title: Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled siRNAs to enhance therapeutic efficacy in drug-resistant ovarian cancer cells.
abstract: Ovarian cancer is the leading cause of death among women with gynecological malignancies. Acquired resistance to chemotherapy is a major limitation for ovarian cancer treatment. We report here the first use of nanoscale metal-organic frameworks (NMOFs) for the co-delivery of cisplatin and pooled small interfering RNAs (siRNAs) to enhance therapeutic efficacy by silencing multiple drug resistance (MDR) genes and resensitizing resistant ovarian cancer cells to cisplatin treatment. UiO NMOFs with hexagonal-plate morphologies were loaded with a cisplatin prodrug and MDR gene-silencing siRNAs (Bcl-2, P-glycoprotein [P-gp], and survivin) via encapsulation and surface coordination, respectively. NMOFs protect siRNAs from nuclease degradation, enhance siRNA cellular uptake, and promote siRNA escape from endosomes to silence MDR genes in cisplatin-resistant ovarian cancer cells. Co-delivery of cisplatin and siRNAs with NMOFs led to an order of magnitude enhancement in chemotherapeutic efficacy in vitro, as indicated by cell viability assay, DNA laddering, and Annexin V staining. This work shows that NMOFs hold great promise in the co-delivery of multiple therapeutics for effective treatment of drug-resistant cancers.
authors.affiliation: Department of Chemistry, University of Chicago , 929 E 57th St, Chicago, Illinois 60637, United States.
authors.forename: Chunbai
authors.initials: C
authors.lastname: He
authors.forename: Kuangda
authors.initials: K
authors.lastname: Lu
authors.forename: Demin
authors.initials: D
authors.lastname: Liu
authors.forename: Wenbin
authors.initials: W
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010316:Particle Size; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D034741:RNA, Small Interfering; D002945:Cisplatin