ABSTRACT
PURPOSE: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed. METHOD: To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells. RESULTS: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR). CONCLUSIONS: The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Nanoparticles/administration & dosage , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Biotin/chemistry , Buthionine Sulfoximine/administration & dosage , Calcium Carbonate/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems/methods , Drug Synergism , Glutathione/metabolism , HeLa Cells , Heparin/chemistry , Humans , MCF-7 Cells , Polymers/chemistry , Protamines/chemistry , Quinolines/administration & dosageABSTRACT
A facile method to prepare inorganic/organic hybrid heparin/CaCO(3)/CaP nanoparticles for drug delivery was developed. The heparin/CaCO(3)/CaP nanoparticles were prepared by the co-precipitation of Ca(2+) ions with carbonate and phosphate ions in the presence of heparin. The effects of ion concentrations on the particle size and properties of the nanoparticles were investigated. The dynamic light scattering (DLS) particle size analysis and scanning electron microscopy (SEM) observation showed that the mean size of the hybrid nanoparticles could be controlled at less than 50 nm in the dried state through adjusting the concentrations of the inorganic ions. Fourier transform infrared (FTIR) spectroscopy indicated that the crystallization of CaCO(3) could be suppressed with the presence of phosphate ions in the co-precipitation system. X-ray photoelectron spectroscopy (XPS) showed that the heparin content in the surface layer of heparin/CaCO(3)/CaP hybrid nanoparticles decreased with the increasing ion concentrations during the nanoparticle preparation. The drug loading and release properties of the hybrid nanoparticles with different sizes and different compositions were studied. The in vitro cellular cytotoxicity indicated that blank hybrid nanoparticles had good biocompatibility, whereas doxorubicin hydrochloride (DOX) loaded nanoparticles exhibited a strong cell inhibition effect, indicating that the heparin/CaCO(3)/CaP hybrid nanoparticles could be promising carriers for drug delivery.
Subject(s)
Calcium Carbonate/chemistry , Calcium Phosphates/chemistry , Drug Carriers/chemistry , Heparin/chemistry , Nanoparticles/chemistry , Cell Survival/drug effects , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Carriers/adverse effects , HeLa Cells , Humans , Microscopy, Electron, Scanning , Nanoparticles/adverse effects , Nanoparticles/ultrastructureABSTRACT
Chitosan-cyclodextrin nanospheres were prepared by in situ formation through Michael addition between N-maleated chitosan (NMC) and per-6-thio-ß-cyclodextrin sodium salt in an aqueous medium. This facile preparation method did not involve any organic solvent and surfactant. Through adjusting the preparation conditions, the nanospheres with a relatively narrow size distribution could be obtained. The obtained nanospheres were characterized by TEM and particle size analyzer. Doxorubicin hydrochloride (DOX·HCl), a water soluble anticancer drug, was loaded in the nanospheres with a high encapsulation efficiency. The in vitro drug release showed that the release of DOX·HCl from the nanospheres could be effectively sustained. The cytotoxicity evaluation showed the drug loaded nanospheres exhibited efficient inhibition on HeLa cells.
