Journal Article

pH-Responsive Mesoporous Silica Nanoparticles Loaded with Naringin for Targeted Osteoclast Inhibition and Bone Regeneration

Gong, Shuwei, Lang, Shuang, Tian, Aixian, Ma, Jianxiong, Ma, Xinlong, Li, Xiongfeng, Wang, Yan

2024

Overview

It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research. First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo. CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent. Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.

• Publisher: Taylor & Francis Ltd,Dove Press,Dove Medical Press
• Subject: Animals / Bone marrow / Bone Regeneration - drug effects / Bone Resorption - drug therapy / Cell Differentiation - drug effects / chitosan / Chitosan - chemistry / Drug Carriers - chemistry / Drug Carriers - pharmacokinetics / Drug delivery systems / Drug Delivery Systems - methods / Drug Liberation / Estrogens / Flavanones - administration & dosage / Flavanones - chemistry / Flavanones - pharmacokinetics / Flavanones - pharmacology / Fourier transforms / Fractures / Hydrogen-Ion Concentration / Male / mesoporous silica nanoparticles / Mice / Morphology / Nanomaterials / Nanoparticles / Nanoparticles - chemistry / naringin / osteoclast / Osteoclasts - drug effects / ph-sensitive gated nano-drug delivery system / pH-sensitive gated nano-drug delivery system / Porosity / Rats / Rats, Sprague-Dawley / RAW 264.7 Cells / Silicon Dioxide - chemistry / Spectrum analysis