TY - JOUR
T1 - Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid
AU - Hatakeyama, Hiroto
AU - Akita, Hidetaka
AU - Ito, Erika
AU - Hayashi, Yasuhiro
AU - Oishi, Motoi
AU - Nagasaki, Yukio
AU - Danev, Radostin
AU - Nagayama, Kuniaki
AU - Kaji, Noritada
AU - Kikuchi, Hiroshi
AU - Baba, Yoshinobu
AU - Harashima, Hideyoshi
N1 - Funding Information:
This study was supported in part by Grants-in-Aid for Young Scientists (B) and by Grant for Industrial Technology Research from New Energy and Industrial Technology Development Organization (NEDO) . We thank M. S. Feather for his helpful advice in writing the English manuscript.
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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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U2 - 10.1016/j.biomaterials.2011.02.045
DO - 10.1016/j.biomaterials.2011.02.045
M3 - Article
C2 - 21429576
AN - SCOPUS:79955084359
SN - 0142-9612
VL - 32
SP - 4306
EP - 4316
JO - Biomaterials
JF - Biomaterials
IS - 18
ER -