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1.
J Med Chem ; 65(3): 1822-1834, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35019659

RESUMO

Herein, we report three new metal-free, photochemically active single, dual, and combinatorial CORMs (photoCORMs) based on a carbazole-fused 1,3-dioxol-2-one moiety which released one equivalent of CO, two equivalent of CO, and a combination of one equivalent of each CO and anticancer drug upon one- and two-photon excitation, respectively. The photoCORMs exhibited good cellular uptake and real-time monitoring ability of CO uncaging by a color change approach in cancerous B16F10 cells. Interestingly, the cytotoxicity assay on B16F10 cells indicated that the dual photoCORM has increased anticancer activity over the single and combinatorial photoCORMs upon irradiation. Our results also showed that CO could accelerate the effectiveness of the well-known anticancer drug (chlorambucil). Finally, the in vivo evaluation of the dual photoCORM on an established murine melanoma tumor (C57BL/6J mouse model) manifested a significant regression of tumor volume and led to significant improvement (>50%) in the overall survivability.


Assuntos
Antineoplásicos/uso terapêutico , Carbazóis/uso terapêutico , Monóxido de Carbono/metabolismo , Dioxóis/uso terapêutico , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Carbazóis/síntese química , Carbazóis/efeitos da radiação , Linhagem Celular Tumoral , Dioxóis/síntese química , Dioxóis/efeitos da radiação , Feminino , Raios Infravermelhos , Camundongos Endogâmicos C57BL , Fótons
2.
Mol Pharm ; 17(6): 1859-1874, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32343904

RESUMO

Glioblastoma multiforme (GBM) is one of the most aggressive tumors with a median survival of only 15 months. Effective therapeutics need to overcome the formidable challenge of crossing the blood-brain barrier (BBB). Receptors and transporters overexpressed on BCECs are being used for designing liposomes, polymers, polymeric micelles, peptides, and dendrimer-based drug carriers for combating brain tumors. Herein, using the orthotopic mouse glioblastoma model, we show that codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066) and STAT3siRNA with nanometric (100-150 nm) α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of RGDK-lipopeptide were found to be internalized in GL261 cells via integrin α5ß1 receptors. Intravenously administered near-infrared (NIR)-dye-labeled α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide were found to be accumulated preferentially in the mouse brain tumor tissue. Importantly, we show that iv injection of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.


Assuntos
Glioblastoma/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Barreira Hematoencefálica/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetulus , Glioblastoma/genética , Integrina alfa5beta1/genética , Integrina alfa5beta1/metabolismo , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genética
3.
Chem Commun (Camb) ; 55(94): 14182-14185, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701969

RESUMO

Near-infrared (NIR) fluorescent probes have been developed as potential bio-materials having profound applications in diagnosis and clinical practice. Herein, we wish to disclose a highly photostable ultra-bright NIR probe for the specific detection of lysosomes in numerous cell lines. Furthermore, the applicability of the developed NIR probe was evaluated for in vivo imaging.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Animais , Feminino , Células HEK293 , Humanos , Raios Infravermelhos , Lisossomos/química , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neoplasias Experimentais/diagnóstico por imagem
4.
Mol Pharm ; 14(11): 3834-3847, 2017 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-28958145

RESUMO

Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioblastoma/metabolismo , Glioblastoma/terapia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Levodopa/química , Lipossomos/química , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Western Blotting , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas por Ionização por Electrospray
5.
Chem Commun (Camb) ; 53(65): 9109-9112, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28759056
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