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The Co-Delivery of Oxaliplatin Abrogates the Immunogenic Response to PEGylated siRNA-Lipoplex
Faculty
Not Specified
Year:
2013
Type of Publication:
Article
Pages:
2344-2354
Authors:
Ishida, Tatsuhiro, Kiwada, Hiroshi, Abu Lila, Amr S, Alaaeldin, Eman, Moriyoshi, Naoto, Sarhan, Hatem A, Khaled, Khaled A
DOI:
10.1007/s11095-013-1078-4
Journal:
PHARMACEUTICAL RESEARCH SPRINGER/PLENUM PUBLISHERS
Volume:
30
Research Area:
Chemistry; Pharmacology \& Pharmacy
ISSN
ISI:000323499900016
Keywords :
anti-PEG IgM, cytokines, PEGylated siRNA cationic liposome (lipoplex), short interfering RNA (siRNA), beta-galctosidase
Abstract:
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. 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. 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. 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.
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