway plays a pivotal role in autoimmune diseases. However, until now, the effect of GCV on non-infectious uveitis has never been explored. In this work, using the rat experimental autoimmune uveitis (EAU) model, we first found STING to be highly expressed in infiltrating cells (CD68+, CD45+, and CD4+) and retinal glial cells (Iba1+ and GFAP+) of the immunized retina. More importantly, GCV treatment can significantly suppress the initiation and progression of EAU by inhibiting infiltration of Th17 and inflammatory cells into the retina. Mechanistically, we found that GCV could reverse the levels of pro-inflammatory factors (such as IL-1ß) and chemokine-related factors (such as Cxcr3), possibly via targeting the STING pathway. The present results suggest that GCV may be considered as a novel therapeutic strategy against human uveitis.

A Rapid Corneal Healing Microneedle for Efficient Ocular Drug Delivery.

Fungal keratitis (FK) remains a serious clinical problem worldwide, so the ultimate goal of the treatment is to develop a minimally invasive, safe, and effective method for ocular drug delivery. Here, a minimally invasive delivery system is reported for treating FK by using a dissolving microneedle (MN)-array patch based on Poly(D,L-lactide) (PLA) and hyaluronic acid (HA). By altering the concentration of PLA, MN patches with excellent properties are modified and optimized. The 30% PLA-HA MN patches penetrate the corneal epithelial layer reversibly with no apparent ocular irritation as well as a short recovery time of less than 12 h, and increase the residence time by 2.5 h in the conjunctival sac, thereby offering higher drug bioavailability. Remarkably, the rabbit model of FK shows that the topical MN(+) patch medication exerts superior therapeutic effects compared with the conventional eye drop formulation, and also presents comparable therapeutic efficacy with that of the clinical mainstay strategy (i.e., intrastromal injection). Therefore, the MN patch, acting as an ocular drug delivery system with high efficacy and ability of rapid corneal healing, promises a cost-effective household solution for the treatment of FK, which may also lead to a new approach for treating FK in clinics.