10 research outputs found
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Melanocortin 1 receptor ligands and methods of use
The subject invention pertains to a modified MC1R peptide ligand comprising a peptide that is a melanocortin 1 receptor (MC1R) ligand and a functionality or linker, such as a click functionality, for conjugation to a surface or agent. The modified MC1R peptide ligand can be coupled, e.g., via a click reaction with a complementary click functionality attached, to a moiety to form an MC1R-targeted agent. Drugs, contrast agents, polymers, particles, micelles, surfaces of larger structures, or other moieties can be targeted to the MC1R. The subject invention also pertains to a MC1R peptide ligand-micelle complex comprising a peptide that is a melanocortin 1 receptor ligand connected via a click reaction product to a micelle. The micelle is stable in vivo and can target melanoma tumor cells by association of the peptide ligand with the MC1R or the tumor and selectively provide a detectable and/or therapeutic agent (such as an imageable contrast agent and/or anti-cancer agent) selectively to the tumor cell.Board of Regents, University of Texas Syste
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Expanded porphyrins as experimental anticancer agents and MRI contrast agents
textTexaphyrins represent the vanguard of experimental anticancer drugs and also symbolize a well-known example of expanded porphyrins, a class of oligopyrrolic macrocycles with tumor localization properties and powerful metal chelating properties. Chapter 1 of this thesis describes the unique structural characteristics of this complex synthetic molecule along with the biological relevance and scientific justifications for studying its anticancer properties and powerful MRI contrast ability. This Chapter also serves to underscore the need to improve further and refine the efficacy of texaphyrins as compounds that may be applied in the struggle against cancer. Chapter 2 details the synthesis of bismuth(III) and lead(II)-texaphyrin complexes that could potentially find use as [alpha]-core emitters for radiotherapy. In principle, porphyrins would ostensibly appear to be ideal ligands for use in radiotherapy due to their tumor-localizing ability. However, Bi(III)- and Pb(II)-porphyrin complexes are extremely rare, most reflecting the vastly challenging synthesis of these compounds as well as their general lack of stability. These limitations provided an incentive for us to use texaphyrins as more versatile ligands to prepare and fully characterize stable bismuth(III) and lead(II) complexes. To be of interest in future medical applications, we needed to prepare these complexes quickly as compared to the relevant time scales set by the half-lives of the isotopes targeted for use in radiotherapy. This goal was successfully realized. As mentioned above, texaphyrin is able to form stable complexes with a large variety of metals particularly in the lanthanide series. Gadolinium(III) complexes of texaphyrin have been studied in considerable detail. Chapter 3 details the synthesis and conjugation methods used to develop a texaphyrin conjugated dual mode nanoparticle contrast agent. This project has been done in collaboration with the group of Prof. Jinwoo Cheon (Yonsei University, Seoul, Korea), who demonstrated fascinating results with the texaphyrin functionalized nanoparticles. Not only do these conjugates act as improved magnetic resonance contrast agents displaying enhanced signals in both the T1 and T2 MRI modes, but also serve to sensitize apoptotic hyperthermia. It is this latter, double effector feature, that has been most extensively studied to date. Chapter 4 of this dissertation describes work done in close collaboration with Dr. Natalie Barkey and Dr. David Morse (Moffitt Cancer Center, Tampa, FL) where a gadolinium texaphyrin complex was developed that is able to target the melanocortin 1 receptor (MC1R) when encapsulated in a micellar system. As detailed in this Chapter, these collaborateurs demonstrated that these gadolinium-texaphyrin micelles are able to target MC1R-expressing xenograft tumors in vivo. This work relied on the supply of a new set of texaphyrin derivatives that were prepared and characterized as part of this dissertation work Chapter 5 of this disseration introduces sapphyrins, another class of expanded porphyrins with tumor selectivity. This project is based on the hypothesis that a direct linkage of sapphyrin with an anticancer agent based on ruthenium(II) could improve the efficacy of both compounds. Since sapphyrins exhibit limited ability to form stable complexes with transition metals, an appended 1,10-phenanthroline unit was chosen as an efficient N-donor aromatic ligand for ruthenium(II). Therefore, extensive synthetic efforts were made to form this sapphyrin-1,10-phenanthroline construct in an effort to stabilize a mixed sapphyrin-metallo-phenanthroline complex. Finally, Chapter 6 of this dissertation demonstrates the author's efforts to synthesize a planar rosarin species. Non-aromatic and non-planar rosarins have been known for over two decades. Through structural modification of the compound, namely through linking of both [Beta] positions on the bipyrrole unit, a new planar rosarin species has been synthesized exhibiting Hückel antiaromaticity.Chemistr
Formation of Ground State Triplet Diradicals from Annulated Rosarin Derivatives by Triprotonation
Annulated rosarins, β,β′-bridged
hexaphyrin(1.0.1.0.1.0)
derivatives <b>1</b>–<b>3</b>, are formally 24
π-electron antiaromatic species. At low temperature, rosarins <b>2</b> and <b>3</b> are readily triprotonated in the presence
of trifluoroacetic acid in dichloromethane to produce ground state
triplet diradicals, as inferred from electron paramagnetic resonance
(EPR) spectral studies. From an analysis of the fine structure in
the EPR spectrum of triprotonated rosarin <b>H</b><sub><b>3</b></sub><b>3</b><sup><b>3+</b></sup>, a distance
of 3.6 Å between the two unpaired electrons was estimated. The
temperature dependence of the singlet–triplet equilibrium was
determined by means of an EPR titration. Support for these experimental
findings came from calculations carried out at the (U)B3LYP/6-31G*
level, which served to predict a very low-lying triplet state for
the triprotonated form of a simplified model system <b>1</b>
Bismuth– and lead–texaphyrin complexes: towards potential α-core emitters for radiotherapy
Amplifying the Sensitivity of Zinc(II) Responsive MRI Contrast Agents by Altering Water Exchange Rates
Given the known water exchange rate
limitations of a previously
reported Zn(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural
targets were rationally designed to increase the rate of water exchange
to improve MRI detection sensitivity. These new sensors exhibit fine-tuned
water exchange properties and, depending on the individual structure,
demonstrate significantly improved longitudinal relaxivities (<i>r</i><sub>1</sub>). Two sensors in particular demonstrate optimized
parameters and, therefore, show exceptionally high longitudinal relaxivities
of about 50 mM<sup>–1</sup> s<sup>–1</sup> upon binding
to Zn(II) and human serum albumin (HSA). This value demonstrates a
3-fold increase in <i>r</i><sub>1</sub> compared to that
displayed by the original sensor, GdDOTA-diBPEN. In addition, this
study provides important insights into the interplay between structural
modifications, water exchange rate, and kinetic stability properties
of the sensors. The new high relaxivity agents were used to successfully
image Zn(II) release from the mouse pancreas <i>in vivo</i> during glucose stimulated insulin secretion
Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate
Development and <i>in Vivo</i> Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor
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 <i>in vitro</i> and <i>in vivo</i> 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