CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy.
Acta Biomater
; 79: 317-330, 2018 10 01.
Article
en En
| MEDLINE
| ID: mdl-30172068
ABSTRACT
Various drugs have been designed in the past to act on intracellular targets. For the desired effects to be exerted, these drugs should reach and accumulate in specific subcellular organelles. CX-5461 represents a potent small-molecule inhibitor of rRNA synthesis that specifically inhibits the transcription driven by RNA polymerase (Pol) I and induces tumor cell death through triggering a pro-death autophagy. In the current study an innovative kind of CX-5461-loaded mesoporous silica nano-particles enveloped by polyethylene glycol (PEG), polydopamine (PDA) and AS-1411 aptamer (MSNs-CX-5461@PDA-PEG-APt) with the aim of treating cancer cells was constructed, in which the high-surface-area MSNs allowed for high drug loading, PDA acted as gatekeeper to prevent the leakage of CX-5461 from MSNs, PEG grafts on PDA surfaces increased the stable and biocompatible property in physiological condition, and AS-1411 aptamer promoted the nucleolar accumulation of CX-5461. MSNs-CX-5461@PDA-PEG-APt was characterized regarding releasing characteristics, steadiness, encapsulation of drugs, phase boundary potential as well as sizes of particles. Expectedly, In vitro assays showed that aptamer AS-1411 significantly increased the nucleolar accumulation of CX-5461. The aptamer-tagged CX-5461-loaded MSNs demonstrated to be more cytotoxic to cervical cancer cells compared to the control MSNs, due to relatively strong inhibition of rRNA transcription and induction of pro-death autophagy. The in vivo treatment with AS-1411-tagged CX-5461-loaded MSNs showed a stronger distribution in tumor tissues by animal imaging assay and a significantly higher inhibition effect on the growth of HeLa xenografts compared to AS-1411-untagged CX-5461-loaded MSNs. In addition, histology analysis indicated that MSNs-CX-5461@PDA-PEG-APt did not exhibit any significant toxicity on main organs. These results collectively suggested that MSNs-CX-5461@PDA-PEG-APt represents both a safe and potentially nucleolus-targeting anti-cancer drug. STATEMENT OF SIGNIFICANCE:
Many drugs function in specific subcellular organelles. CX-5461 is a specific inhibitor of nucleolar rRNA synthesis. Here, we reported a novel aptamer-tagged nucleolus-targeting CX-5461-loaded nanoparticle, which specifically accumulated in nucleoli and significantly inhibited the tumor growth in vitro and in vivo through inhibiting rRNA transcription and triggering a pro-death autophagy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Autofagia
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Nucléolo Celular
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Benzotiazoles
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Nanopartículas
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Naftiridinas
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Acta Biomater
Año:
2018
Tipo del documento:
Article