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

Hiroto Hatakeyama, Hidetaka Akita, Erika Ito, Yasuhiro Hayashi, Motoi Oishi, Yukio Nagasaki, Radostin Danev, Kuniaki Nagayama, Noritada Kaji, Hiroshi Kikuchi, Yoshinobu Baba, Hideyoshi Harashima

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4306-4316
Number of pages11
JournalBiomaterials
Volume32
Issue number18
DOIs
Publication statusPublished - Jun 1 2011

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Nanoparticles
Lipids
Small Interfering RNA
Polyethylene glycols
Tumors
Peptides
Equipment and Supplies
Neoplasms
Liver
Spleen
Microarray Analysis
Microarrays
Nucleic acids
Oligonucleotide Array Sequence Analysis
Matrix Metalloproteinases
Nucleic Acids
Permeability
Genes
DNA
Tissue

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Hatakeyama, H., Akita, H., Ito, E., Hayashi, Y., Oishi, M., Nagasaki, Y., ... Harashima, H. (2011). Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid. Biomaterials, 32(18), 4306-4316. https://doi.org/10.1016/j.biomaterials.2011.02.045

Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid. / Hatakeyama, Hiroto; Akita, Hidetaka; Ito, Erika; Hayashi, Yasuhiro; Oishi, Motoi; Nagasaki, Yukio; Danev, Radostin; Nagayama, Kuniaki; Kaji, Noritada; Kikuchi, Hiroshi; Baba, Yoshinobu; Harashima, Hideyoshi.

In: Biomaterials, Vol. 32, No. 18, 01.06.2011, p. 4306-4316.

Research output: Contribution to journalArticle

Hatakeyama, H, Akita, H, Ito, E, Hayashi, Y, Oishi, M, Nagasaki, Y, Danev, R, Nagayama, K, Kaji, N, Kikuchi, H, Baba, Y & Harashima, H 2011, 'Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid', Biomaterials, vol. 32, no. 18, pp. 4306-4316. https://doi.org/10.1016/j.biomaterials.2011.02.045
Hatakeyama, Hiroto ; Akita, Hidetaka ; Ito, Erika ; Hayashi, Yasuhiro ; Oishi, Motoi ; Nagasaki, Yukio ; Danev, Radostin ; Nagayama, Kuniaki ; Kaji, Noritada ; Kikuchi, Hiroshi ; Baba, Yoshinobu ; Harashima, Hideyoshi. / Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid. In: Biomaterials. 2011 ; Vol. 32, No. 18. pp. 4306-4316.
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