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Nanogold-core Multifunctional Dendrimer for Pulsatile Chemo-, Photothermal- and Photodynamic- Therapy of Rheumatoid Arthritis
摘要： This investigation reports a novel nanoGold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis (RA). Architecturally, the nanocomposites comprised of a nanoGold (Au) at the focal whose surface is functionalized by hydroxy-terminated thiolated-dendrons following Au-thiol bond formation to produce nanoGold-core multifunctional dendrimer (Au-DEN). The surface hydroxyl groups of Au-DEN were then conjugated with methotrexate (MTX; a disease-modifying first line anti-rheumatic drug; DMARD; 74.29±0.48 % loading) to form Au-DEN-MTX-NPs (Particle size: 100.15±28.36 nm; poly dispersibility index, PDI: 0.39±0.02; surface zeta potential, ζ: -22.45±1.06 mV). MTX was strategically selected to serve as an anti-rheumatic DMARD as well as a targeting ligand to attain selective localization of the formulation in arthritic tissue via folate receptors upregulated on arthritic tissues. The docking study was performed to confirm the viable binding efficiency of MTX towards β-folate receptors that are overexpressed on arthritic tissues taking folic acid as a reference standard. The IR780, a NIR active bioactive was also loaded in Au-DEN-MTX NPs to offer photothermal benefit upon irradiation with NIR laser (wavelength: 808 nm). The hypothesis was tested by elucidation of in vitro drug release profile, photothermal activity, cellular uptake (Fluorescence and confocal laser scanning microscopy; CLSM), cell viability assay (MTT protocol) and Intracellular reactive oxygen species (ROS) generation in mouse macrophage RAW264.7 cells and Lipopolysaccharide (LPS) activated RAW264.7 cells. Furthermore, the hemolytic toxicity and stability studies were also investigated to determine the blood compatibility as well as ideal storage condition of NPs. The outcome of this investigations presents developed multifunctional targeted NPs to be potential therapeutics for the improved treatment of RA. The approach can also be applied to other clinical interventions involving countering inflammatory conditions.
关键词： Rheumatoid arthritis,NanoGold-core multifunctional dendrimer,Methotrexate,Photothermal,Near-infrared,Dendron
更新于2025-11-21 11:24:58
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Multifunctional N,S co-doped carbon dots for sensitive probing of temperature, ferric ion, and methotrexate
摘要： In this paper, we have presented a facile method to fabricate nitrogen and sulfur co-doped carbon dots (N,S-CDs) for blood methotrexate (MTX) sensing applications. The N,S-CDs with quantum yield up to 75% were obtained by one-step hydrothermal carbonization, using reduced glutathione and citric acid as the precursors. With this approach, the formation and the surface passivation of N,S-CDs were carried out simultaneously, resulting in intrinsic fluorescence emission. Owing to their pronounced temperature dependence of the fluorescence emission spectra, resultant N,S-CDs can work as versatile nanothermometry devices by taking advantage of the temperature sensitivity of their emission intensity. In addition, the obtained N,S-CDs facilitated high selectivity detection of Fe3+ ions with a detection limit as low as 0.31 μM and a wide linear range from 3.33 to 99.90 μM. More importantly, the added MTX selectively led to the fluorescence quenching of the N,S-CDs. Such fluorescence responses were used for well quantifying MTX in the range of 2.93 to 117.40 μM, and the detection limit was down to 0.95 μM. Due to Binert^ surface, the N,S-CDs well resisted the interferences from various biomolecules and exhibited excellent selectivity. The proposed sensing system was successfully used for the assay of MTX in human plasma. Due to simplicity, sensitivity, selectivity, and low cost, it exhibits great promise as a practical platform for MTX sensing in biological samples.
关键词： Hydrothermal carbonization,Doped carbon dots,Excitation-independent emission,Multifunctional probe,Methotrexate,Surface passivation
更新于2025-11-19 16:46:39
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NTOX-07. LASER INTERSTITIAL THERMAL THERAPY WITH ADJUVANT RADIOTHERAPY INDUCED CEREBRAL EDEMA IN PATIENTS WITH BRAIN TUMOR
摘要： High-dose methotrexate (HD-MTX) is a key component of chemotherapy for CNS lymphoma (CNSL) but can be associated with leukoencephalopathy. The methylenetetrahydrofolate reductase (MTHFR) gene single-nucleotide polymorphisms (SNPs) C667T and A1298C reduce MTX metabolism and may increase the risk for systemic toxicity following HD-MTX. The correlation of these SNPs with neurotoxicity has not been evaluated. We performed a retrospective study on 52 patients (female n=20, male n=32) with CNSL who tested positive for MTHFR C677T and/or A1298 and who received HD-MTX (> 3.5 gm/m2) as part of their induction chemotherapy. MRI T2/FLAIR changes were assessed (grade 0=no abnormalities, grade 1=mild white matter changes, grade 2= pronounced and diffuse bilateral T2 hyperintensities) at baseline, 6, 12, and 60 months following treatment.Of all 52 patients, 30 harbored MTHFR C677T (n=10 homozygote, n=20 heterozygote), 14 had MTHFR A1298C (n=11 heterozygote, n=3 homozygote), and eight patients were compound heterozygote. We observed a high rate of progressive white matter changes compared to the literature which estimates a 25% incidence of leukoencephalopathy in this patient population. At 12 months, 33/52 patients (64%) showed T2/FLAIR abnormalities within the cerebral white matter (grade 1, n=27 (52%); grade 2, n=6 (12%)). At 60 months, presence of white matter changes increased to 38/52 (73%; grade 1, n=27 (52%); grade 2, n=11 (21%)). There was no significant difference in frequency of neurotoxicity between MTHFR subtypes. We observed two distinct radiographic patterns of white matter changes: a patchy, multifocal white matter T2/FLAIR hyperintensity and a more diffuse homogenous bi-hemispheric leukoencephalopathy. Our study is limited by its small sample size and retrospective design. A larger prospective radiographic and neurocognitive analysis with comparison to patients with MTHFR wildtype status would allow for a better characterization of the estimated risk, radiographic progression pattern, and functional consequences of chemotherapy associated white matter changes in CNSL patients.
关键词： CNS lymphoma,single-nucleotide polymorphisms,High-dose methotrexate,leukoencephalopathy,MTHFR
更新于2025-09-23 15:19:57
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Effect of Laser Irradiation on Reversibility and Drug Release of Light-Activatable Drug-Encapsulated Liposomes
摘要： Although several studies have demonstrated repetitive drug release using light-activatable liposomes, inconsistent drug release at each activation limits widespread usage. Here, we report reversible plasmonic material-coated encapsulated liposomes for proportional controlled delivery of methotrexate (MTX), which is a common drug for cancer and autoimmune diseases, using repetitive laser irradiation. Our results suggest a proportional increase in total drug release after repetitive laser irradiation. We hypothesize that the drug is released via “melted” lipid bilayers when the plasmonic materials on the liposome surface are heated by laser irradiation followed by reversible formation of the liposome. To evaluate our hypothesis, the number density of liposomes after laser irradiation was measured using single-particle (liposome) collision experiments at an ultramicroelectrode. Collisional frequency data suggest that the number density of liposomes remains unaltered even after 60 s of laser irradiation at 1.1 and 1.8 W, indicating that the liposome structure is reversible. The results were further compared with gold nanorod-coated nanodroplets where drug is released via irreversible phase transition. In contrast to what was observed with the liposome particles, the number density of the nanodroplets decreased with increasing laser irradiation duration. The structure reversibility of our liposome particles may be responsible for repetitive drug release with laser heating. We also studied the temperature rise in the lipid bilayer by incorporating polymerized 10,12-pentacosadiynoic acid (PCDA) in the lipid composition. The red shift in the UV?vis spectrum due to the structural change in PCDA lipids after laser irradiation indicates a rise in temperature above 75 °C, which is also above the chain-melting temperature of the main lipid used in the liposomes. All these results indicate that drug is released from the light-activatable liposomes due to reversible nanostructural alteration in the lipid bilayer by plasmonic resonance heating. The liposomes have potential to be a drug carrier for dose-controlled repetitive drug delivery.
关键词： drug release,reversible nanostructural alteration,light-activatable liposomes,plasmonic materials,laser irradiation,methotrexate
更新于2025-09-23 15:19:57
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Light-wavelength-based Quantitative Control of Dihydrofolate Reductase Activity Using Photochromic Isostere of Inhibitor
摘要： Photopharmacology has attracted research attention as a new tool to achieve the optical control of biomolecules following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor, azoMTX, for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to obtain the photoisomerization property. This fine molecular design enabled the quick structural conversion between the active 'bent' Z-isomer and the inactive 'extended' E-isomer of azoMTX, and this property afforded quantitative control of the enzyme activity, depending on the wavelength of irradiated light. The real-time photoreversible control of enzyme activity was also achieved.
关键词： methotrexate,photochromism,enzymes,azobenzene,photopharmacology
更新于2025-09-19 17:15:36