Awakening p53 in vivo by D-peptides-functionalized ultra-small nanoparticles: Overcoming biological barriers to D-peptide drug delivery
PublisherIvyspring International Publisher
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AbstractPeptides are a rapidly growing class of therapeutics with many advantages over conventional small molecule drugs. Dextrorotary (D)-peptides, with increased enzymatic stability and prolonged plasma half-life in comparison with natural L-peptides, are considered to have great potential as recognition molecules and therapeutic agents. However, the in vivo efficacy of current therapeutic D-peptides is hindered by their inefficient cellular uptake in diseased tissues. Methods: To overcome physiological and cellular barriers to D-peptides, we designed a gold-based ultra-small nanocarrier coupled with polylysine (PLL) and a receptor-targeted peptide to deliver therapeutic D-peptides. Using a D-peptide p53 activator (DPA) as a proof of concept, we synthesized, functionalized and characterized gold- and DPA-based nanoparticles termed AuNP-DPA. Results: AuNP-DPA were effectively enriched in tumor sites and subsequently internalized by cancer cells, thereby suppressing tumor growth via reactivating p53 signaling. More importantly, through a series of in vivo experiments, AuNP-DPA showed excellent biosafety without the common side effects that hinder p53 therapies in clinic trials. Conclusion: The present study not only sheds light on the development of AuNP-DPA as a novel class of antitumor agents for drugging the p53 pathway in vivo, but also supplies a new strategy to use D-peptides as intracellular PPI inhibitors for cancer-targeted therapy. Copyright Ivyspring International Publisher.
SponsorsThis work was supported by the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University (No. XJTU1AF-CRF-2017-003 to P. H. and W. H.). The authors gratefully acknowledge financial support from the China Scholarship Council (to W. H. and J. Y.) and thank Prof. Bert Vogelstein (Ludwig Center at John Hopkins, USA) for kindly providing the human colon cancer cell HCT116 p53-/- cell line with both p53 alleles deleted.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85056753121&doi=10.7150%2fthno.27165&partnerID=40&md5=f25f9052e1a80bf18135f321c9613fab; http://hdl.handle.net/10713/9662