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Journal of Porphyrins and... Jul 2011The synthesis and characterization of two 18-crown-6 functionalized analogues of an extensively studied gadolinium texaphyrin derivative, motexafin gadolinium (1, MGd),...
The synthesis and characterization of two 18-crown-6 functionalized analogues of an extensively studied gadolinium texaphyrin derivative, motexafin gadolinium (1, MGd), are reported. These are the monomeric and dimeric species, compounds 2 and 3, respectively. Both crown ether functionalized species proved to be stable at physiological pH and revealed distinct shifts in the UV spectrum when treated with sodium-, potassium-, ammonium- or zinc(II)-salts. Zinc(II) is believed to play a major role regulating apoptosis mechanisms in cancerous cells. Therefore, cytotoxicity studies of 2 and 3 were carried out using Ramos cell lines in the presence and absence of zinc(II).
PubMed: 22025887
DOI: 10.1142/S108842461100315X -
Angewandte Chemie (International Ed. in... Dec 2012Highly efficient apoptotic hyperthermia is achieved using a double-effector nanoparticle that can generate reactive oxygen species (ROS) and heat. ROS render cancer...
Highly efficient apoptotic hyperthermia is achieved using a double-effector nanoparticle that can generate reactive oxygen species (ROS) and heat. ROS render cancer cells more susceptible to subsequent heat treatment, which remarkably increases the degree of apoptotic cell death. Xenograft tumors (100 mm(3)) in mice are completely eliminated within 8 days after a single mild magnetic hyperthermia treatment at 43 °C for 30 min.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Hyperthermia, Induced; Magnetic Fields; Metal Nanoparticles; Metalloporphyrins; Mice; Neoplasms; Reactive Oxygen Species; Temperature; Transplantation, Heterologous
PubMed: 23139178
DOI: 10.1002/anie.201206400 -
PloS One 2014MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin...
MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.
Topics: Brachytherapy; Contrast Media; Gadolinium; Humans; Metalloporphyrins; Monte Carlo Method; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage
PubMed: 25275550
DOI: 10.1371/journal.pone.0109389 -
Radiology Mar 2012To investigate the feasibility of using magnetic resonance (MR) imaging to monitor intrabiliary delivery of motexafin gadolinium (MGd) into pig common bile duct (CBD)...
PURPOSE
To investigate the feasibility of using magnetic resonance (MR) imaging to monitor intrabiliary delivery of motexafin gadolinium (MGd) into pig common bile duct (CBD) walls.
MATERIALS AND METHODS
Animal studies were approved by the Institutional Animal Care and Use Committee. Initially, human cholangiocarcinoma cells were treated with various concentrations of MGd, a compound serving as a T1-weighted MR imaging contrast agent, chemotherapy drug, and cell marker. These cells were then examined by means of confocal microscopy to confirm the intracellular uptake of MGd. In addition, an MGd/trypan blue mixture was locally infused into CBD walls of six cadaveric pigs using a microporous balloon catheter. CBDs of six pigs were infused with saline to serve as controls. Ex vivo T1-weighted MR imaging of these CBDs was performed. For in vivo technical validation, the microporous balloon catheter was placed in the CBD by means of a transcholecytic access to deliver MGd/trypan blue into CBD walls of six living pigs. T1-weighted images were obtained with both a surface coil and an intrabiliary MR imaging guidewire, and contrast-to-noise ratios of CBD walls before and after MGd/trypan blue infusions were compared in the two groups by means of paired t test, with subsequent histologic analysis to confirm the penetration and distribution of the MGd/trypan blue agent into CBD walls.
RESULTS
In vitro experiments confirmed uptake of MGd by human cholangiocarcinoma cells. The ex vivo experiments demonstrated the penetration of MGd/trypan blue into the CBD walls. The in vivo experiment confirmed the uptake of MGd/trypan blue, showing an increased contrast-to-noise ratio for the CBD after administration of the mixture, compared with images obtained prior to MGd/trypan blue administration (11.6 ± 4.2 [standard deviation] vs 5.7 ± 2.8; P = .04). Histologic results depicted the blue dye stains and red fluorescence of MGd in CBD walls, confirming the imaging findings.
CONCLUSION
It is feasible to use MR imaging to monitor the penetration of locally delivered MGd into pig CBD walls.
Topics: Animals; Antineoplastic Agents; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Catheterization; Cholangiocarcinoma; Contrast Media; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Feasibility Studies; Fluoroscopy; Humans; Magnetic Resonance Imaging, Interventional; Metalloporphyrins; Microscopy, Confocal; Swine; Trypan Blue; Tumor Cells, Cultured
PubMed: 22357886
DOI: 10.1148/radiol.11110723 -
Technology in Cancer Research &... Jun 2004Radiation therapy is a central modality in the treatment of glioblastoma multiforme (GBM). Integral to adequate radiation therapy delivery is the appropriate... (Comparative Study)
Comparative Study
Radiation therapy is a central modality in the treatment of glioblastoma multiforme (GBM). Integral to adequate radiation therapy delivery is the appropriate determination of tumor volume and extent at the time treatment is being delivered. As a matter of routine practice, radiation therapy treatment fields are designed based on tumor volumes evident on pre-operative or immediate post-operative MRIs; another MRI is generally not obtained for planning boost fields. In some instances the time interval from surgery to radiotherapy initiation is up to 5 weeks and the boost or "cone-down phase" commences 4-5 weeks later. The contrast enhanced T1 MRI may not be a totally reliable indicator of active tumor, especially in regions where such blood-brain barrier breakdown has not occurred. Moreover, these volumes may change during the course of treatment. This may lead to a geographic miss when mid-treatment boost volumes are designed based on a pre-radiotherapy MRI. The goal of this study is to examine how a mid-treatment MRI impacts the delineation and definition of the boost volume in GBM patients in comparison to the pre-treatment MRI scan, particularly when the tumor-specific agent Motexafin-Gadolinium is used.
Topics: Brain Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Contrast Media; Glioblastoma; Humans; Magnetic Resonance Imaging; Metalloporphyrins; Postoperative Period; Radiotherapy; Radiotherapy Planning, Computer-Assisted; Tumor Burden
PubMed: 15161323
DOI: 10.1177/153303460400300308 -
Radiation Oncology (London, England) Sep 2012Unresectable pancreatic cancer (UPC) has low survival. With improving staging techniques and systemic therapy, local control in patients without metastatic disease may...
BACKGROUND
Unresectable pancreatic cancer (UPC) has low survival. With improving staging techniques and systemic therapy, local control in patients without metastatic disease may have increasing importance. We investigated whether the radiation dose used in chemoradiation (CRT) as definitive treatment for UPC and the CA 19-9 response to therapy have an impact on overall survival (OS).
METHODS
From 1997-2009 46 patients were treated with CRT for non-metastatic UPC. Median prescribed RT dose was 54 Gy (range 50.4-59.4 Gy). All patients received concurrent chemotherapy (41: 5-fluorouracil, 5: other) and 24 received adjuvant chemotherapy.
RESULTS
41 patients were inoperable due to T4 disease and 5 patients with T3 disease were medically inoperable. Five patients did not complete CRT due to progressive disease or treatment-related toxicity (median RT dose 43.2 Gy). Overall, 42 patients were dead of disease at the time of last follow-up. The median and 12 month OS were 8.8 months and 35%, respectively. By univariate analysis, minimum CA 19-9 post-CRT <90 U/mL was favorably associated with OS (12.3 versus 8.8 months, p = 0.012). Radiotherapy dose ≥54 Gy trended towards improved OS (11.3 versus 6.8 months, p = 0.089). By multivariable analysis, a delivered RT dose of ≥54 Gy (HR 0.47, p = 0.028) and minimum CA 19-9 post-CRT of <90 U/mL (HR 0.35, p = 0.008) were associated with OS.
CONCLUSIONS
CRT as definitive treatment for UPC had low survival. However, our retrospective data suggest that patients treated to ≥54 Gy or observed to have a minimum post-CRT CA 19-9 <90 U/mL had improved likelihood of long-term survival.
Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; CA-19-9 Antigen; Capecitabine; Carcinoma; Chemoradiotherapy; Chemotherapy, Adjuvant; Deoxycytidine; Disease Progression; Dose-Response Relationship, Radiation; Female; Fluorouracil; Genetic Therapy; Genetic Vectors; Humans; Kaplan-Meier Estimate; Male; Metalloporphyrins; Middle Aged; Pancreatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha; Gemcitabine
PubMed: 22974515
DOI: 10.1186/1748-717X-7-156 -
Dalton Transactions (Cambridge, England... Apr 2006The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described....
The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described. These new derivatives contain either 1,2-diaminobenzene or 2,3-diaminonaphthalene subunits as the source of the imine nitrogens and bear multiple 2-[2-(2-methoxyethoxy)ethoxy]ethoxy (PEG) groups, on either meso aryl or beta-pyrrolic substituents, to increase their water solubility. All four analogues were found to be more active in vitro than the parent system MGd as judged from cell proliferation assays using the PC3 and A549 cell lines.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Electrochemistry; Humans; Models, Molecular; Molecular Structure; Porphyrins; Structure-Activity Relationship
PubMed: 16609763
DOI: 10.1039/b515636j -
The Journal of Investigative Dermatology May 1998Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the...
Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.
Topics: Animals; Apolipoproteins E; Apoptosis; Blood Proteins; Female; Longevity; Melanoma; Metalloporphyrins; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Photochemotherapy; Photosensitizing Agents; Tissue Distribution
PubMed: 9579539
DOI: 10.1046/j.1523-1747.1998.00182.x -
Proceedings of the National Academy of... Jun 1996Gadolinium(III) texaphyrin (Gd-tex2+) is representative of a new class of radiation sensitizers detectable by magnetic resonance imaging (MRI). This porphyrin-like...
Gadolinium(III) texaphyrin (Gd-tex2+) is representative of a new class of radiation sensitizers detectable by magnetic resonance imaging (MRI). This porphyrin-like complex has a high electron affinity [E1/2 (red.) approximately = -0.08 V versus normal hydrogen electrode] and forms a long-lived pi-radical cation upon exposure to hydrated electrons, reducing ketyl radicals, or superoxide ions. Consistent with these chemical findings, Gd-tex2+ was found to be an efficient radiation sensitizer in studies carried out with HT29 cells in in vitro as well as in in vivo single and multifraction irradiation studies with a murine mammary carcinoma model. Selective localization of Gd-tex2+ in tumors was confirmed by MRI scanning.
Topics: Animals; Humans; Magnetic Resonance Imaging; Mammary Neoplasms, Experimental; Metalloporphyrins; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Radiation-Sensitizing Agents; Radiography; Sarcoma, Experimental; Tumor Cells, Cultured
PubMed: 8692865
DOI: 10.1073/pnas.93.13.6610