A straightforward synthetic route for a new multifunctional 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) derivative is described. To demonstrate the versatility of this pro‐chelator for the preparation of radiolabeled hybrid compounds containing two different biological targeting moieties, an antitumor agent (e.g., a DNA‐intercalating agent) and an estrogen receptor (ER) ligand (e.g., LXXLL‐based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabeled with the auger electron emitter indium‐111, and the resulting radioconjugate was demonstrated to induce DNA damage in vitro, which, along with the nuclear internalization exhibited in breast cancer cells, might enhance its therapeutic activity. This favorable in vitro performance suggests that these hybrid compounds could be attractive probes for theranostic applications.
Heterobimetallic complexes with the evolutionary, well-preserved, histidyl-alanyl-valinyl (HAV) sequence for cadherin targeting, an organometallic Ru core with anticancer activity and a radioactive moiety for imaging may hold potential as theranostic agents for cancer. Visible-light irradiation of the HAVAY-NH2 pentapeptide in the presence of [(η(5)-Cp)Ru(η(6)-naphthalene)](+) resulted in the formation of a full sandwich type complex, (η(6)-Tyr-RuCp)-HAVAY-NH2 in aqueous solution, where the metal ion is connected to the Tyr (Y) unit of the peptide. Conjugation of this complex to 2,2'-(7-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-GA) and subsequent metalation of the resulting product with stable ((nat)Ga) and radioactive ((67)Ga) isotope yielded (nat)Ga/(67)Ga-NODA-GA-[(η(6)-Tyr-RuCp)-HAVAY-NH2]. The non-radioactive compounds were characterized by NMR spectroscopy and Mass Spectrometry. The cellular uptake and cytotoxicity of the radioactive and non-radioactive complexes, respectively, were evaluated in various human cancer cell lines characterized by different levels of N- or E-cadherins expression. Results from these studies indicate moderate cellular uptake of the radioactive complexes. However, the inhibition of the cell proliferation was not relevant.
The aim of this work was to study the release, permeation and skin retention profiles of 0.05% tretinoin hydrogel formulations in which tretinoin was in free form or complexed with dimethyl-beta-cyclodextrin in a stoichiometry of 1:4. Theoretically, this complexation will mainly allow to: overcome drug's low water solubility and low stability; enhance the drug permeation by promoting skin absorption and alleviate drug inducing local irritation. In vitro release, permeation and skin retention tests were performed in both formulations in order to compare the main advantages of this complexation. The influence of the thermodynamic activity on the drug release profile was also investigated. This study proved that tretinoin inclusion complexes formulation with excess of cyclodextrins had better release profile than the free tretinoin formulation. It was concluded that in this study, thermodynamic activity was not the driving force for the release rate improvement observed with cyclodextrins. Probably, this improvement was due to the increased availability of tretinoin near the membrane surface. In fact, the percentage of total drug that had been retained in the skin was 0.41 ± 0.08% for complexed tretinoin gel and 0.17 ± 0.04% for the free tretinoin gel.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.