title: Self-Assembled ROS-Sensitive Polymer-Peptide Therapeutics Incorporating Built-in Reporters for Evaluation of Treatment Efficacy.
abstract: One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(β-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to ∼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.
authors.forename: Zeng-Ying
authors.initials: ZY
authors.lastname: Qiao
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.|School of Chemical Engineering and Technology, Hebei University of Technology , Tianjin, 300130, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Zhao
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cong
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: School of Chemical Engineering and Technology, Hebei University of Technology , Tianjin, 300130, China.
authors.forename: Zhong-Yu
authors.initials: ZY
authors.lastname: Duan
authors.affiliation: CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) , Beijing, 100190, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003503:Cyclobutanes / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D010636:Phenols / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D003503:Cyclobutanes; D004337:Drug Carriers; D008823:Micelles; D010446:Peptide Fragments; D010636:Phenols; D011108:Polymers; D017382:Reactive Oxygen Species; C480596:squaraine; D011092:Polyethylene Glycols