title: Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo.
abstract: We used a multifunctional mesoporous silica nanoparticle (MSNP) carrier to overcome doxorubicin (Dox) resistance in a multidrug resistant (MDR) human breast cancer xenograft by codelivering Dox and siRNA that targets the P-glycoprotein (Pgp) drug exporter. The Pgp siRNA selection from among a series of drug resistance targets was achieved by performing high throughput screening in a MDR breast cancer cell line, MCF-7/MDR. Following the establishment of a MCF-7/MDR xenograft model in nude mice, we demonstrated that a 50 nm MSNP, functionalized by a polyethyleneimine-polyethylene glycol (PEI-PEG) copolymer, provides protected delivery of stably bound Dox and Pgp siRNA to the tumor site. The effective biodistribution and reduced reticuloendothelial uptake, as a result of our nanocarrier design, allowed us to achieve an 8% enhanced permeability and retention effect at the tumor site. Compared to free Dox or the carrier loaded with either drug or siRNA alone, the dual delivery system resulted in synergistic inhibition of tumor growth in vivo. Analysis of multiple xenograft biopsies demonstrated significant Pgp knockdown at heterogeneous tumor sites that correspond to the regions where Dox was released intracellularly and induced apoptosis. We emphasize that the heterogeneity originates in the tumor microenvironment, which influences the vascular access, rather than heterogeneous Pgp expression in the MDR cells. Taken together, these data provide proof-of-principle testing of the use of a dual drug/siRNA nanocarrier to overcome Dox resistance in a xenograft. The study also provides the first detailed analysis of the impact of heterogeneity in the tumor microenvironment on the efficacy of siRNA delivery in vivo.
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA, USA. hmeng@mednet.ucla.edu
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Wilson X
authors.initials: WX
authors.lastname: Mai
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Sijie
authors.initials: S
authors.lastname: Lin
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002319:Cardiovascular System / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D016062:Porosity; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D012822:Silicon Dioxide / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D034741:RNA, Small Interfering; D012822:Silicon Dioxide; D004317:Doxorubicin