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Jonathan L. Sessler - One of the best experts on this subject based on the ideXlab platform.
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Recent Developments in Texaphyrin Chemistry and Drug Discovery
Inorganic chemistry, 2013Co-Authors: Christian Preihs, Jonathan F. Arambula, Darren Magda, Zahid H. Siddik, Heeyeong Jeong, Dongwon Yoo, Jinwoo Cheon, Jonathan L. SesslerAbstract:Texaphyrins are pentaaza expanded porphyrins with the ability to form stable complexes with a variety of metal cations, particularly those of the lanthanide series. In biological milieus, Texaphyrins act as redox mediators and mediate the production of reactive oxygen species (ROS). In this review, newer studies involving Texaphyrin complexes targeting several different applications in anticancer therapy are described. In particular, the preparation of bismuth and lead Texaphyrin complexes as potential α-core emitters for radiotherapy is detailed, as are Gadolinium Texaphyrin functionalized magnetic nanoparticles with features that make them of interest as dual-mode magnetic resonance imaging contrast agents and as constructs with anticancer activity mediated through ROS-induced sensitization and concurrent hyperthermia. Also discussed are Gadolinium Texaphyrin complexes as possible carrier systems for the targeted delivery of platinum payloads.
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Crown ether functionalized Texaphyrin monomers and dimers.
Journal of porphyrins and phthalocyanines, 2011Co-Authors: Christian Preihs, Darren Magda, Jonathan L. SesslerAbstract: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 the Ramos cell line in the presence and absence of zinc(II).
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Gadolinium Texaphyrin (Gd-Tex)-Malonato-Platinum Conjugates: Synthesis and Comparison with Carboplatin in Normal and Pt-Resistant Cell Lines
Dalton transactions (Cambridge England : 2003), 2009Co-Authors: Jonathan F. Arambula, Jonathan L. Sessler, Mark Fountain, Wen Hao Wei, Darren Magda, Zahid H. SiddikAbstract:The synthesis of a new PEG-solubilized Gadolinium Texaphyrin (Gd-Tex) conjugate containing a malonate-Pt(NH3)2 moiety is described. The effect of the tumor localizing Gd-Tex macrocycle on platinum activity was evaluated in cell culture. The malonate moiety, analogous to that present in carboplatin, is expected to release an aquated Pt(NH3)2 species under physiological conditions. The half-life in phosphate-buffered saline was found to be ca. 3 days at room temperature, and the hydrolytic product released from the conjugate was collected and confirmed as Pt-based by flameless atomic absorption spectrophotometry. Anti-proliferative activity was tested using A549 human lung cancer and A2780 human ovarian cancer cell lines. In both cell lines, the activity of the Gd-Tex conjugate was found to be similar to that of carboplatin. Efficacy against a Pt-resistant ovarian cell line greater than that displayed by carboplatin was also observed.
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Gadolinium Texaphyrin-methotrexate conjugates. Towards improved cancer chemotherapeutic agents.
Organic & biomolecular chemistry, 2005Co-Authors: Wen Hao Wei, Mark Fountain, Darren Magda, Dale Miles, Zhong Wang, Phil Lecane, Mimi Mesfin, Jonathan L. SesslerAbstract:Conjugates between methotrexate (MTX, Matrex®, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin Gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.
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In vivo animal studies with Gadolinium (III) Texaphyrin as a radiation enhancer.
International journal of radiation oncology biology physics, 1999Co-Authors: Richard A. Miller, Qing Fan, Jonathan L. Sessler, Kathryn W. Woodburn, M.f. Renschler, Jason A. KoutcherAbstract:Abstract Purpose: Gadolinium Texaphyrin (Gd-Tex, PCI-0120) is an expanded porphyrin that has demonstrated radiation enhancement. In this study, we evaluated the radiation enhancement and biolocalization of Gd-Tex in three animal tumor models. Methods and Materials: EMT6, SMT-F, and MCa tumors were established intramuscularly or subcutaneously. Gd-Tex and other metalloTexaphyrins were administered prior to single or multiple fractions of radiation. 14 C-labeled Gd-Tex was used for biolocalization studies. Results: Gd-Tex, in combination with radiation, produced significant tumor growth delay compared to irradiated control groups in both single and multifraction radiation studies. Gd-Tex radiation enhancement was observed only when the drug was given before, but not after irradiation. Several metalloTexaphyrins, identical except for the metal ion, were studied in the EMT6 tumor model including Gadolinium (Gd), lutetium (Lu), europium (Eu), yttrium (Y), and cadmium (Cd) Texaphyrin complexes. Only Gd-Tex produced radiation enhancement. Biodistribution studies using 14 C-labeled Gd-Tex demonstrated drug selectivity and retention in tumors growing intramuscularly compared to uninvolved muscle and plasma. Conclusions: Gd-Tex produces reproducible radiation enhancement in a variety of in vivo tumor models. This drug’s unique radiochemistry, tumor selectivity, and in vivo activity suggests possible mechanisms of action not addressed by in vitro assay methods.
Vladimir J. Hruby - One of the best experts on this subject based on the ideXlab platform.
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development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor
Journal of Medicinal Chemistry, 2013Co-Authors: Natalie M Barkey, Christian Preihs, Heather H Cornnell, Gary V Martinez, Adam Carie, Josef Vagner, Mark C Lloyd, Vincent M Lynch, Liping Xu, Vladimir J. HrubyAbstract:Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new Gadolinium Texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payload...
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Development and in Vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor
2013Co-Authors: Natalie M Barkey, Christian Preihs, Heather H Cornnell, Adam Carie, Josef Vagner, Mark C Lloyd, Vincent M Lynch, Gary Martinez, Vladimir J. HrubyAbstract:Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new Gadolinium Texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R
Stuart W. Young - One of the best experts on this subject based on the ideXlab platform.
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A Phase I Single-Dose Trial of Gadolinium Texaphyrin (Gd-Tex), a Tumor Selective Radiation Sensitizer Detectable by Magnetic Resonance Imaging
Clinical cancer research : an official journal of the American Association for Cancer Research, 1999Co-Authors: David I. Rosenthal, Stuart W. Young, Pamela Nurenberg, Carlos Becerra, Eugene P. Frenkel, David P. Carbone, Bert L. Lum, Richard A. Miller, Julie Engel, Dale MilesAbstract:Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35–77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.
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Selective uptake of Texaphyrins in atheromatous plaque
Lasers in Surgery: Advanced Characterization Therapeutics and Systems VI, 1996Co-Authors: Kathryn W. Woodburn, Stuart W. Young, Qing Fan, David Kessel, Richard A. MillerAbstract:Texaphyrins are water soluble porphyrinoids which selectively localize in atheromatous plaque. The paramagnetic Gadolinium Texaphyrin is an excellent contrast agent which enables plaque detection by MRI. The diamagnetic lutetium Texaphyrin, using fluorescence methods, was also shown to label atheromatous plaque. The chemical environment of bound lutetium Texaphyrin within plaque was determined by fluorescence emission spectra to be predominantly lipophilic. The Texaphyrin was found to bind to the lower density lipoproteins in the atherosclerotic-induced animals. Lutetium Texaphyrin is an excellent candidate for photoatherolytic therapy.
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Experimental acute cerebral ischemia with reperfusion. Evaluation with Gadolinium-Texaphyrin.
Investigative radiology, 1996Co-Authors: Stuart W. Young, Qing Fan, David M. Kunis, Gary K. SteinbergAbstract:RATIONALE AND OBJECTIVES The authors explore the potential usefulness of the new contrast medium Gadolinium (Gd)-Texaphyrin (PCI-0101) in magnetic resonance imaging of experimental acute cerebral ischemia with reperfusion. METHODS Four New Zealand white rabbits underwent 2 hours of transorbital occlusion of the left internal carotid, anterior, and middle cerebral arteries, followed by 2 hours of reperfusion with normal saline. Immediately thereafter, the rabbits were injected with 25 mumol/kg of 2 mmol/L Gd-Texaphyrin and killed by barbiturate overdose. Postmortem T1- and T2-weighted coronal scans were performed at 1.5 Tesla and correlated with histopathologic findings. RESULTS Postcontrast T1-weighted images showed high signal within extensive cortical and basal ganglia infarcts. Areas of high signal on T1-weighted images were less extensive than on T2-weighted images, and corresponded to only a portion of the region of neuronal damage seen histologically. Signal intensity of infarcted brain on postcontrast T1-weighted images was significantly greater than normal brain in the contralateral hemisphere (P < 0.0014). CONCLUSIONS Experimental reperfused infarcts only 2 hours old demonstrate contrast enhancement with Gd-Texaphyrin.
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IMAGING OF HUMAN COLON CANCER XENOGRAFT WITH Gadolinium-Texaphyrin
Investigative radiology, 1996Co-Authors: Stuart W. Young, Qing FanAbstract:RATIONALE AND OBJECTIVES The authors explore the efficacy of Gadolinium (Gd)-Texaphyrin (PCI-0101), an expanded porphyrin, as a contrast medium for magnetic resonance imaging of nude mice implanted with the human colon cancer xenograft LS174T. METHODS Magnetic resonance images were obtained in six nude mice 7 to 8 days after implantation of LS174T cells in dorsal subcutaneous tissues. Spin-echo T1-weighted images were obtained at baseline and at 5, 15, and 60 minutes after injection of 10 or 20 mumols/kg of Gd-Texaphyrin. Delayed images were obtained at 24 and 48 hours after injection. Region-of-interest measurements were taken of the tumors and of enhancing tumor rims at all time points. Percent enhancement was calculated and compared among the various time points. RESULTS All tumors were enhanced after injection of Gd-Texaphyrin. Heterogeneous patterns of enhancement were seen, with peak enhancement seen at the 15-minute time point; however, greater enhancement was seen at 48 hours than at 24 hours after Gd-Texaphyrin intravenous injection. CONCLUSIONS Gadolinium-Texaphyrin may prove to be a useful contrast medium for magnetic resonance imaging of tumors.
Darren Magda - One of the best experts on this subject based on the ideXlab platform.
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Recent Developments in Texaphyrin Chemistry and Drug Discovery
Inorganic chemistry, 2013Co-Authors: Christian Preihs, Jonathan F. Arambula, Darren Magda, Zahid H. Siddik, Heeyeong Jeong, Dongwon Yoo, Jinwoo Cheon, Jonathan L. SesslerAbstract:Texaphyrins are pentaaza expanded porphyrins with the ability to form stable complexes with a variety of metal cations, particularly those of the lanthanide series. In biological milieus, Texaphyrins act as redox mediators and mediate the production of reactive oxygen species (ROS). In this review, newer studies involving Texaphyrin complexes targeting several different applications in anticancer therapy are described. In particular, the preparation of bismuth and lead Texaphyrin complexes as potential α-core emitters for radiotherapy is detailed, as are Gadolinium Texaphyrin functionalized magnetic nanoparticles with features that make them of interest as dual-mode magnetic resonance imaging contrast agents and as constructs with anticancer activity mediated through ROS-induced sensitization and concurrent hyperthermia. Also discussed are Gadolinium Texaphyrin complexes as possible carrier systems for the targeted delivery of platinum payloads.
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Crown ether functionalized Texaphyrin monomers and dimers.
Journal of porphyrins and phthalocyanines, 2011Co-Authors: Christian Preihs, Darren Magda, Jonathan L. SesslerAbstract: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 the Ramos cell line in the presence and absence of zinc(II).
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Gadolinium Texaphyrin (Gd-Tex)-Malonato-Platinum Conjugates: Synthesis and Comparison with Carboplatin in Normal and Pt-Resistant Cell Lines
Dalton transactions (Cambridge England : 2003), 2009Co-Authors: Jonathan F. Arambula, Jonathan L. Sessler, Mark Fountain, Wen Hao Wei, Darren Magda, Zahid H. SiddikAbstract:The synthesis of a new PEG-solubilized Gadolinium Texaphyrin (Gd-Tex) conjugate containing a malonate-Pt(NH3)2 moiety is described. The effect of the tumor localizing Gd-Tex macrocycle on platinum activity was evaluated in cell culture. The malonate moiety, analogous to that present in carboplatin, is expected to release an aquated Pt(NH3)2 species under physiological conditions. The half-life in phosphate-buffered saline was found to be ca. 3 days at room temperature, and the hydrolytic product released from the conjugate was collected and confirmed as Pt-based by flameless atomic absorption spectrophotometry. Anti-proliferative activity was tested using A549 human lung cancer and A2780 human ovarian cancer cell lines. In both cell lines, the activity of the Gd-Tex conjugate was found to be similar to that of carboplatin. Efficacy against a Pt-resistant ovarian cell line greater than that displayed by carboplatin was also observed.
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Gadolinium Texaphyrin-methotrexate conjugates. Towards improved cancer chemotherapeutic agents.
Organic & biomolecular chemistry, 2005Co-Authors: Wen Hao Wei, Mark Fountain, Darren Magda, Dale Miles, Zhong Wang, Phil Lecane, Mimi Mesfin, Jonathan L. SesslerAbstract:Conjugates between methotrexate (MTX, Matrex®, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin Gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.
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Phototherapy of cancer and atheromatous plaque with Texaphyrins.
Journal of clinical laser medicine & surgery, 1996Co-Authors: Kathryn W. Woodburn, Qing Fan, Jonathan L. Sessler, Darren Magda, David Kessel, Meredith Wright, Tarak D. Mody, Gregory W. Hemmi, William C. Dow, Richard A. MillerAbstract:ABSTRACT Cancer and cardiovascular disease are the leading causes of death in the western world. Photodynamic therapy (PDT) has demonstrated activity in the treatment of superficial cancerous lesions and as an intraoperative adjunct during surgical debulking. Texaphyrins are pure, synthetic water-soluble macrocycles that localize in both cancerous lesions and atheromatous plaque. Lutetium Texaphyrin (PCI-0123) is activated by tissue-penetrating far red light (720–760 nm). Patient diagnosis and treatment planning is possible via magnetic resonance imaging (MRI) with the paramagnetic Gadolinium Texaphyrin (PCI-0120) or via fluorescence imaging using the diamagnetic PCI-0123. In this study it is shown that Texaphyrins localize selectively in cancer and atheromatous plaque. PDT with PCI-0123 is found to cause selective photodamage to the diseased tissue. Specifically, PCI-0123 acts to eradicate the SMT-F murine mammary tumors and diet-induced atheromatous plaque in rabbits.
Christian Preihs - One of the best experts on this subject based on the ideXlab platform.
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development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor
Journal of Medicinal Chemistry, 2013Co-Authors: Natalie M Barkey, Christian Preihs, Heather H Cornnell, Gary V Martinez, Adam Carie, Josef Vagner, Mark C Lloyd, Vincent M Lynch, Liping Xu, Vladimir J. HrubyAbstract:Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new Gadolinium Texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payload...
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Recent Developments in Texaphyrin Chemistry and Drug Discovery
Inorganic chemistry, 2013Co-Authors: Christian Preihs, Jonathan F. Arambula, Darren Magda, Zahid H. Siddik, Heeyeong Jeong, Dongwon Yoo, Jinwoo Cheon, Jonathan L. SesslerAbstract:Texaphyrins are pentaaza expanded porphyrins with the ability to form stable complexes with a variety of metal cations, particularly those of the lanthanide series. In biological milieus, Texaphyrins act as redox mediators and mediate the production of reactive oxygen species (ROS). In this review, newer studies involving Texaphyrin complexes targeting several different applications in anticancer therapy are described. In particular, the preparation of bismuth and lead Texaphyrin complexes as potential α-core emitters for radiotherapy is detailed, as are Gadolinium Texaphyrin functionalized magnetic nanoparticles with features that make them of interest as dual-mode magnetic resonance imaging contrast agents and as constructs with anticancer activity mediated through ROS-induced sensitization and concurrent hyperthermia. Also discussed are Gadolinium Texaphyrin complexes as possible carrier systems for the targeted delivery of platinum payloads.
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Development and in Vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor
2013Co-Authors: Natalie M Barkey, Christian Preihs, Heather H Cornnell, Adam Carie, Josef Vagner, Mark C Lloyd, Vincent M Lynch, Gary Martinez, Vladimir J. HrubyAbstract:Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new Gadolinium Texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R
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Crown ether functionalized Texaphyrin monomers and dimers.
Journal of porphyrins and phthalocyanines, 2011Co-Authors: Christian Preihs, Darren Magda, Jonathan L. SesslerAbstract: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 the Ramos cell line in the presence and absence of zinc(II).