A DNA Microarray-based Analysis of the Host Response to a Nonviral Gene Carrier: A Strategy for Improving the Immune Response

Hatakeyama, Hiroto; Ito, Erika; Yamamoto, Masatsugu; Akita, Hidetaka; Hayashi, Yasuhiko; Kajimoto, Kazuaki; Kaji, Noritada; Baba, Yoshinobu; Harashima, Hideyoshi

doi:10.1038/mt.2011.24

Cited by 20 publications

(13 citation statements)

References 42 publications

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“…It has been reported that intravenous injection of cationic nanoparticles encapsulating pDNA without PEG modification induced proinflammatory cytokines as well as hepatic toxicity (Hatakeyama H et al, 2011). In contrast, in the case of siRNA systems, IL-6 and IFN-gamma responses were greatly reduced (Table 3).…”

Section: Discussionmentioning

confidence: 84%

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

Hayashi

Yamauchi

Khalil

et al. 2011

International Journal of Pharmaceutics

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Footnote:Yasuhiro Hayashi and Jun Yamauchi equally contributed to this study. These authors are listed alphabetically in accordance with family name. AbstractThe Cell-penetrating peptide (CPP) is one of the most attractive tools for efficiently delivering biomolecules to a target organnelle. Here, we describe the use of octaarginine (R8)-modified lipid nanoparticles for the efficient and targeted in vivo delivery of siRNA to the liver. In this study, SR-BI (a scavenger receptor class B, member 1) was targeted by this nanoparticle. Our results demonstrate that R8-modified lipid nanoparticles can be used for the efficient and targeted delivery of liver siRNA to induce the specific knock-down of an endogenous gene with minimum liver toxicity and immune response, and that this CPP based technology holds considerable promise for further in vivo biological applications of siRNA.

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Section: Discussionmentioning

confidence: 84%

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

Hayashi

Yamauchi

Khalil

et al. 2011

International Journal of Pharmaceutics

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“…However, the response of a host to a systemically administrated non-viral gene vector has not been examined using this approach. We recently conducted a DNA microarray based analysis of the host response to a systemically administered MEND encapsulating pDNA core [24]. In this study, we performed a DNA microarray-based analysis for the systemically administrated PEG-unmodified MEND and PPD/PEG 5K -MEND in the liver and spleen.…”

Section: Discussionmentioning

confidence: 99%

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

et al. 2011

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Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment.In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen.

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“…GALA modification diminished the expression of type I IFNs. 35,115) 3.4. pH-Sensitive Cationic Lipids As mentioned above, a cationic characteristic of nucleic acid carriers requires considerable PEG modification to avoid interactions with the biological milieu. Another strategy for overcoming the PEG dilemma is offered by pH-sensitive cationic devices.…”

Section: )mentioning

confidence: 99%

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Hatakeyama

Akita

Harashima

2013

Biological & Pharmaceutical Bulletin

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425

276

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Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.

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A DNA Microarray-based Analysis of the Host Response to a Nonviral Gene Carrier: A Strategy for Improving the Immune Response

Cited by 20 publications

References 42 publications

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

Cell penetrating peptide-mediated systemic siRNA delivery to the liver

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

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