Theranostics 2018; 8(19):5320-5335. doi:10.7150/thno.27165
Awakening p53 in vivo by D-peptides-functionalized ultra-small nanoparticles: Overcoming biological barriers to D-peptide drug delivery
1. Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
2. Department of general surgery, General Hospital of Shenyang Military Area Command, Shenyang, 110016, Liaoning Province, China.
3. Department of Biologic and Materials Sciences, Department of Biomedical Engineering, Macromolecular Science and Engineering Center, Department of Materials Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
4. Frontier Institute of Science and Technology, State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China
5. Key Laboratory for Tumor Precision Medicine of Shaanxi Province, and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
6. Center for Translational Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
7. Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
8. Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
9. Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
*These authors contributed equally.
Peptides 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.
Keywords: gold nanoparticle, ultra-small nanoparticle, dextrorotary peptide, p53, biosafety
Bian Z, Yan J, Wang S, Li Y, Guo Y, Ma B, Guo H, Lei Z, Yin C, Zhou Y, Liu M, Tao K, Hou P, He W. Awakening p53 in vivo by D-peptides-functionalized ultra-small nanoparticles: Overcoming biological barriers to D-peptide drug delivery. Theranostics 2018; 8(19):5320-5335. doi:10.7150/thno.27165. Available from http://www.thno.org/v08p5320.htm