Targeted and redox-responsive drug delivery systems based on carbonic anhydrase IX-decorated mesoporous silica nanoparticles for cancer therapy

Minmin Chen,Zhicheng Ju,Lujing Wang,Chenghao Zhu,Ming Shi,Zhuoqi Zhang,Yanru Li,Chen Chen,Jinxia Hu,Xichuan Cao

doi:10.1038/s41598-020-71071-1

Abstract

In this work, we developed a new antibody-targeted and redox-responsive drug delivery system “MSNs-CAIX” by binding the anti-carbonic anhydrase IX antibody (A-CAIX Ab) on the surface of mesoporous silica nanoparticles (MSNs) via disulfide linkages. The design of the composite particles “MSNs-CAIX” involved the synthesis and surface functionalization with thiol groups, 2,2′-dipyridyl disulfide and CAIX antibody. In vitro, CAIX capping the doxorubicin hydrochloric (DOX)-loaded nanoparticles (DOX@MSNs-CAIX) exhibited effectively redox-responsive release in the presence of glutathione (GSH) owing to the cleavage of the disulfide bond. Compared with CAIX negative Mef cells (mouse embryo fibroblast), remarkably more DOX@MSNs-CAIX was internalized into CAIX positive 4T1 cells (mouse breast cancer cells) by receptor-mediation. Tumor targeting in vivo studies clearly demonstrated DOX@MSNs-CAIX accumulated in tumors and induced more tumor cells apoptosis in 4T1 tumor-bearing mice. With great potential, this drug delivery system is a promising candidate for targeted and redox-responsive cancer therapy.

Highlights

Cancer is the second leading cause of death globally with a growing incidence and mortality rates year by year[1,2]
We found that mesoporous silica nanoparticles (MSNs) capped with A-CAIX Ab “MSNs-CAIX” could be used as a redox-responsive controlled-release and targeted delivery carrier
The MSNs-CAIX could significantly facilitate cell internalization in CAIX-positive cancer cells owing to the targeted capacity of A-CAIX Ab

Summary

Introduction

Cancer is the second leading cause of death globally with a growing incidence and mortality rates year by year[1,2]. Since the first-generation drug delivery system (DDS) was reported in 196513, a wide range of nanoparticles have been investigated, including liposome[14,15,16], polymer n anoparticles[17,18], magnetic nanoparticles[19,20], carbon nanomaterials[21,22], gold nanoparticles[23,24] and mesoporous silica nanoparticles (MSNs)[25,26,27,28]. To actively target the tumor sites and reduce damage to normal tissues, diverse biological recognition ligands were modified on the outer surface of MSNs to recognize the receptors overexpressed on tumor c ells[35], including small molecules, monoclonal antibodies, aptamers, peptides and proteins[36,37]. CAIX was drafted on the surface of MSNs via redox-responsive disulfide linkages, which could efficiently trigger drug release by GSH

Methods

Results

Conclusion