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1.
Inorg Chem ; 52(21): 12292-304, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24147771

RESUMO

Starting in ancient China and Greece, arsenic-containing compounds have been used in the treatment of disease for over 3000 years. They were used for a variety of diseases in the 20th century, including parasitic and sexually transmitted illnesses. A resurgence of interest in the therapeutic application of arsenicals has been driven by the discovery that low doses of a 1% aqueous solution of arsenic trioxide (i.e., arsenous acid) lead to complete remission of certain types of leukemia. Since Food and Drug Administration (FDA) approval of arsenic trioxide (As2O3) for treatment of acute promyelocytic leukemia in 2000, it has become a front-line therapy in this indication. There are currently over 100 active clinical trials involving inorganic arsenic or organoarsenic compounds registered with the FDA for the treatment of cancers. New generations of inorganic and organometallic arsenic compounds with enhanced activity or targeted cytotoxicity are being developed to overcome some of the shortcomings of arsenic therapeutics, namely, short plasma half-lives and a narrow therapeutic window.


Assuntos
Antineoplásicos/farmacologia , Arsênio/farmacocinética , Arsênio/uso terapêutico , Antineoplásicos/química , Arsênio/toxicidade , Trióxido de Arsênio , Arsenicais/uso terapêutico , Ensaios Clínicos como Assunto , Portadores de Fármacos , Humanos , Inativação Metabólica , Leucemia Promielocítica Aguda/tratamento farmacológico , Nanopartículas/uso terapêutico , Óxidos/uso terapêutico , Compostos de Sulfidrila/metabolismo , Termodinâmica
2.
Mol Cancer Ther ; 12(12): 2628-39, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24061648

RESUMO

The urokinase system is overexpressed in epithelial ovarian cancer cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in ovarian cancer, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide-loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA-targeted nanobins were internalized by ovarian cancer cells, whereas both inductively coupled plasma optical mass spectrometry (ICP-MS) and fluorescence-activated cell sorting (FACS) analyses confirmed more than four-fold higher uptake of targeted nanobins when compared with untargeted nanobins. In a coculture assay, the targeted nanobins showed efficient uptake in ovarian cancer cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either downregulating uPA receptor expression in the ovarian cancer cells using short-hairpin RNA (shRNA) or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% vs. 27%; P < 0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared with untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, aldehyde dehydrogenase-1A1 (ALDH1A1), expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA-targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy using protease receptors.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/toxicidade , Antineoplásicos/química , Antineoplásicos/toxicidade , Arseniatos/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Lipossomos , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polietilenoglicóis/química , Ligação Proteica , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Carga Tumoral/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Part Part Syst Charact ; 30(9): 770-774, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24516291

RESUMO

A PCN theranostic platform comprises a doxorubicin (DXR)-loaded liposomal core and an acid-sensitive polymer shell that is functionalized with Herceptin and GdIII-based MRI contrast agents. In vitro testing reveals a 14-fold increase in DXR-based cytotoxicity versus a non-targeted analogue and an 120-fold improvement in cellular GdIII-uptake in comparison with clinically approved DOTA-GdIII, leading to significant T1 MRI contrast enhancement.

4.
Langmuir ; 21(5): 2022-6, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15723505

RESUMO

The self-assembly of surfactant-protected gold nanorods (aspect ratio 3.3 +/- 0.3, 20.6 +/- 5.5 nm width, and 67.5 +/- 9.0 nm length) into ordered structures using adipic acid is presented. As made, the gold nanorods are coated with cationic surfactant, which gives them a net positive charge in aqueous solution. The pH-dependent assembly is directed by electrostatic interactions between the positively charged nanorods and negatively charged, deprotonated adipic acid. Absorption spectra and light scattering measurements of these nanorods suggest that aggregation is initiated in solution in the presence of adipic acid at pH 7-8, but not at pH 3, to form small assemblies of nanorods. Zeta potential measurements show that the assembly is significantly less positively charged in the presence of deprotonated adipic acid than when adipic acid is fully protonated.

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