title: A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery.
abstract: Tumor cell nucleus-targeted delivery of antitumor agents is of great interest in cancer therapy, since the nucleus is one of the most frequent targets of drug action. Here we report a smart polymeric conjugate platform, which utilizes stimulus-responsive strategies to achieve multistage nuclear drug delivery upon systemic administration. The conjugates composed of a backbone based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer and detachable nucleus transport sub-units that sensitive to lysosomal enzyme. The sub-units possess a biforked structure with one end conjugated with the model drug, H1 peptide, and the other end conjugated with a novel pH-responsive targeting peptide (R8NLS) that combining the strength of cell penetrating peptide and nuclear localization sequence. The conjugates exhibited prolonged circulation time and excellent tumor homing ability. And the activation of R8NLS in acidic tumor microenvironment facilitated tissue penetration and cellular internalization. Once internalized into the cell, the sub-units were unleashed for nuclear transport through nuclear pore complex. The unique features resulted in 50-fold increase of nuclear drug accumulation relative to the original polymer-drug conjugates in vitro, and excellent in vivo nuclear drug delivery efficiency. Our report provides a strategy in systemic nuclear drug delivery by combining the microenvironment-responsive structure and detachable sub-units.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Jiaju
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Guan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, NO. 17, Block 3, South Renmin Road, Chengdu 610041, PR China. Electronic address: huangyuan0@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000178:Acrylamides / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D019913:Nuclear Localization Signals; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D003692:Delayed-Action Preparations; D019913:Nuclear Localization Signals; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Cancer therapy; Double-stimuli responsive; Drug delivery; Multistage; Nucleus-targeted; Polymer conjugates