ABSTRACT
The prognosis of esophageal squamous cell carcinoma is poor. We hereby presented a highly integrated and clinically relevant precision nanomedicine strategy to target ESCC molecularly and physically for significant improvement of the treatment efficacy. We firstly identified PI3K overexpression in patient samples and its relation to poor patient survival. With our highly versatile tumor-targeted drug delivery platform (DCM), we were able to load a potent but toxic docetaxel (DTX) and a PI3K inhibitor (AZD8186) with favorable physical properties. The combination of the DTX-DCM and AZD8186-DCM showed a highly efficacious and synergistic anti-tumor effect and decreased hematotoxicity. A pro-apoptotic protein, Bax was significantly upregulated in ESCC cells treated with combination therapy compared to that with monotherapy. This study utilized a highly integrated precision nano-medicine strategy that combines the identification of cancer molecular target from human patients, precision drug delivery and effective combination therapy for the development of better ESCC treatment.
Subject(s)
Aniline Compounds/pharmacology , Carcinoma, Squamous Cell/drug therapy , Chromones/pharmacology , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Docetaxel/pharmacology , Drug Delivery Systems , Esophageal Neoplasms/drug therapy , Nanomedicine , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases/metabolism , Docetaxel/administration & dosage , Docetaxel/chemistry , Drug Therapy, Combination , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Esophageal Neoplasms/drug therapy , Nanostructures/therapeutic use , Taxoids/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Apoptosis/drug effects , Bortezomib/chemistry , Bortezomib/pharmacokinetics , Cell Cycle/drug effects , Cell Survival/drug effects , Docetaxel , Dose-Response Relationship, Drug , Drug Compounding , Drug Screening Assays, Antitumor , Esophageal Neoplasms/pathology , Humans , Nanostructures/chemistry , Structure-Activity Relationship , Taxoids/chemistry , Taxoids/pharmacokinetics , Tumor Cells, CulturedABSTRACT
Six volatile compounds, curdione (1), curcumol (2), germacrone (3), curzerene (4), 1,8-cineole (5) and beta-elemene (6), were successfully isolated from the essential oil of Curcuma wenyujin by high-performance centrifugal partition chromatography using a nonaqueous two-phase solvent system consisting of petroleum ether-acetonitrile-acetone (4:3:1 v/v/v). A total of 8 mg of curdione (1), 4 mg of curcumol (2), 10 mg of germacrone (3), 18 mg of curzerene (4), 9 mg of 1,8-cineole (5) and 17 mg of beta-elemene (6) were isolated from the essential oil (300 mg) in 500 min. Their structures were determined by comparison of their retention times and MS data with those of the authentic samples as well as NMR spectroscopic analysis.
Subject(s)
Chromatography, High Pressure Liquid/methods , Oils, Volatile/isolation & purification , Centrifugation , Chemistry Techniques, Analytical , Curcuma/metabolism , Gas Chromatography-Mass Spectrometry/methods , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Models, Chemical , Oils, Volatile/chemistry , Plant Extracts/chemistry , Solvents/chemistry , Time FactorsABSTRACT
The title compound, C(14)H(14)N(2)O(6)S, is an inter-mediate for the synthesis of ß-3-adrenergic receptor agonists. The two meth-oxy groups are approximately coplanar with the attached benzene ring [C-O-C-C = -2.7â (4) and 9.4â (4)°]. The dihedral angle between the two aromatic rings is 67.16â (12)°. An intra-molecular N-Hâ¯O hydrogen bond is observed. In the crystal, mol-ecules are linked into chains along the c axis by C-Hâ¯O hydrogen bonds.