ABSTRACT
Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia.
Subject(s)
Adenocarcinoma/therapy , Hyperthermia, Induced , Lung Neoplasms/therapy , Micelles , Nanoparticles/chemistry , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Cell Line, Tumor , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Delayed-Action Preparations/pharmacology , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathologyABSTRACT
Thiol-responsive gemini micelles consisting of hydrophilic poly(ethylene glycol) (PEG) blocks and hydrophobic polylactide (PLA) blocks with a cystine disulfide spacer were reported as effective intracellular nanocarriers of drugs. In the presence of cellular glutathione (GSH) as a reducing agent, gemini micelles gradually destabilize into monomeric micelles through cleavage of the cystine linkage. This destabilization of the gemini micelles changed their size distribution, with the appearance of small aggregates, and led to the enhanced release of encapsulated doxorubicin (DOX). The results obtained from cell culture via confocal laser scanning microscopy (CLSM) for cellular uptake, as well as cell viability measurements for anticancer efficacy suggest the potential of disulfide-based gemini polymeric micelles as controlled drug delivery carriers.
Subject(s)
Cystine/chemistry , Disulfides/chemistry , Drug Carriers/chemistry , Drug Delivery Systems , Nanoparticles/chemistry , Polyesters/chemistry , Polyethylene Glycols/chemistry , Sulfhydryl Compounds/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chromatography, Gel , Doxorubicin/pharmacology , Glutathione/pharmacology , Humans , Micelles , Nanoparticles/ultrastructure , Particle Size , Polyesters/chemical synthesis , Polyethylene Glycols/chemical synthesisABSTRACT
In this study, we have shown the potential of a voxel-based analysis for imaging amyloid plaques and its utility in monitoring therapeutic response in Alzheimer's disease (AD) mice using manganese oxide nanoparticles conjugated with an antibody of Aß1-40 peptide (HMON-abAß40). T1-weighted MR brain images of a drug-treated AD group (n=7), a nontreated AD group (n=7), and a wild-type group (n=7) were acquired using a 7.0 T MRI system before (D-1), 24-h (D+1) after, and 72-h (D+3) after injection with an HMON-abAß40 contrast agent. For the treatment of AD mice, DAPT was injected intramuscularly into AD transgenic mice (50 mg/kg of body weight). For voxel-based analysis, the skull-stripped mouse brain images were spatially normalized, and these voxels' intensities were corrected to reduce voxel intensity differences across scans in different mice. Statistical analysis showed higher normalized MR signal intensity in the frontal cortex and hippocampus of AD mice over wild-type mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). After the treatment of AD mice, the normalized MR signal intensity in the frontal cortex and hippocampus decreased significantly in comparison with nontreated AD mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). These results were confirmed by histological analysis using a thioflavin staining. This unique strategy allows us to detect brain regions that are subjected to amyloid plaque deposition and has the potential for human applications in monitoring therapeutic response for drug development in AD.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Brain/pathology , Dipeptides/therapeutic use , Magnetic Resonance Imaging/methods , Plaque, Amyloid/pathology , Amyloid beta-Peptides/immunology , Animals , Antibodies , Brain/drug effects , Contrast Media , Enzyme Inhibitors/therapeutic use , Female , Frontal Lobe/drug effects , Frontal Lobe/pathology , Hippocampus/drug effects , Hippocampus/pathology , Image Processing, Computer-Assisted , Manganese Compounds , Mice , Mice, Transgenic , Nanoparticles , Oxides , Peptide Fragments/immunology , Plaque, Amyloid/drug therapy , Time FactorsABSTRACT
Annealing of MnO@SiO(2) nanospheres in a reducing gas environment resulted in the transformation of the core-shell structure into a hollow structure as a result of outward diffusion of MnO species into the thermodynamically more stable silicate phase. When the hollow silicate nanospheres were oxidized, the interior cavities were refilled with a Mn(3)O(4) phase segregated from the silicate phase, and the hollow structure reverted to the initial core-shell structure. More interestingly, when catalytically active Pt nanocrystals were introduced into the manganese oxide/silica system, the Mn(3)O(4) was readily reduced to the chemically reactive MnO, even at low temperature, which enabled reconversion of the solid nanospheres with a Mn(3)O(4) core to hollow nanostructures during reductive annealing. Therefore, when MnO@SiO(2)/Pt(II) nanospheres were subjected to an oxidation/reduction cycle by repeatedly switching the flowing gas between air and hydrogen, the nanospheres underwent a reversible change between solid and hollow structures, depending on the gas environment. The solid-to-hollow-to-solid transformation was successfully cycled many times simply by repeatedly switching the flowing gas during annealing.
Subject(s)
Manganese Compounds/chemistry , Nanostructures/chemistry , Oxides/chemistry , Silicon Dioxide/chemistry , Particle Size , Surface PropertiesABSTRACT
In this study, we have shown the feasibility of hollow manganese oxide nanoparticles (HMON) conjugated with an antibody of Aß1-40 peptide (abAß40) (HMON-abAß40) for MRI of amyloid plaques in APP/PS1 transgenic mice. MR brain images in APP/PS1 transgenic mice and their nontransgenic littermates were acquired using a 7.0 T MRI system before, and 24 and 72 h after an injection of HMON-abAß40. After the injection of HMON-abAß40, we found hyperenhanced spots in the frontal cortex area on T1-weighted MR images for transgenic mice, which corresponded qualitatively to amyloid plaques detected by thioflavin-S staining. For quantitative analysis, percent MR signal changes in six brain regions (olfactory cortex, frontal cortex, cerebral cortex, thalamus, hippocampus, and cerebellar cortex) were compared between transgenic and wild-type mice. We found significant increases in the percent MR signal changes in the olfactory cortex, frontal cortex, cerebral cortex, and hippocampus, but there were no significant differences in the thalamus and cerebellar cortex for transgenic mice compared with wild-type mice. This unique strategy allowed us to detect brain regions subjected to amyloid plaque deposition in Alzheimer's disease transgenic mouse models and has a potential to be developed for human applications, which has a current utility in preclinical research, particularly in monitoring therapeutic response for drug development in Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/immunology , Antibodies , Brain/pathology , Manganese Compounds , Nanoparticles , Oxides , Peptide Fragments/immunology , Plaque, Amyloid/diagnosis , Amyloid beta-Protein Precursor/genetics , Animals , Brain Mapping , Disease Models, Animal , Humans , Magnetic Resonance Imaging , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/genetics , Presenilin-1/genetics , Time FactorsABSTRACT
A platform protocol developed based on the hollow manganese oxide nanoparticles provided multimodal diagnostic agents, which allow the selectively detect vulva cancer with T(1)-weighted in vivo MRI.
