title: Clickable protein nanocapsules for targeted delivery of recombinant p53 protein.
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.
authors.affiliation: Department of Chemical and Biomolecular Engineering and Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Muxun
authors.initials: M
authors.lastname: Zhao
authors.forename: Yarong
authors.initials: Y
authors.lastname: Liu
authors.forename: Renee S
authors.initials: RS
authors.lastname: Hsieh
authors.forename: Nova
authors.initials: N
authors.lastname: Wang
authors.forename: Wanyi
authors.initials: W
authors.lastname: Tai
authors.forename: Kye-Il
authors.initials: KI
authors.lastname: Joo
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000595:Amino Acid Sequence; D001386:Azides / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D065546:Drug Liberation; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D053769:Nanocapsules / Q000737:chemistry* / Q000633:toxicity; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D001386:Azides; D004337:Drug Carriers; D008024:Ligands; D053769:Nanocapsules; D010446:Peptide Fragments; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D016159:Tumor Suppressor Protein p53; D007987:Gonadotropin-Releasing Hormone; D011092:Polyethylene Glycols