Papers by Ruth Goldschmidt
Bioorganic & Medicinal Chemistry, 2012
Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthes... more Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthesized and evaluated as antioxidants capable of preserving mitochondrial function. The compounds, having a different redox core but the same side chain as idebenone, exhibited a range of potencies, reflecting differences in their structures. The results obtained provide guidance in the design of such analogues with improved properties. Analogues were identified that have significantly improved antioxidant activity compared with idebenone in cultured lymphocytes, and which exhibit lesser inhibition of the electron transport chain.
Bioorganic & Medicinal Chemistry, 2013
Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characteri... more Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q 10-deficient human lymphocytes. The more lipophilic side chains attached to the pyrimidinol redox core in these compounds resulted in less inhibition of the electron transport chain and improved antioxidant activity.
ACS Medicinal Chemistry Letters, 2011
Supplementary Method, Supplementary Tables, and Supplementary Figures from Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer
(i) Supplementary Methods 1. Synthesis of L-BPD and L-IRI via freeze-thaw extrusion method 2. Pha... more (i) Supplementary Methods 1. Synthesis of L-BPD and L-IRI via freeze-thaw extrusion method 2. Pharmacokinetics and biodistribution of L-BPD and L-IRI 3. In-vitro quantification of changes in ABCG2 expression using immunofluorescence 4. Ultrasound Imaging 5. Histology and immunofluorescence of tumor samples 6. Quantification of H&E and immunofluorescence biomarkers 7. Determination of Synergism (ii) Supplementary Tables Supplementary Table S1. Comparison of PDT and irinotecan doses used in this study versus in clinic Supplementary Table S2. List of antibodies used for immunofluorescence Supplementary Table S3. The synergistic effect of combination PDT and L-IRI Supplementary Table S4. Physical parameters of L-BPD and L-IRI (iii) Supplementary Figures and Legends Supplementary Fig. S1. Treatment schedule and longitudinal monitoring of PanCa tumors in vivo Supplementary Fig. S2. Sub-cytotoxic PDT leads to decreased levels of ABCG2 and increased intracellular irinotecan in AsPC-1 cells Supplementary Fig. S3. Tumor growth kinetics of MIA PACa-2 and AsPC-1 in vivo Supplementary Fig. S4. Change in mouse body weight after combination treatment
PURPOSE. We evaluated the efficacy and safety of photochemical corneal stiffening by palladium ba... more PURPOSE. We evaluated the efficacy and safety of photochemical corneal stiffening by palladium bacteriochlorin 13 0 -(2-sulfoethyl)amide dipotassium salt (WST11) and near infrared (NIR) illumination, using ex vivo and in vivo rabbit eye models. METHODS. Corneas of post mortem rabbits and living rabbits were pretreated topically with 2.5 mg/mL WST11 in saline or in 20% dextran T-500 (WST-D), washed and illuminated with an NIR diode laser (755 nm, 10 mW/cm 2 . Studies with corneas of untreated fellow eyes served as controls. Tensile strength measurements, histopathology, electron spin resonance, and optical spectroscopy and fluorescence microscopy were used to assess treatment effects. Comparative studies were performed with standard riboflavin/ultraviolet-A light (UVA) treatment. RESULTS. WST11/NIR treatment significantly increased corneal stiffness following ex vivo or in vivo treatment, compared to untreated contralateral eyes. The incremental ultimate stress and Young's modul...
Cornea Stiffening of Rabbit Corneas by the Bacteriochlorophyll Derivative WST 11 Using Near Infrared Light
METHODS. Corneas of post mortem rabbits and living rabbits were pretreated topically with 2.5 mg/... more METHODS. Corneas of post mortem rabbits and living rabbits were pretreated topically with 2.5 mg/mL WST11 in saline or in 20% dextran T-500 (WST-D), washed and illuminated with an NIR diode laser (755 nm, 10 mW/cm. Studies with corneas of untreated fellow eyes served as controls. Tensile strength measurements, histopathology, electron spin resonance, and optical spectroscopy and fluorescence microscopy were used to assess treatment effects. Comparative studies were performed with standard riboflavin/ultravioletA light (UVA) treatment.
Vascular Targeted Photodynamic Therapy Monitored by Real-Time Laser Speckle Imaging
World Academy of Science, Engineering and Technology, International Journal of Medical and Health Sciences, 2017
Long term follow-up of stiffening of rabbit corneas by WST11 using near infrared light
Investigative Ophthalmology & Visual Science, 2013
Intranasal administration of drugs is gaining popularity in medicine, and several animal models h... more Intranasal administration of drugs is gaining popularity in medicine, and several animal models have been used to test the safety and efficacy of this delivery route. Nevertheless, the nasal anatomy of animals is different from humans, which can lead to pathological changes that stem from the delivery device and not the drug itself. Here, we report on nasal inflammation and ulceration in rabbits, secondary to the repeated trauma caused by the intranasal device. Similar changes were noted in the animals treated with the vehicle and with the tested drug, and therefore, these changes were not attributed to the drug itself. In some animals, superficial ulcer and stromal inflammation were noted in the eyes, secondary to nasal duct obstruction from the nasal inflammation. These observations emphasize the importance of proper interpretation of histopathological changes, attributed to trauma-induced pathological changes related to the handling of the animal and not to the tested product, wh...
Excimer laser‐assisted corneal epithelial pattern ablation for corneal cross‐linking
Acta Ophthalmologica
PURPOSE To determine corneal cross-linking (CXL) efficacy and chromophore penetration after excim... more PURPOSE To determine corneal cross-linking (CXL) efficacy and chromophore penetration after excimer laser-assisted patterned de-epithelialization. METHODS Two-hundred-twenty porcine eyes were de-epithelialized ex vivo, either fully (mechanical; n = 88) or patterned (excimer laser; n = 132). Consecutively, corneas were impregnated with hypo- or hyperosmolar riboflavin (RF; n = 20, RF-D; n = 40, respectively) or water-soluble taurine (WST11; n = 40, and WST-D; n = 40, respectively), or kept unimpregnated (n = 80). Sixty corneas were subsequently irradiated, inducing CXL, with paired contralateral eyes serving as controls. Outcome measurements included strip extensiometry to assess CXL efficacy, and spectrophotometry and fluorescence microscopy to determine stromal chromophore penetration. RESULTS All tested chromophores induced significant CXL (p < 0.001), ranging from 7.6% to 14.6%, with similar stiffening for all formulations (p = 0.60) and both de-epithelialization methods (p = 0.56). Light transmittance was significantly lower (p < 0.001) after full compared with patterned de-epithelialization. Stromal chromophore penetration was comparable between fully and patterned de-epithelialized samples, with full penetration in RD and RF-D samples and penetration depths measuring 591.7 ± 42.8 µm and 592.9 ± 63.5 µm for WST11 (p = 0.963) and 504.2 ± 43.2 µm and 488.8 ± 93.1 µm for WST-D (p = 0.669), respectively. CONCLUSIONS Excimer laser-assisted patterned de-epithelialization allows for effective CXL. Stromal chromophore concentration is, however, reduced, which may have safety implications given the need for sufficient UVA attenuation in RF/UVA CXL. The different safety profile of near-infrared (NIR) may allow safe WST11/NIR CXL even with reduced stromal chromophore concentration values. In vivo studies are needed to evaluate the benefits and further assess safety of excimer laser-assisted patterned de-epithelialization for corneal CXL.
97PVascular targeted photodynamic therapy for pancreatic ductal adenocarcinoma: A pre-clinical success
Annals of Oncology
Oncotarget
Effective treatment of advanced metastatic disease remains the primary challenge in the managemen... more Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinicallyapproved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporallyspaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanisticallydistinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer.
Real time laser speckle imaging monitoring vascular targeted photodynamic therapy
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVI
Laser speckle imaging is a technique that has been developed to non-invasively monitor in vivo bl... more Laser speckle imaging is a technique that has been developed to non-invasively monitor in vivo blood flow dynamics and vascular structure, at high spatial and temporal resolution. It can record the full-field spatio-temporal characteristics of microcirculation and has therefore, often been used to study the blood flow in tumors after photodynamic therapy (PDT). Yet, there is a paucity of reports on real-time laser speckle imaging (RTLSI) during PDT. Vascular-targeted photodynamic therapy (VTP) with WST11, a water-soluble bacteriochlorophyll derivative, achieves tumor ablation through rapid occlusion of the tumor vasculature followed by a cascade of events that actively kill the tumor cells. WST11-VTP has been already approved for treatment of early/intermediate prostate cancer at a certain drug dose, time and intensity of illumination. Application to other cancers may require different light dosage. However, incomplete vascular occlusion at lower light dose may result in cancer cell survival and tumor relapse while excessive light dose may lead to toxicity of nearby healthy tissues. Here we provide evidence for the feasibility of concomitant RTLSI of the blood flow dynamics in the tumor and surrounding normal tissues during and after WST11-VTP. Fast decrease in the blood flow is followed by partial mild reperfusion and a complete flow arrest within the tumor by the end of illumination. While the primary occlusion of the tumor feeding arteries and draining veins agrees with previous data published by our group, the late effects underscore the significance of light dose control to minimize normal tissue impairment. In conclusion- RTSLI application should allow to optimize VTP efficacy vs toxicity in both the preclinical and clinical arenas.
Mechanistic exploration of a bi-directional PDT-based combination in pancreatic cancer (Conference Presentation)
Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXV, 2016
It is increasingly evident that the most effective cancer treatments will involve interactive reg... more It is increasingly evident that the most effective cancer treatments will involve interactive regimens that target multiple non-overlapping pathways, preferably such that each component enhances the others to improve outcomes while minimizing systemic toxicities. Toward this goal, we developed a combination of photodynamic therapy and irinotecan, which mechanistically cooperate with each other, beyond their individual tumor destruction pathways, to cause synergistic reduction in orthotopic pancreatic tumor burden. A three-way mechanistic basis of the observed the synergism will be discussed: (i) PDT downregulates drug efflux transporters to increase intracellular irinotecan levels. (ii) Irinotecan reduces the expression of hypoxia-induced marker, which is upregulated by PDT. (iii) PDT downregulates irinotecan-induced survivin expression to amplify the apoptotic and anti-proliferative effects. The clinical translation potential of the combination will also be highlighted.
Cancer research, Jan 30, 2015
The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival an... more The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple non-overlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is FDA-approved for gemcitabine-refractory metastatic pancreatic cancer (PanCa). However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here we demonstrate that benzoporphyrin derivative (BPD)-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in PanCa. Moreover, we show that PDT inhibited survivin expression. While PDT potentiated irinotecan ...
Abstract B148: Ultrasound image guided combination therapies involving photodynamic therapy and irinotecan
Introduction: The field of cancer therapeutics is moving towards attacking the pathology with mec... more Introduction: The field of cancer therapeutics is moving towards attacking the pathology with mechanistically distinct or synergistic combination therapies. In addition to possessing distinct cytotoxicity mechanisms, factors such as dose and sequence of combination therapy needs to be determined for effective therapeutic outcome. Non-invasive imaging techniques play a major role in personalizing these therapies by providing quantitative information on tumor volume, perfusion, oxygenation status, drug concentration etc. In particular we utilized ultrasound imaging to gauge the efficacy of photodynamic therapy (PDT) and irinotecan combination therapy in orthotopic pancreatic tumors of different volume. The rationale behind choosing PDT and irinotecan combination is that Irinotecan intracellular concentrations are increased, as PDT is known to cause destruction of ABC transporters that are responsible for the efflux of the drug and its metabolites outside of the cells. Photoacoustic imaging (a technique that provides contrast based on optical absorption properties of the tissue) was utilized to monitor changes in blood volume and oxygen saturation post photodynamic therapy. Materials and Methods: Orthotopic or subcutaneous pancreatic tumor models were established using MIA PaCA-2 cell line in Swiss Nu/Nu mice (4-6 weeks old). Cells (1 × 106in 50 μL of Matrigel-containing media) were injected into the pancreas or subcutaneously using a 301/2-gauge needle. Orthotopic tumors were imaged to gauge the combination treatment efficacy while the subcutaneous tumors provided change in tumor blood volume post PDT. Ultrasound imaging was used to non-invasively monitor tumor volume in mice and treatment was initiated when the tumors reached ∼35 mm3or ∼70 mm3. Irinotecan and photosensitizer, Benzoporphyrin derivative (BPD) were encapsulated in liposomes and injected via tail vein at concentrations 0.25 mg/kg and 20 mg/kg respectively, 60 minutes prior to PDT light irradiation. Interstitial PDT (690 nm laser, 100mW/cm2, 75 J/cm2) was performed on the exteriorized pancreas of the anesthetized mice with orthotopic tumors. Subcutaneous tumors also received the same PDT dose. Ultrasound and photoacoustic imaging was performed using commercially available Vevo LAZR system. Results and Conclusions: The longitudinal non-invasive ultrasound monitoring of orthotopic tumor volume in response to combination therapy was carried out with appropriate controls. We observed that PDT significantly enhances the tumoricidal efficacy of irinotecan and significantly inhibited tumor growth up to at least 3 weeks post-treatment (p < 0.05). A second combination treatment given at this point did not yield a reduction in tumor volume. In addition we also observed the treatment was ineffective in larger tumors. Photoacoustic imaging of subcutaneous tumors showed decrease in oxygen saturation and blood volume post PDT. The findings of this study recognize the importance of longitudinally monitoring tumor volume, vasculature and blood oxygen status for success of combination treatments. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B148. Citation Format: Srivalleesha Mallidi, Huang-Chiao Huang, Zhiming Mai, Ruth Goldschmidt, Joyce Liu, Patrick Chiang, Dmitriy Timerman, Imran Rizvi, Bryan Spring, Akilan Palanisami, Tayyaba Hasan. Ultrasound image guided combination therapies involving photodynamic therapy and irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B148.
Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates
Proceedings of the National Academy of Sciences, 2014
Drug-resistant micrometastases that escape standard therapies often go undetected until the emerg... more Drug-resistant micrometastases that escape standard therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-infrared chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resolution of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of “tumor-targeted, activatable photoimmunotherapy” in a mous...
Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST11, noncovalently bound to serum albumin
The Journal of …, 2009
Light-induced radical generation is the hallmark of fundamental processes and many applications i... more Light-induced radical generation is the hallmark of fundamental processes and many applications including photosynthesis and photodynamic therapy (PDT). In this manuscript, we present two novel observations made upon monitoring light-induced generation of ...
Effects of alkyl side chain modification of coenzyme Q10 on mitochondrial respiratory chain function and cytoprotection
Bioorganic & Medicinal Chemistry, 2013
The effect of the alkyl side chain length of coenzyme Q10 on mitochondrial respiratory chain func... more The effect of the alkyl side chain length of coenzyme Q10 on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption and mitochondrial membrane potential, and also conferred significant cytoprotection on cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. The analogues also exhibited lesser inhibition of the electron transport chain than idebenone. The results obtained provide guidance for the design of CoQ10 analogues with improved activity compared to that of idebenone (1), the latter of which is undergoing evaluation in the clinic as a therapeutic agent.
335533 Nanoparticle-Assisted, Mechanism-Based Combination Photodynamic and Irinotecan Therapy for Pancreatic Cancer
The purpose of this study is to strategically combine two clinical-relevant, nanotechnology-based... more The purpose of this study is to strategically combine two clinical-relevant, nanotechnology-based therapies to facilitate rapid clinical translation and immediately improve on the dismal statistics of pancreatic cancer (PanCa) patients. We hypothesized that benzoporphyrin derivative (BPD)-based photodynamic therapy (PDT) (Phase I/II study, solid PanCa) destroys tumor efflux transporters, which may help maintain high intracellular concentrations of Irinotecan (CPT-11) (Phase III study, metastatic PanCa) to reduce tumor burden and prolong survival. We test our hypothesis in orthotopic PanCa models. Two types of liposomes were fabricated by adapting procedures from literature. They are: (i) Liposome with BPD in lipid bilayer (LBPD) and (ii) Liposome encapsulating CPT-11 in aqueous core (LCPT-11). Lipids (DPPC, DOTAP, Cholesterol, DSPE-mPEG at a molar ratio of 2:0.2:1.0:0.2) were mixed in chloroform (for LBPD, dissolve with 0.2 mM BPD), and the chloroform was evaporated. Lipid films wer...
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Papers by Ruth Goldschmidt