scholarly journals Heat-activated nanomedicine formulation improves the anticancer potential of the HSP90 inhibitor luminespib in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brittany Epp-Ducharme ◽  
Michael Dunne ◽  
Linyu Fan ◽  
James C. Evans ◽  
Lubabah Ahmed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Chemical Properties ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Synergistic Activity ◽  
Triggered Release ◽  
Optimal Drug ◽  
Thermosensitive Liposomes

AbstractThe heat shock protein 90 inhibitor, luminespib, has demonstrated potent preclinical activity against numerous cancers. However, clinical translation has been impeded by dose-limiting toxicities that have necessitated dosing schedules which have reduced therapeutic efficacy. As such, luminespib is a prime candidate for reformulation using advanced drug delivery strategies that improve tumor delivery efficiency and limit off-target side effects. Specifically, thermosensitive liposomes are proposed as a drug delivery strategy capable of delivering high concentrations of drug to the tumor in combination with other chemotherapeutic molecules. Indeed, this work establishes that luminespib exhibits synergistic activity in lung cancer in combination with standard of care drugs such as cisplatin and vinorelbine. While our research team has previously developed thermosensitive liposomes containing cisplatin or vinorelbine, this work presents the first liposomal formulation of luminespib. The physico-chemical properties and heat-triggered release of the formulation were characterized. Cytotoxicity assays were used to determine the optimal drug ratios for treatment of luminespib in combination with cisplatin or vinorelbine in non-small cell lung cancer cells. The formulation and drug combination work presented in this paper offer the potential for resuscitation of the clinical prospects of a promising anticancer agent.

Redox Sensitive Polysaccharide Based Nanoparticles for Improved Cancer Treatment: A Comprehensive Review

2018 ◽  
Vol 24 (28) ◽  
pp. 3303-3319 ◽  
Author(s):  
Erfaneh Ghassami ◽  
Jaleh Varshosaz ◽  
Somayeh Taymouri
Keyword(s):  
Drug Delivery ◽  
Cancer Treatment ◽  
Drug Delivery Systems ◽  
Chemical Properties ◽  
Delivery Systems ◽  
Exchange Reactions ◽  
Triggered Release ◽  
Redox Responsive

Background: Among the numerous bio-responsive polymeric drug delivery systems developed recently, redox-triggered release of molecular payloads have gained great deal of attention, especially in the field of anticancer drug delivery. In most cases, these systems rely on disulfide bonds located either in the matrix crosslinks, or in auxiliary chains to achieve stimuli-responsive drug release. These bonds keep their stability in extracellular environments, yet, rapidly break by thiol–disulfide exchange reactions in the cytosol, due to the presence of greater levels of glutathione. Polysaccharides are macromolecules with low cost, natural abundance, biocompatibility, biodegradability, appropriate physical and chemical properties, and presence of numerous functional groups which facilitate chemical or physical cross-linking. Methods: With regards to the remarkable advantages of polysaccharides, in the current study, various polysaccharide-based redox-responsive drug delivery systems are reviewed. In most cases the in vitro/in vivo effects of the developed system were also evaluated. Results: Considering the hypoxic and reducing nature of the tumor microenvironment, with several folds higher glutathione levels than the systemic tissues, redox-sensitive polymeric systems could be implemented for tumorspecific drug delivery and the results of the previous researches in this field indicated satisfactory achievements. Conclusion: According to the reviewed papers, the efficiency of diverse redox-responsive polysaccharide-based nanoparticles with therapeutic payloads in cancer chemotherapy could be concluded. Nevertheless, more comprehensive studies are required to understand the exact intracellular and systemic fate of these nano-carriers, as well as their clinical efficacy for cancer treatment.

scholarly journals Magnetic tri-bead microrobot assisted near-infrared triggered combined photothermal and chemotherapy of cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoxia Song ◽  
Zhi Chen ◽  
Xue Zhang ◽  
Junfeng Xiong ◽  
Teng Jiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Stimuli Responsive ◽  
Lung Cancer Cell ◽  
Precise Movement ◽  
Photothermal Property

AbstractMagnetic micro/nanorobots attracted much attention in biomedical fields because of their precise movement, manipulation, and targeting abilities. However, there is a lack of research on intelligent micro/nanorobots with stimuli-responsive drug delivery mechanisms for cancer therapy. To address this issue, we developed a type of strong covalently bound tri-bead drug delivery microrobots with NIR photothermal response azobenzene molecules attached to their carboxylic surface groups. The tri-bead microrobots are magnetic and showed good cytocompatibility even when their concentration is up to 200 µg/mL. In vitro photothermal experiments demonstrated fast NIR-responsive photothermal property; the microrobots were heated to 50 °C in 4 min, which triggered a significant increase in drug release. Motion control of the microrobots inside a microchannel demonstrated the feasibility of targeted therapy on tumor cells. Finally, experiments with lung cancer cells demonstrated the effectiveness of targeted chemo-photothermal therapy and were validated by cell viability assays. These results indicated that tri-bead microrobots have excellent potential for targeted chemo-photothermal therapy for lung cancer cell treatment.

Determination of the enhancing action of HSP90 on neuronal nitric oxide synthase by EPR spectroscopy

2001 ◽  
Vol 281 (6) ◽  
pp. C1819-C1824 ◽  
Author(s):  
Yao Song ◽  
Jay L. Zweier ◽  
Yong Xia
Keyword(s):  
Nitric Oxide ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Heat Shock Protein 90 ◽  
Tryptophan Fluorescence ◽  
Hsp90 Inhibitor ◽  
Resonance Spectroscopy ◽  
No Production ◽  
Dependent Manner ◽  
Intact Cells

Recent studies showed that heat shock protein 90 (HSP90) enhances nitric oxide (NO) synthesis from endothelial and neuronal NO synthase (eNOS and nNOS, respectively). However, these findings were based on indirect NO measurements. Moreover, although our previous studies showed that the action of HSP90 involves increased Ca2+/calmodulin (Ca2+/CaM) binding, quantitative measurements of the effect of HSP90 on CaM binding to nNOS have been lacking. With electron paramagnetic resonance spectroscopy, we directly measured NO signals from purified nNOS. HSP90 augmented NO formation from nNOS in a dose-dependent manner. Tryptophan fluorescence-quenching measurements revealed that HSP90 markedly reduced the K d of CaM to nNOS (0.5 ± 0.1 nM vs. 9.4 ± 1.8 nM in the presence and absence of HSP90, P < 0.01). Ca2+ ionophore triggered strong NO production from nNOS-transfected cells, and this was significantly reduced by the HSP90 inhibitor geldanamycin. Thus these studies provide direct evidence demonstrating that HSP90 enhances nNOS catalytic function in vitro and in intact cells. The effect of HSP90 is mediated by the enhancement of CaM binding to nNOS.

scholarly journals The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Diana Spiegelberg ◽  
Andris Abramenkovs ◽  
Anja Charlotte Lundgren Mortensen ◽  
Sara Lundsten ◽  
Marika Nestor ◽  
...  
Keyword(s):  
Tumor Growth ◽  
External Beam Radiotherapy ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Control Group ◽  
A431 Cells ◽  
Anti Cancer ◽  
Client Proteins

AbstractOncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Study on the Effect and Mechanism of Paclitaxel-Succinic Acid Drug-Loaded Nanofibers in Treating Lung Cancer

2021 ◽  
Vol 21 (2) ◽  
pp. 909-913
Author(s):  
Bin Pan ◽  
Peipei Li ◽  
Jing Chen ◽  
Jian Sun ◽  
Na Huang
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Tumor Tissues ◽  
Nano Drug Delivery ◽  
Poorly Soluble ◽  
New Type ◽  
Related Proteins ◽  
Development Prospects

In recent years, nanotechnology has made great progress in the development and application of tumor detection, diagnosis, and treatment, and eventually formed a “tumor nanomedicine.” The emerging field of “materials.” Nanoparticles have attracted much attention because they can overcome physiological barriers, effectively deliver hydrophobic drugs, and specifically target tumor tissues. At present, nanomedicines mainly include lipid nanoparticles, polymer nanoparticles granules, gold nanoparticles, magnetic nanoparticles, mesoporous silica, and other dosage forms. The use of nanomaterials as carriers in the treatment of lung cancer has unique advantages in achieving targeted drug delivery, slow-release drugs, and improvement of poorly soluble drugs and peptide drugs show obvious advantages in terms of bioavailability and reduction of adverse reactions, and have broad research and development prospects. This paper reports a new type of self-assembled Ptx-SA drug-loaded nanometers based on the carrier-free concept fiber, and it was found that the drug-loaded fiber has better cellophilicity, anti-tumor effect in vitro and in vivo than naked drug, and may be mediated by regulating the expression of related proteins. Therefore, the paclitaxel-loaded nano drug delivery system serves as a new type of nano preparation for treating lung cancer is worth further research.

scholarly journals Ganetespib (STA-9090), a Nongeldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in In Vitro and In Vivo Models of Non–Small Cell Lung Cancer

2012 ◽  
Vol 18 (18) ◽  
pp. 4973-4985 ◽  
Author(s):  
Takeshi Shimamura ◽  
Samanthi A. Perera ◽  
Kevin P. Foley ◽  
Jim Sang ◽  
Scott J. Rodig ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Hsp90 Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
In Vivo Models

scholarly journals Microfluidic Fabrication of Monodisperse Microcapsules for Thermo-Triggered Release of Liposoluble Drugs

Polymers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2200
Author(s):  
Yuanyuan Wang ◽  
Yongyue Li ◽  
Jinghua Gong ◽  
Jinghong Ma
Keyword(s):  
Drug Delivery ◽  
Methacrylic Acid ◽  
Environmental Temperature ◽  
In Vitro Release ◽  
Loading Capacity ◽  
Triggered Release ◽  
Model Drug ◽  
Monodisperse Microcapsules ◽  
Vitro Release

Here, we report a novel thermo-triggered-releasing microcapsule for liposoluble drug delivery. Monodisperse microcapsules with a poly(N-isopropylacrylamide-co-methacrylic acid) hydrogel shell and an oil core were successfully fabricated by a double coaxial microfluidic device. Fluorescent dye Lumogen Red F300 as a model liposoluble drug was dissolved in the oil core with controllable loading capacity. The volume phase transition temperature (VPTT) of the microcapsule was adjusted by copolymerizing with the hydrophilic methacrylic acid. The in vitro release study demonstrates that the shells shrink, leading to the thermo-triggered release of the model drug from the microcapsules at the environmental temperature above the VPTT, while the swollen hydrogel shells can protect the encapsulated drug from leakage and contamination below the VPTT. The proposed microcapsule is a promising liposoluble drug delivery system with controllable loading and smart thermo-triggered release.

scholarly journals 17-Allylamino-demethoxygeldanamycin Used Alone or in Combination with Sodium Orthovanadate Promotes Apoptosis and Inhibits Invasion of SH-SY5Y Cells by Modulating PIWIL2

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiaohong Tian ◽  
Wumei Wei ◽  
Xiaohong Wang ◽  
Qiang Ao ◽  
Jun Fan ◽  
...  
Keyword(s):  
Heat Shock Protein 90 ◽  
Multimodality Treatment ◽  
Hsp90 Inhibitor ◽  
Sodium Orthovanadate ◽  
Treatment Protocols ◽  
Cellular Signal ◽  
Cell Growth And Viability ◽  
Induced Apoptosis ◽  
Novel Drug

Neuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and accounts for 15% of cancer deaths. Even with the multimodality treatment protocols, the advanced-stage tumor overall 5-year survival rate is less than 50%. Therefore, novel drug therapy targeting cellular signal transduction pathways regulating the apoptotic cascade may be important for the treatment of drug-resistant NB. In our previous studies, we have demonstrated that 5 μM sodium orthovanadate (SOV) induced the apoptosis of SH-SY5Y cells. 17-Allylamino-demethoxygeldanamycin (17-AAG) is a geldanamycin- (GA-) derived heat shock protein 90 (Hsp90) inhibitor, and it has been shown to have potent antitumor activity in head and neck cancers. However, the effect of 17-AAG on the apoptosis of NB cells has not been reported. Therefore, the purpose of this study was to determine the effects of 17-AAG and SOV on the growth and invasion of SH-SY5Y cells in vitro and explore the related mechanism. In this study, we first investigated the antiviability effect of 17-AAG on SH-SY5Y cells, then studied the cell apoptosis and invasion influenced by 17-AAG and SOV, and assessed the role of PIWI-Like2 (PIWIL2) and piRNA-PIWI signaling in it. The results showed that 5 μM 17-AAG inhibited cell growth and viability and induced apoptosis in SH-SY5Y cells. Both 17-AAG and SOV reduced the level of PIWIL2 and Bcl-xl proteins and inhibited the invasion of SH-SY5Y cells. In addition, the combined use of the two drugs had greater effect than the single use of any drug.

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