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1.
J Neurooncol ; 129(1): 47-56, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27177628

RESUMO

Vestibular schwannoma is a benign neoplasm arising from the Schwann cell sheath of the auditory-vestibular nerve. It most commonly affects both sides in the genetic condition Neurofibromatosis type 2, causing progressive high frequency sensorineural hearing loss. Here, we describe a microsurgical technique and stereotactic coordinates for schwannoma cell grafting in the vestibular nerve region that recapitulates local tumor growth in the cerebellopontine angle and inner auditory canal with resulting hearing loss. Tumor growth was monitored by bioluminescence and MRI in vivo imaging, and hearing assessed by auditory brainstem responses. These techniques, by potentially enabling orthotopic grafting of a variety of cell lines will allow studies on the pathogenesis of tumor-related hearing loss and preclinical drug evaluation, including hearing endpoints, for NF2-related and sporadic schwannomas.


Assuntos
Modelos Animais de Doenças , Perda Auditiva/fisiopatologia , Neuroma Acústico/fisiopatologia , Transplante Homólogo , Animais , Linhagem Celular Tumoral , Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Neurofibromatose 2/genética , Neuroma Acústico/complicações , Nervo Vestibulococlear/cirurgia
2.
J Control Release ; 217: 92-101, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26334483

RESUMO

Water-soluble corroles with inherent fluorescence can form stable self-assemblies with tumor-targeted cell penetration proteins, and have been explored as agents for optical imaging and photosensitization of tumors in pre-clinical studies. However, the limited tissue-depth of excitation wavelengths limits their clinical applicability. To examine their utility in more clinically-relevant imaging and therapeutic modalities, here we have explored the use of corroles as contrast enhancing agents for magnetic resonance imaging (MRI), and evaluated their potential for tumor-selective delivery when encapsulated by a tumor-targeted polypeptide. We have found that a manganese-metallated corrole exhibits significant T1 relaxation shortening and MRI contrast enhancement that is blocked by particle formation in solution but yields considerable MRI contrast after tissue uptake. Cell entry but not low pH enables this. Additionally, the corrole elicited tumor-toxicity through the loss of mitochondrial membrane potential and cytoskeletal breakdown when delivered by the targeted polypeptide. The protein-corrole particle (which we call HerMn) exhibited improved therapeutic efficacy compared to current targeted therapies used in the clinic. Taken together with its tumor-preferential biodistribution, our findings indicate that HerMn can facilitate tumor-targeted toxicity after systemic delivery and tumor-selective MR imaging activatable by internalization.


Assuntos
Antineoplásicos , Meios de Contraste , Manganês , Neuregulina-1 , Porfirinas , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Meios de Contraste/uso terapêutico , Feminino , Humanos , Imageamento por Ressonância Magnética , Manganês/farmacocinética , Manganês/farmacologia , Manganês/uso terapêutico , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neuregulina-1/farmacocinética , Neuregulina-1/farmacologia , Neuregulina-1/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos
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