ABSTRACT
A facile self-assembly strategy was developed to decorate polymer/inorganic hybrid nano-sized drug delivery systems with functional peptides. To enhance drug delivery efficacy and overcome tumor drug resistance, a functional fusion peptide containing an RGD sequence for tumor targeting and an R8 sequence for cell penetration was introduced onto the surface of biotinylated carboxymethyl chitosan/CaCO3 (BCMC/CaCO3) hybrid nanoparticles through biotin-avidin interaction to obtain peptide functionalized nanoparticles (PNP). The peptide functionalization results in improved delivery efficiency and effective inhibition for drug resistant tumor cells. Co-delivery of an anti-cancerous drug (doxorubicin hydrochloride, DOX) and a cyclooxygenase-2 inhibitor (celecoxib, CXB) by PNP can further improve the therapeutic efficiency by effectively down-regulating P-gp expression to reduce P-gp mediated drug efflux and increase intracellular drug accumulation.
ABSTRACT
To effectively reverse multiple drug resistance (MDR) in tumor treatments, a functional nano-sized drug delivery system with active targeting function and pH sensitivity was prepared for the co-delivery of multiple drug resistance inhibitors. Buthionine sulfoximine (BSO) to inhibit GSH synthesis and celecoxib (CXB) to down-regulate P-gp expression were co-loaded in polymer/inorganic hybrid nanoparticles to form buthionine sulfoximine/celecoxib@biotin-heparin/heparin/calcium carbonate/calcium phosphate nanoparticles (BSO/CXB@BNP). To investigate the reversal of MDR, the drug resistant cells (MCF-7/ADR) were pretreated by the dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) followed by the treatment of doxorubicin (DOX) loaded nanoparticles (DOX@BNP). The dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) exhibited greatly enhanced efficiency in down-regulation of GSH and P-gp since BSO and CXB had combined effects on the reduction of GSH and P-gp in drug resistant tumor cells. As a result, BSO/CXB@BNP exhibited a significantly improved capability in reversal of MDR compared with mono-inhibitor loaded nanoparticles (CXB@BNP and BSO@BNP). As compared with free drug resistance inhibitors, delivery of drug resistance inhibitors by functional nanocarriers could obviously improve the therapeutic efficiency due to enhanced cellular uptake and increased intracellular drug accumulation. The study on immunostimulatory effects of different treatments showed that BSO/CXB@BNP treatment resulted in the lowest concentration of interleukin 10, a cytokine related to tumor development. These results suggest the nanoparticulate drug delivery platform developed in this study has promising applications in multiple drug delivery to overcome drug resistance in tumor treatments.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Buthionine Sulfoximine/pharmacology , Celecoxib/pharmacology , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Nanoparticles/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antibiotics, Antineoplastic/chemistry , Biological Transport , Buthionine Sulfoximine/chemistry , Celecoxib/chemistry , Cell Survival/drug effects , Doxorubicin/chemistry , Drug Carriers , Drug Compounding , Drug Resistance, Neoplasm/genetics , Gene Expression , Glutathione/antagonists & inhibitors , Glutathione/biosynthesis , Humans , Hydrogen-Ion Concentration , Interleukin-10/antagonists & inhibitors , Interleukin-10/genetics , Interleukin-10/metabolism , MCF-7 Cells , Nanoparticles/ultrastructureABSTRACT
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
With the aim to develop a facile strategy to prepare functional drug carriers to overcome multidrug resistance (MDR), we prepared heparin/protamine/calcium carbonate (HP/PS/CaCO3) hybrid nanovesicles with enhanced cell internalization, good serum stability, and pH sensitivity for drug delivery. All the functional components including protamine to improve the cell uptake, heparin to enhance the stability, and CaCO3 to improve drug loading and endow the system with pH sensitivity were introduced to the nanovesicles by self-assembly in an aqueous medium. An antitumor drug (doxorubicin, DOX) and a drug resistance inhibitor (tariquidar, TQR) were coloaded in the nanovesicles during self-assembly preparation of the nanovesicles. The drug loaded nanovesicles, which had a mean size less than 200 nm, exhibited a pH-sensitive drug release behavior. In vitro study was carried out in both nonresistant cells (HeLa and MCF-7) and drug-resistant cancer cells (MCF-7/ADR). Because of the enhanced intracellular and nuclear drug accumulation through effective inhibition of the P-gp efflux transporter, DOX/TQR coloaded nanovesicles showed significantly improved tumor cell inhibitory efficiency, especially for drug-resistant cells. These results suggest the self-assembled nanovesicles have promising applications in multidrug delivery to overcome drug resistance in tumor treatments.
