A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance.
Mater Sci Eng C Mater Biol Appl
; 108: 110403, 2020 Mar.
Article
en En
| MEDLINE
| ID: mdl-31923941
ABSTRACT
Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pIâ¯=â¯6.8), and were stable in the physiological condition (pHâ¯7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pHâ¯6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirrolidinas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Proteína p53 Supresora de Tumor
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Sistemas de Liberación de Medicamentos
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Resistencia a Antineoplásicos
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Indoles
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Liposomas
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Mater Sci Eng C Mater Biol Appl
Año:
2020
Tipo del documento:
Article