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The Co-Delivery of Oxaliplatin Abrogates the Immunogenic Response to PEGylated siRNA-Lipoplex

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ABSTRACT

Purpose

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.

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Abbreviations

ABC:

Accelerated blood clearance

CHOL:

Cholesterol

DC-6-14 O,O’:

O,O’- ditetradecanoyl-N- (α-trimethylammonio acetyl) diethanolamine chloride

DOPE:

Dioleoylphospatidyl-ethanolamine

HRP:

Horseradish peroxidase

HSPC:

Hydrogenated soy phosphatidyl choline

IL-6:

Interleukin 6

IFN-γ:

Interferon gamma

l-OHP:

Oxaliplatin

mPEG2000-DSPE:

2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethylene glycol)-2000

NF-κB:

Nuclear factor kappa B

POPC:

1-1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

RNAi:

RNA interference

siCL:

siRNA-lipoplex

siRNA:

Short interfering RNA

ssiRNA:

Single stranded siRNA

TLRs:

Toll like receptors (TLRs)

Tm:

Thermal melting

TNF-α:

Tumor necrosis factor alpha

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Acknowledgments and Disclosures

We thank Mr. J.L. McDonald for his helpful advice in preparing this manuscript. This study was supported by the Egyptian government represented in the cultural affairs and missions sector (Ministry of High Education), the Takeda Science Foundation, the Takahashi Industrial and Economic Research Foundation, and a Grant-in-Aid for scientific Research (B) (2339001220).

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Authors and Affiliations

  1. Department of Pharmacokinetics and Biopharmaceutics Institute of Health bioscience, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, Japan

    Eman Alaaeldin, Amr S. Abu Lila, Naoto Moriyoshi, Tatsuhiro Ishida & Hiroshi Kiwada

  2. Department of Pharmaceutics, , Minia University, Minia, Egypt

    Eman Alaaeldin, Hatem A. Sarhan & Khaled A. Khaled

  3. Department of Pharmaceutics and Industrial Pharmacy, Zagazig University, Zagazig, Egypt

    Amr S. Abu Lila

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  1. Eman Alaaeldin
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  2. Amr S. Abu Lila
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Correspondence to Tatsuhiro Ishida.

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Alaaeldin, E., Abu Lila, A.S., Moriyoshi, N. et al. The Co-Delivery of Oxaliplatin Abrogates the Immunogenic Response to PEGylated siRNA-Lipoplex. Pharm Res 30, 2344–2354 (2013). https://doi.org/10.1007/s11095-013-1078-4

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  • DOI: https://doi.org/10.1007/s11095-013-1078-4

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