title: Delivering siRNA and Chemotherapeutic Molecules Across BBB and BTB for Intracranial Glioblastoma Therapy.
abstract: For aggressive brain glioblastoma, the therapy is significantly impaired by blood-brain barrier (BBB) and blood-tumor barrier (BTB). Choosing more than one target from the pool of tumor-stroma interactions is profoundly beneficial to therapeutic approaches. Thus, a multifunctional liposomal system based on anchoring two receptor-specific and penetrable peptides was designed for the combination delivery of BBB-impermeable siRNA and chemotherapeutic docetaxel to brain glioblastoma. Both macroscopic and microscopic specific distributions and targeting effect of the liposomes in the intracranial glioblastoma were confirmed. Superiority in therapeutic efficacies of the siRNA and DTX combination delivery system was revealed from encouraged VEGF gene silencing, tumor cell apoptosis, prolonged survival time, subdued glioblastoma cells in intracranial glioblastoma, and negligible system toxicities after systemic application. Furthermore, the liposomes made better modulation of glioblastoma microenvironment such as the down-regulation of CD31-positive tumor vessels and HIF-1α expression. The transport mechanism of the liposomes delivering the cargos across BBB via receptor-mediated transcytosis without destroying the integrity of BBB has been evaluated from in vitro and in vivo. Therefore, the dual peptides-modified liposomal system provides a safe and noninvasive approach for the delivery of siRNA and chemotherapeutic molecules across the BBB and BTB to target therapy of brain glioblastoma.
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Pang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.|State Key Laboratory of Natural and Biomimetic Drugs , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Xian-Rong
authors.identifier: 0000-0002-8264-0794
authors.initials: XR
authors.lastname: Qi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D010455:Peptides; D034741:RNA, Small Interfering; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel
keywords: biodistribution; blood−brain barrier; blood−tumor barrier; glioblastoma; real-time bioluminescence imaging; receptor-mediated transcytosis; tight junction