title: Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.
abstract: A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Rm 76-553, Cambridge, Massachusetts 02139, United States .
authors.forename: Zhou J
authors.initials: ZJ
authors.lastname: Deng
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Elana
authors.initials: E
authors.lastname: Ben-Akiva
authors.forename: Erik C
authors.initials: EC
authors.lastname: Dreaden
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Shopsowitz
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001704:Biopolymers / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001704:Biopolymers; D004337:Drug Carriers; D008081:Liposomes; D034741:RNA, Small Interfering