Intra-articular Delivery of Celastrol by Hollow Mesoporous Silica Nanoparticles for pH-sensitive Anti-inflammatory Therapy against Knee Osteoarthritis

Abstract Celastrol has been proven effective in anti-inflammatory but was limited in the clinic due to the poor solubility and side effects induced by low bioavailability. Osteoarthritis has acidic and inflammatory environment. Our aim was to load celastrol into HMSNs and capped with chitosan to construct a pH-responsive nanoparticle medicine(CSL@HMSNs-Cs), which is of high solubility for osteoarthritis intra-articular injection treatment. Methods: The CSL@HMSNs-Cs were assembled and the characteristics were measured. The CSL@HMSNs-Cs was applied in vitro in the chondrocytes collected from rats cartilage tissue and in vivo in the MIA induced knee osteoarthritis rats via intra-articular injection. Cytotoxicity assay, pH-responsive release, pain behavior, MRI, safranin o fast green staining, ELISA and western blot analysis were applied to evaluate the bioavailability and therapeutic effect of [email protected]: CSL@HMSNs-Cs was stable due to the protection of the chitosan layers in alkaline environment(pH=7.7) but revealed good solubility and therapeutic effect in acidic environment(pH=6.0). The cytotoxicity assay showed no cytotoxicity at relatively low concentration(200 μg/mL) and the cell viability of chondrocytes stimulated by IL-1β was increased in CSL@HMSNs-Cs group. Paw withdrawal threshold in CSL@HMSNs-Cs group is increased, and MRI and Safranin O Fast Green staining showed improvements in articular surface erosion and joint effusion. The upregulated expression levels of IL-1β, TNF-α, IL-6, MMP-3 and MMP-13 and NF-κB signaling pathway of chondrocytes were inhibited in CSL@HMSNs-Cs group.Conclusion: Hollow mesoporous silica nanoparticles were an ideal carrier for natural drugs with poor solubility and were of high biocompatibility for intra-articular injection. These intra-articular injectable CSL@HMSNs-Cs with improved solubility, present a pH-responsive therapeutic strategy against osteoarthritis.

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Intra-articular Delivery of Celastrol by Hollow Mesoporous Silica Nanoparticles for pH-sensitive Anti-inflammatory Therapy against Knee Osteoarthritis

10.21203/rs.3.rs-15743/v1 ◽

2020 ◽

Author(s):

Tian Jin ◽

Di Wu ◽

Xiao-Ming Liu ◽

Jiang-Tao Xu ◽

Bing-Jie Ma ◽

...

Keyword(s):

Mesoporous Silica ◽

Knee Osteoarthritis ◽

Silica Nanoparticles ◽

Therapeutic Effect ◽

Mesoporous Silica Nanoparticles ◽

Ph Responsive ◽

Fast Green ◽

Poor Solubility ◽

Hollow Mesoporous Silica ◽

Safranin O

Abstract Celastrol, like other natural drugs, has proven effective in anti-inflammatory but was limited in clinic because of the poor solubility and side effects induced by low bioavailability. In recent years, hollow mesoporous silica nanoparticles (HMSNs) have received extensive attention in biomedical field due to their outstanding biocompatibility and multiple modification. Osteoarthritis has acidic and inflammatory environment. In this study, celastrol was loaded in HMSNs and capped with chitosan to construct a pH-responsive nanoparticle medicine(CSL@HMSNs-Cs) with high solubility for osteoarthritis intra-articular injection treatment. Methods: The CSL@HMSNs-Cs were assembled and the characteristics were measured. The CSL@HMSNs-Cs was applied in vitro in the chondrocytes collected from rats cartilage tissue and in vivo in the MIA induced knee osteoarthritis rats via intra-articular injection. Cytotoxicity assay, pH-responsive release, pain behavior, MRI, safranin o fast green staining, ELISA and western blot analysis were applied to evaluate the bioavailability and therapeutic effect of CSL@HMSNs-Cs. Results: CSL@HMSNs-Cs was stable due to the protection of the chitosan layers in alkaline environment(pH=7.7) but revealed good solubility and therapeutic effect in acidic environment(pH=6.0). The cytotoxicity assay showed no cytotoxicity at relatively low concentration(200 μg/mL) and the cell viability of chondrocytes stimulated by IL-1β was increased in CSL@HMSNs-Cs group. Paw withdrawal threshold in CSL@HMSNs-Cs group is increased, and MRI and Safranin O Fast Green staining showed improvements in articular surface erosion and joint effusion. The upregulated expression levels of IL-1β, TNF-α, IL-6, MMP-3 and MMP-13 and NF-κB signaling pathway of chondrocytes were inhibited in CSL@HMSNs-Cs group. Conclusion: Hollow mesoporous silica nanoparticles were idea carrier for natural drug with poor solubility and were of high biocompatibility for intra-articular injection. These intra-articular injectable CSL@HMSNs-Cs with improved solubility present a pH-responsive therapeutic strategy against osteoarthritis.

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Hyaluronic acid targeted and pH-responsive nanocarriers based on hollow mesoporous silica nanoparticles for chemo-photodynamic combination therapy

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2020.111166 ◽

2020 ◽

Vol 194 ◽

pp. 111166 ◽

Cited By ~ 2

Author(s):

Kai Chen ◽

Cong Chang ◽

Zuhao Liu ◽

Yimin Zhou ◽

Qingni Xu ◽

...

Keyword(s):

Hyaluronic Acid ◽

Combination Therapy ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Ph Responsive ◽

Hollow Mesoporous Silica

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Glucosamine Modified the Surface of pH-Responsive Poly(2-(diethylamino)ethyl Methacrylate) Brushes Grafted on Hollow Mesoporous Silica Nanoparticles as Smart Nanocarrier

Polymers ◽

10.3390/polym12112749 ◽

2020 ◽

Vol 12 (11) ◽

pp. 2749 ◽

Cited By ~ 1

Author(s):

Abeer Beagan ◽

Shatha Lahmadi ◽

Ahlam Alghamdi ◽

Majed Halwani ◽

Mohammed Almeataq ◽

...

Keyword(s):

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Hybrid Nanoparticles ◽

Ph Responsive ◽

Ethyl Methacrylate ◽

Drug Concentrations ◽

Cytotoxicity Studies ◽

Hollow Mesoporous Silica ◽

Mcf 7

This work presents the synthesis of pH-responsive poly(2-(diethylamino) ethyl methacrylate) (PDEAEMA) brushes anchored on hollow mesoporous silica nanoparticles (HMSN-PDEAEMA) via a surface-initiated ARGET ATRP technique. The average size of HMSNs was ca. 340 nm, with a 90 nm mesoporous silica shell. The dry thickness of grafted PDEAEMA brushes was estimated to be ca 30 nm, as estimated by SEM and TEM. The halogen group on the surface of PDEAMA brushes was successfully derivatized with glucosamine, as confirmed by XPS. The effect of pH on the size of the hybrid nanoparticles was investigated by DLS. The size of fabricated nanoparticle decreased from ca. 950 nm in acidic media to ca. 500 nm in basic media due to the deprotonation of tertiary amine in the PDEAEMA. The PDEAEMA modified HMSNs nanocarrier was efficiently loaded with doxorubicin (DOX) with a loading capacity of ca. 64%. DOX was released in a relatively controlled pH-triggered manner from hybrid nanoparticles. The cytotoxicity studies demonstrated that DOX@HMSN-PDEAEMA-Glucosamine showed a strong ability to kill breast cancer cells (MCF-7 and MCF-7/ADR) at low drug concentrations, in comparison to free DOX.

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