Person: Hamblin, Michael
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Hamblin
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Hamblin, Michael
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Publication Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response(American Association for Cancer Research (AACR), 2009-05-12) Szokalska, A.; Makowski, M.; Nowis, D.; Wilczynski, G. M.; Kujawa, M.; Wojcik, C.; Mlynarczuk-Bialy, I.; Salwa, P.; Bil, J.; Janowska, S.; Agostinis, P.; Verfaillie, T.; Bugajski, M.; Gietka, J.; Issat, T.; Glodkowska, E.; Mrowka, P.; Stoklosa, T.; Mroz, P.; Jakobisiak, M.; Golab, J.; Hamblin, MichaelPhotodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors.Publication Smart Micro/nanoparticles in Stimulus-Responsive Drug/gene Delivery Systems(Royal Society of Chemistry (RSC), 2016) Karimi, Mahdi; Ghasemi, Amir; Sahandi Zangabad, Parham; Rahighi, Reza; Moosavi Basri, S. Masoud; Mirshekari, H.; Amiri, M.; Shafaei Pishabad, Z.; Aslani, A.; Bozorgomid, M.; Ghosh, D.; Beyzavi, A.; Vaseghi, A.; Aref, A. R.; Haghani, L.; Bahrami, S.; Hamblin, MichaelNew achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive "smart'' MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo-or magnetic-responsive nanoparticles (NPs), mechanical-or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.Publication Bacteriophages and Phage-Inspired Nanocarriers for Targeted Delivery of Therapeutic Cargos(Elsevier BV, 2016-11) Karimi, Mahdi; Mirshekari, Hamed; Moosavi Basri, Seyed Masoud; Bahrami, Sajad; Moghoofei, Mohsen; Hamblin, MichaelThe main goal of drug delivery systems is to target therapeutic cargoes to desired cells and to ensure their efficient uptake. Recently a number of studies have focused on designing bio-inspired nanocarriers, such as bacteriophages, and synthetic carriers based on the bacteriophage structure. Bacteriophages are viruses that specifically recognize their bacterial hosts. They can replicate only inside their host cell and can act as natural gene carriers. Each type of phage has a particular shape, a different capacity for loading cargo, a specific production time, and their own mechanisms of supramolecular assembly, that have enabled them to act as tunable carriers. New phage-based technologies have led to the construction of different peptide libraries, and recognition abilities provided by novel targeting ligands. Phage hybridization with non-organic compounds introduces new properties to phages and could be a suitable strategy for construction of bio-inorganic carriers. In this review we try to cover the major phage species that have been used in drug and gene delivery systems, and the biological application of phages as novel targeting ligands and targeted therapeutics.Publication Infrared Radiative Properties and Thermal Modeling of Ceramic-Embedded Textile Fabrics(The Optical Society, 2017-02-21) Anderson, David M.; Fessler, John R.; Pooley, Matthew A.; Seidel, Scott; Beckham, Haskell W.; Brennan, James F.; Hamblin, MichaelThe infrared optical properties of textiles are of great importance in numerous applications, including infrared therapy and body thermoregulation. Tuning the spectral response of fabrics by the engineering of composite textile materials can produce fabrics targeted for use in these applications. We present spectroscopic data for engineered polyester fabric containing varying amounts of ceramic microparticles within the fiber core and report a spectrally- dependent shift in infrared reflectance, transmittance and absorptance. A thermal transport model is subsequently implemented to study the effect of these modified properties on the spectral distribution of infrared radiation incident upon the wearer of a garment constructed of this fabric.Publication Eradication of Multidrug-Resistant Pseudomonas Biofilm With Pulsed Electric Fields(Wiley, 2015-09-09) Khan, Saiqa I.; Blumrosen, Gaddi; Vecchio, Daniela; Golberg, Alexander; Hamblin, Michael; McCormack, Michael; Yarmush, Martin; Austen, WilliamBiofilm formation is a significant problem, accounting for over eighty percent of microbial infections in the body. Biofilm eradication is problematic due to increased resistance to antibiotics and antimicrobials as compared to planktonic cells. The purpose of this study was to investigate the effect of Pulsed Electric Fields (PEF) on biofilm-infected mesh. Prolene mesh was infected with bioluminescent Pseudomonas aeruginosa and treated with PEF using a concentric electrode system to derive, in a single experiment, the critical electric field strength needed to kill bacteria. The effect of the electric field strength and the number of pulses (with a fixed pulse length duration and frequency) on bacterial eradication was investigated. For all experiments, biofilm formation and disruption were confirmed with bioluminescent imaging and Scanning Electron Microscopy (SEM). Computation and statistical methods were used to analyze treatment efficiency and to compare it to existing theoretical models. In all experiments 1500V are applied through a central electrode, with pulse duration of 50s, and pulse delivery frequency of 2Hz. We found that the critical electric field strength (Ecr) needed to eradicate 100-80% of bacteria in the treated area was 121 +/- 14V/mm when 300 pulses were applied, and 235 +/- 6.1V/mm when 150 pulses were applied. The area at which 100-80% of bacteria were eradicated was 50.5 +/- 9.9mm(2) for 300 pulses, and 13.4 +/- 0.65mm(2) for 150 pulses. 80% threshold eradication was not achieved with 100 pulses. The results indicate that increased efficacy of treatment is due to increased number of pulses delivered. In addition, we that showed the bacterial death rate as a function of the electrical field follows the statistical Weibull model for 150 and 300pulses. We hypothesize that in the clinical setting, combining systemic antibacterial therapy with PEF will yield a synergistic effect leading to improved eradication of mesh infections.Publication Significant Improvement in Cognition in Mild to Moderately Severe Dementia Cases Treated with Transcranial Plus Intranasal Photobiomodulation: Case Series Report(Mary Ann Liebert, Inc., 2017) Saltmarche, Anita E.; Naeser, Margaret A.; Ho, Kai Fai; Hamblin, Michael; Lim, LewAbstract Objective: This study investigated whether patients with mild to moderately severe dementia or possible Alzheimer's disease (AD) with Mini-Mental State Exam (MMSE) Baseline scores of 10–24 would improve when treated with near-infrared photobiomodulation (PBM) therapy. Background: Animal studies have presented the potential of PBM for AD. Dysregulation of the brain's default mode network (DMN) has been associated with AD, presenting the DMN as an identifiable target for PBM. Materials and methods: The study used 810 nm, 10 Hz pulsed, light-emitting diode devices combining transcranial plus intranasal PBM to treat the cortical nodes of the DMN (bilateral mesial prefrontal cortex, precuneus/posterior cingulate cortex, angular gyrus, and hippocampus). Five patients with mild to moderately severe cognitive impairment were entered into 12 weeks of active treatment as well as a follow-up no-treatment, 4-week period. Patients were assessed with the MMSE and Alzheimer's Disease Assessment Scale (ADAS-cog) tests. The protocol involved weekly, in-clinic use of a transcranial-intranasal PBM device; and daily at-home use of an intranasal-only device. Results: There was significant improvement after 12 weeks of PBM (MMSE, p < 0.003; ADAS-cog, p < 0.023). Increased function, better sleep, fewer angry outbursts, less anxiety, and wandering were reported post-PBM. There were no negative side effects. Precipitous declines were observed during the follow-up no-treatment, 4-week period. This is the first completed PBM case series to report significant, cognitive improvement in mild to moderately severe dementia and possible AD cases. Conclusions: Results suggest that larger, controlled studies are warranted. PBM shows potential for home treatment of patients with dementia and AD.Publication Red (660 nm) or near-infrared (810 nm) photobiomodulation stimulates, while blue (415 nm), green (540 nm) light inhibits proliferation in human adipose-derived stem cells(Nature Publishing Group UK, 2017) Wang, Yuguang; Huang, Ying-Ying; Wang, Yong; Lyu, Peijun; Hamblin, MichaelWe previously showed that blue (415 nm) and green (540 nm) wavelengths were more effective in stimulating osteoblast differentiation of human adipose-derived stem cells (hASC), compared to red (660 nm) and near-infrared (NIR, 810 nm). Intracellular calcium was higher after blue/green, and could be inhibited by the ion channel blocker, capsazepine. In the present study we asked what was the effect of these four wavelengths on proliferation of the hASC? When cultured in proliferation medium there was a clear difference between blue/green which inhibited proliferation and red/NIR which stimulated proliferation, all at 3 J/cm2. Blue/green reduced cellular ATP, while red/NIR increased ATP in a biphasic manner. Blue/green produced a bigger increase in intracellular calcium and reactive oxygen species (ROS). Blue/green reduced mitochondrial membrane potential (MMP) and lowered intracellular pH, while red/NIR had the opposite effect. Transient receptor potential vanilloid 1 (TRPV1) ion channel was expressed in hADSC, and the TRPV1 ligand capsaicin (5uM) stimulated proliferation, which could be abrogated by capsazepine. The inhibition of proliferation caused by blue/green could also be abrogated by capsazepine, and by the antioxidant, N-acetylcysteine. The data suggest that blue/green light inhibits proliferation by activating TRPV1, and increasing calcium and ROS.Publication Facial Manifestations of Pachydermoperiostosis Treated with Botulinum Toxin Type-A: Report of 3 Cases(2017) WEN, Xiang; LI, Yong; Hamblin, Michael; JIANG, XianPublication Antimicrobial photodynamic therapy mediated by methylene blue and potassium iodide to treat urinary tract infection in a female rat model(Nature Publishing Group UK, 2018) Huang, Ying-Ying; Wintner, Anton; Seed, Patrick C.; Brauns, Timothy; Gelfand, Jeffrey; Hamblin, MichaelDrug-resistant urinary tract infections (UTIs) are difficult and sometimes impossible to treat. Many UTIs are caused by uropathogenic Escherichia coli (UPEC). We developed an intact rat model of UTI, by catheterizing female rats and introducing a bioluminescent UPEC strain into the female rat bladder which lasted for up to six days. We recently showed that antimicrobial photodynamic inactivation (aPDI) of a bacterial infection mediated by the well-known phenothiazinium salt, methylene blue (MB) could be strongly potentiated by addition of the non-toxic salt potassium iodide (KI). In the intact rat model we introduced MB into the bladder by catheter, followed by KI solution and delivered intravesicular illumination with a diffusing fiber connected to a 1 W 660 nm laser. Bioluminescent imaging of the bacterial burden was carried out during the procedure and for 6 days afterwards. Light-dose dependent loss of bioluminescence was observed with the combination of MB followed by KI, but recurrence of infection was seen the next day in some cases. aPDT with MB + KI gave a significantly shorter duration of infection compared to untreated controls. aPDT with MB alone was the least effective. No signs of aPDT damage to the bladder lining were detected. This procedure to treat urinary tract infections without antibiotics by using already approved pharmaceutical substances (MB and KI) may have clinical applicability, either initially as a stand-alone therapy, or as an adjunct to antibiotic therapy by a rapid and substantial reduction of the bacterial burden.Publication Tetracyclines function as dual-action light-activated antibiotics(Public Library of Science, 2018) He, Ya; Huang, Ying-Ying; Xi, Liyan; Gelfand, Jeffrey; Hamblin, MichaelAntimicrobial photodynamic inactivation (aPDI) employs photosensitizing dyes activated by visible light to produce reactive oxygen species. aPDI is independent of the antibiotic resistance status of the target cells, and is thought unlikely to produce resistance itself. Among many PS that have been investigated, tetracyclines occupy a unique niche. They are potentially dual-action compounds that can both kill bacteria under illumination, and prevent bacterial regrowth by inhibiting ribosomes. Tetracycline antibiotics are regarded as bacteriostatic rather than bactericidal. Doxycycline (DOTC) is excited best by UVA light (365 nm) while demeclocycline (DMCT) can be efficiently activated by blue light (415 nm) as well as UVA. Both compounds were able to eradicate Gram-positive (methicillin-resistant Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria (>6 log(10) steps of killing) at concentrations (10–50μM) and fluences (10-20J/cm2). In contrast to methylene blue, MB plus red light, tetracyclines photoinactivated bacteria in rich growth medium. When ~3 logs of bacteria were killed with DMCT/DOTC+light and the surviving cells were added to growth medium, further bacterial killing was observed, while the same experiment with MB allowed complete regrowth. MIC studies were carried out either in the dark or exposed to 0.5mW/cm2 blue light. Up to three extra steps (8-fold) increased antibiotic activity was found with light compared to dark, with MRSA and tetracycline-resistant strains of E. coli. Tetracyclines can accumulate in bacterial ribosomes, where they could be photoactivated with blue/UVA light producing microbial killing via ROS generation.