title: The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex.
abstract: OBJECTIVE
  In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex.
  
  
  METHODS
  Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated.
  
  
  RESULTS
  Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses.
  
  
  CONCLUSIONS
  Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics Institute of Health bioscience, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, Japan.
authors.forename: Eman
authors.initials: E
authors.lastname: Alaaeldin
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.forename: Naoto
authors.initials: N
authors.lastname: Moriyoshi
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Sarhan
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Khaled
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D008081:Liposomes / Q000737:chemistry / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007075:Immunoglobulin M; D008081:Liposomes; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D000077150:Oxaliplatin; D011092:Polyethylene Glycols