Synthesis and Evaluation of a Nanoglobular Dendrimer 5-Aminosalicylic Acid Conjugate with a Hydrolyzable Schiff Base Spacer for Treating Retinal Degeneration

Abstract

Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolysable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4−/−Rdh8−/− mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.

Construction of pH‐Responsive Supramolecular Assemblies Based on Dynamic Covalent Bonds for Tunable Drug Release

“…The formation of the acylhydrazone bond was also characterized using UV–vis spectrophotometry (Wu et al, ). As can be seen from Fig.…”

“…Release of IAH from C 12 ‐CHIM by the hydrolysis of the dynamic covalent bond was evaluated using UV–vis spectroscopy (Wu et al, ). The time course of variation of UV–vis adsorption at pH 2 is depicted in Fig.…”

Molecular Magnetic Resonance Imaging of Tumor Response to Therapy

“…Enzyme-triggered nanoaggregation harnesses the benefits of enhanced retention and MR signal generation typical of nanoparticles, but utilizes small molecule probes and so overcomes the safety concerns generally limiting the use of nanoparticles in clinical imaging 49 . To further improve upon the tolerability of this new MR probe, particularly concerning the tissue residence lifetime of formed nano-aggregates, the probe scaffold can be made to self-immolate and induce nanoparticle disassembly after imaging is completed (approximately 2 to 4 hours), as has been shown with other nanoparticles 50 51 . This would ensure that the probe enters and leaves the body as a small molecule, allowing efficient clearance of the metal chelate, which merely resides in apoptotic tumor tissue temporarily.…”

Preclinical studies of dendrimer prodrugs

“…Wu et al synthesized an octa (3-aminopropyl)silsesquioxane-core polylysine dendrimer, which was conjugated to 5-ASA via a degradable Schiff base linker. After intraperitoneal injection, the dendrimer prodrug exhibited an enhanced and prolonged protective effect against bright light-induced retinal degeneration in a mouse model than free 5-ASA [69].…”