Clickable protein nanocapsules for targeted delivery of recombinant p53 protein

J Am Chem Soc. 2014 Oct 29;136(43):15319-25. doi: 10.1021/ja508083g. Epub 2014 Oct 17.

Abstract

Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH-conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Azides / chemistry
  • Cell Survival / drug effects
  • Click Chemistry
  • Drug Carriers / chemistry*
  • Drug Carriers / metabolism
  • Drug Carriers / toxicity
  • Drug Liberation
  • Gonadotropin-Releasing Hormone / chemistry
  • HeLa Cells
  • Humans
  • Ligands
  • Nanocapsules / chemistry*
  • Nanocapsules / toxicity
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Polyethylene Glycols / chemistry
  • Recombinant Proteins / chemistry*
  • Single-Chain Antibodies / chemistry
  • Single-Chain Antibodies / metabolism
  • Surface Properties
  • Tumor Suppressor Protein p53 / chemistry*

Substances

  • Azides
  • Drug Carriers
  • Ligands
  • Nanocapsules
  • Peptide Fragments
  • Recombinant Proteins
  • Single-Chain Antibodies
  • Tumor Suppressor Protein p53
  • Gonadotropin-Releasing Hormone
  • Polyethylene Glycols