title: An in vitro investigation of a detachable fork-like structure as efficient nuclear-targeted sub-unit in A2780 cell cultures.
abstract: The pharmacological target of many anticancer drugs is those molecules associated with genetic information which are localized in nucleus. To efficiently deliver drugs into cancer cell nucleus, in our previous study, a fork-like sub-unit, with one end conjugated with a targeting peptide named R8NLS (CRRRRRRRRPKKKRKV) and the other end conjugated with c-Myc oncogene inhibitor H1-S6A,F8A (H1) peptide, was linked onto the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an enzyme degradable glycylphenylalanylleucylglycine (GFLG) tetrapeptide spacer. Here, an in vitro mechanism investigation of the fork-like sub-unit was studied in detail. We found that the fusion with two complementary R8 and NLS motifs is required to exert the multifunctional targeting capability of the tandem R8NLS peptide in overcoming various intracellular barriers, including enhancing cellular uptake, facilitating endosomal escape and penetrating through the double-layered nuclear membrane. Also required is the tactful detachment of the fork-like sub-unit from the copolymer in response to intracellular stimulus, because a smaller sub-unit not only increases the intracellular trafficking efficiency by reducing the size burden of magical bullet R8NLS, but also guarantees successful entry through the restricted nucleopore. Herein, this study highlights that both nuclear targeting ligand R8NLS and detachable fork-like sub-unit are dispensable for programmed nuclear delivery and may show feasibility on other drug delivery systems, such as nanoparticles and micelles.
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, Southern 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, Southern 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, Southern 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, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Yang
authors.initials: Y
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, Southern 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, Southern 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; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004705:Endocytosis; D006801:Humans; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000178:Acrylamides; D004337:Drug Carriers; D010455:Peptides; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Cancer therapy; Detachable fork-like structure; HPMA copolymers; Nuclear-targeted