title: γ-PGA-coated mesoporous silica nanoparticles with covalently attached prodrugs for enhanced cellular uptake and intracellular GSH-responsive release.
abstract: Poor cellular uptake of drug delivery carriers and uncontrolled drug release remain to be the major obstacles in cancer therapy due to their low delivery efficiency. In this study, a multifunctional intracellular GSH (glutathione)-responsive silica-based drug delivery system with enhanced cellular uptake capability is developed. Uniform 50 nm colloidal mesoporous silica nanoparticles (MSNs) with mercaptopropyl-functionalized core and silanol-contained silica surface (MSNs-SHin ) are designed and fabricated as a platform for drug covalent attachment and particle surface modification. Doxorubicin (DOX) with primary amine group as an anticancer model drug is covalently conjugated to the mesopores of MSNs-SHin via disulfide bonds in the presence of a heterobifunctional linker (N-Succinimidyl 3-(2-pyridyldithio) propionate). Poly(γ-glutamic acid) (γ-PGA) can be coated onto the particle surface by sequential electrostatic adsorption of polyethyleneimine (PEI) and γ-PGA. The constructed delivery system exhibits enhanced cellular uptake via a speculated γ-glutamyl transpeptidase (GGT)-mediated endocytosis pathway and controlled drug release capacity via intracellular GSH-responsive disulfide-bond cleavage, and thus significantly inhibits the growth of cancer cells. The multifunctional delivery system paves a new way for developing high-efficient particle-based nanotherapeutic approach for cancer treatment.
authors.affiliation: School of Chemical Engineering, University of Adelaide, Adelaide, SA5005, Australia.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Xiong
authors.forename: Sheng
authors.initials: S
authors.lastname: Dai
authors.forename: Shi Zhang
authors.initials: SZ
authors.lastname: Qiao
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D005978:Glutathione / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics; D012822:Silicon Dioxide / Q000737:chemistry* / Q000633:toxicity
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011355:Prodrugs; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D012822:Silicon Dioxide; D005978:Glutathione
keywords: GSH-responsive release; disulfide bonds; doxorubicin; enhanced cellular uptake; mesoporous silica nanoparticles; γ-PGA surface coating