title: A drug-specific nanocarrier design for efficient anticancer therapy.
abstract: The drug-loading properties of nanocarriers depend on the chemical structures and properties of their building blocks. Here we customize telodendrimers (linear dendritic copolymer) to design a nanocarrier with improved in vivo drug delivery characteristics. We do a virtual screen of a library of small molecules to identify the optimal building blocks for precise telodendrimer synthesis using peptide chemistry. With rationally designed telodendrimer architectures, we then optimize the drug-binding affinity of a nanocarrier by introducing an optimal drug-binding molecule (DBM) without sacrificing the stability of the nanocarrier. To validate the computational predictions, we synthesize a series of nanocarriers and evaluate systematically for doxorubicin delivery. Rhein-containing nanocarriers have sustained drug release, prolonged circulation, increased tolerated dose, reduced toxicity, effective tumour targeting and superior anticancer effects owing to favourable doxorubicin-binding affinity and improved nanoparticle stability. This study demonstrates the feasibility and versatility of the de novo design of telodendrimer nanocarriers for specific drug molecules, which is a promising approach to transform nanocarrier development for drug delivery.
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Changying
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Guo
authors.affiliation: Laboratory of Non-human Primate Disease Model Research, National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019826:Cholic Acid / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry*; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D019826:Cholic Acid; C020491:rhein