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1.
Pharm Dev Technol ; 25(8): 949-961, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32343624

RESUMO

The adrenal cortical carcinoma (ACC) treatment, for which mitotane (o,p'-DDD) is the drug of choice, still remains a challenge both because of the well-known solubility problems of the drug, and its serious side effects. Mitotane is currently administered as oral tablets. The loading of mitotane into nanocarriers has been suggested as a way to circumvent the low solubility of the drug and its limited oral bioavailability. In this work, we have developed liposomes containing mitotane to enhance its intestinal absorption and oral bioavailability. Liposomes were produced by spray-drying of a mixture of phospholipids and the developed formulation was optimized by studying the degree of crystallinity, spray-drying conditions, phospholipid/mitotane ratio, and influence of mannitol in the hydrating ethanolic solution. An optimal liposomal formulation was produced with a phospholipid:mitotane combination (3.34:1), exhibiting a mean hydrodynamic diameter around 1 µm and spherical shape. The produced mitotane liposomes were re-suspended by hydrating the spray-dried powders in a stirred tank, and tested their intestinal permeability (ex vivo) and relative bioavailability (in vivo), against a free drug solution (with or without Trigliceril®CM). Our results support the conclusion that the loading of mitotane in liposomes enhanced its intestinal absorption and relative bioavailability.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Lipossomos/farmacologia , Mitotano/metabolismo , Mitotano/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Absorção Intestinal/efeitos dos fármacos , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Fosfolipídeos/metabolismo , Fosfolipídeos/farmacologia , Pós/farmacologia , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos , Comprimidos/metabolismo , Comprimidos/farmacologia
2.
Nanomedicine (Lond) ; 14(6): 689-705, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30691340

RESUMO

AIM: To develop a monoclonal antibody against dehydroepiandrosterone (DHEA) and miniaturize it, generating a single-chain antibody variable fragment (scFv) against DHEA as an adrenocortical carcinoma (ACC) marker. MATERIAL & METHODS: DHEA conjugated to keyhole limpet hemocyanin was used as an immunogen to obtain anti-DHEA hybridomas. Variable fragments were cloned from hybridoma 5B7 total RNA, and used to detect DHEA in normal adrenal tissue and ACC cells. RESULTS: IgM monoclonal antibody was highly specific, and the recombinant scFv preserved parental antibody characteristics, allowing tissue localization of DHEA. CONCLUSION: Undefined small lesions are challenges for clinicians and impact clinical adrenocortical tumor management. Generating an anti-DHEA scFv facilitates development of imaging tests for early diagnosis of pediatric ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Biomarcadores Tumorais/análise , Desidroepiandrosterona/análise , Anticorpos de Cadeia Única/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Desidroepiandrosterona/metabolismo , Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Conformação Proteica , Engenharia de Proteínas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Anticorpos de Cadeia Única/genética , Zona Reticular/metabolismo
3.
J Clin Oncol ; 31(20): 2619-26, 2013 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-23733769

RESUMO

PURPOSE: The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. PATIENTS AND METHODS: Free newborn screening was offered at all hospitals in the state of Paraná. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. RESULTS: Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48). CONCLUSION: These findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable.


Assuntos
Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/genética , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Proteína Supressora de Tumor p53/genética , Neoplasias do Córtex Suprarrenal/diagnóstico , Brasil/epidemiologia , Criança , Pré-Escolar , Detecção Precoce de Câncer/métodos , Feminino , Regulação da Expressão Gênica , Heterozigoto , Humanos , Incidência , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Linhagem , Medição de Risco , Distribuição por Sexo
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