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CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy.
Acta Biomater. 2018 10 01; 79:317-330.AB

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.

Authors+Show Affiliations

School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China; The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China.School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China.Xinhua College of Sun Yat-Sen University, Guangzhou 510520, PR China.Department of Microbiology and Immunology, 3775 University Street, McGill University, Montreal, Quebec H3A2B4, Canada.School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China.The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China.The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China.The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China.The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China; Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen, Guangdong 518055, China. Electronic address: huanglq@tsinghua.edu.cn.School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China; The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China. Electronic address: zengxw23@mail.sysu.edu.cn.School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China; The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology and Biomedicine, State Key Laboratory of Health Sciences and Technology (prep), State Key Laboratory of Chemical Oncogenomics, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, China. Electronic address: chenhb7@mail.sysu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30172068

Citation

Duo, Yanhong, et al. "CX-5461-loaded Nucleolus-targeting Nanoplatform for Cancer Therapy Through Induction of Pro-death Autophagy." Acta Biomaterialia, vol. 79, 2018, pp. 317-330.
Duo Y, Yang M, Du Z, et al. CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy. Acta Biomater. 2018;79:317-330.
Duo, Y., Yang, M., Du, Z., Feng, C., Xing, C., Wu, Y., Xie, Z., Zhang, F., Huang, L., Zeng, X., & Chen, H. (2018). CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy. Acta Biomaterialia, 79, 317-330. https://doi.org/10.1016/j.actbio.2018.08.035
Duo Y, et al. CX-5461-loaded Nucleolus-targeting Nanoplatform for Cancer Therapy Through Induction of Pro-death Autophagy. Acta Biomater. 2018 10 1;79:317-330. PubMed PMID: 30172068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy. AU - Duo,Yanhong, AU - Yang,Min, AU - Du,Zhenya, AU - Feng,Chuhan, AU - Xing,Chen, AU - Wu,Yanping, AU - Xie,Zhenhua, AU - Zhang,Fang, AU - Huang,Laiqiang, AU - Zeng,Xiaowei, AU - Chen,Hongbo, Y1 - 2018/08/30/ PY - 2018/02/22/received PY - 2018/08/22/revised PY - 2018/08/28/accepted PY - 2018/9/2/pubmed PY - 2019/6/8/medline PY - 2018/9/2/entrez KW - Autophagy KW - Cancer nanotechnology KW - Mesoporous silica KW - Nucleolus-targeting KW - Polydopamine SP - 317 EP - 330 JF - Acta biomaterialia JO - Acta Biomater VL - 79 N2 - : 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. SN - 1878-7568 UR - https://www.unboundmedicine.com/medline/citation/30172068/CX_5461_loaded_nucleolus_targeting_nanoplatform_for_cancer_therapy_through_induction_of_pro_death_autophagy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1742-7061(18)30502-6 DB - PRIME DP - Unbound Medicine ER -