Dendritic Effects of Injectable Biodegradable Thermogels on Pharmacotherapy of Inflammatory Glaucoma‐Associated Degradation of Extracellular Matrix

Abstract

111.8 million people worldwide by 2040. [1] High intraocular pressure (IOP) has been considered the major indicator for diagnosing glaucoma, and the reduction of elevated IOP is the current clinical approach used to prevent disease progression. [2] Several models of glaucoma have indicated that inflammatory components can directly link elevated IOP with retinal degeneration. [3][4][5][6] As a result, the expression of inflammatory molecules, including nitric oxide, [7] interleukins (ILs), [8] p38 MAPK, [9] and prostaglandin E2 (PGE2), [10] are increased in progressive glaucoma. Furthermore, inflammatory progression is also associated with the increased expression of matrix metalloproteinases (MMPs), [11] which consequently induce the degradations of extracellular matrix (ECM) components such as stromal collagen [12] and retinal laminin. [13] It is noteworthy that ECM possesses adhesive characteristics that can regulate cell function and survival; changes in composition and status of ECM components can result in disruptions of cell-cell and cell-ECM interactions, consequently inducing cell apoptosis. [14][15][16] Therefore, it is highly imperative to develop new therapies for effectively attenuating the upregulation of inflammatory molecules as well as the degradation of stromal collagen and retinal laminin in glaucoma.Dendrimers, which are synthetic macromolecules with well-defined 3D shapes that contain a central core, repeating branched units, and dense shells with terminal functional groups, have been emerging in polymeric architecture in biomedical engineering. These macromolecules can increase the water solubility, bioavailability, and biocompatibility of pharmaceutical agents and show promise for practical use as drug carriers. [17] More interestingly, dendrimers can also be exploited as a key component that regulates the encapsulation and release of other carriers to achieve improved drug delivery. For example, the interior cavities of polyamidoamine (PAMAM) dendrimers can entrap drug molecules, while their amine-terminated surface groups are available for crosslinking with poly(ethylene glycol) mono/diacrylate to generate hydrogel materials with the ability to release drugs in a sustained manner through a twostage process, which involves the release of drug-entrapping dendrimers from degradable hydrogels and the release of drug The development of advanced drug delivery systems with extensively sustained release and multiple functions is highly imperative for effective attenuation of the degradation of ocular extracellular matrix that is associated with inflammatory glaucoma. Here, the generation of amine-terminated polyamidoamine dendrimers in an injectable biodegradable thermogel is demonstrated to be important for achieving prolonged drug release profiles and potent anti-inflammatory effects. Among various generations (Gx, x = 0, 1, 3, 5), third-generation G3 is proved as the most effective material for optimizing the synergistic effects of gelatin and poly(N-isopropylacrylamide) and generating a thermo...

Advancing the stimuli response of polymer-based drug delivery systems for ocular disease treatment

“…In this context, polyamidoamine (PAMAM) dendrimers have been explored in PNIPAAm/gelatin thermo-responsive carriers because they are biodegradable and regulate the inflammatory response. 131 This study showed that the drug release profile and anti-inflammatory effects were strongly influenced by the generation of PAMAM dendrimers. Due to the specific structure of the third generation of the PAMAM dendrimers, such as sufficiently large interior cavities and an adequate number of amine surface groups, the synergistic effects in the PNIPAAm-gelatin copolymer can be optimized.…”

Intravitreal Injectable Hydrogels for Sustained Drug Delivery in Glaucoma Treatment and Therapy

“…Ophthalmic applications of intravitreal injectable drug-loaded hydrogels for glaucomic treatment to the posterior section of the eye have been shown to overcome ocular barriers and effectively treat glaucoma [132,133]. This novel drug delivery system has properties of good adherence and viscosity, and achieves the objective of retention and therapeutic treatment of ocular diseases in the most remote areas of the eye.…”

Glaucoma Treatment and Hydrogel: Current Insights and State of the Art

“…All prepared copolymeric carriers exhibit a relevant intraocular pressure-lowering and an excellent miotic effect [ 111 ]. Afterward, Nguyen and colleagues prepared injectable biodegradable thermogels coloaded with pilocarpine and ascorbic acid [ 112 ]. The synthesized gel obtained the double effect of lowering elevated IOP and reducing stromal collagen degradation in inflammation-induced glaucoma.…”