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Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy

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Abstract

Purpose

To test whether co-delivery of anticancer small interfering RNA (siRNA) and a chemical MEK inhibitor using cationic liposomes enhances anticancer activity in vitro and in vivo.

Method

MEK inhibitor PD0325901 was encapsulated in lipid layers of N',N''-dioleylglutamide-based cationic liposomes (DGL). Mcl1-specific siRNA (siMcl1) was complexed to DGL or PD0325901-loaded liposomes (PDGL). Efficiency of cellular siRNA delivery was tested using fluorescent double-stranded RNA. Silencing of target proteins was evaluated using Western blotting and real-time quantitative polymerase chain reactions. In vivo anticancer activity was tested using xenografted mice.

Results

Size and zeta potential of PDGL were similar to DGL. PDGL could deliver double-stranded RNA into cells with efficiencies comparable to DGL. Cellular co-delivery of siMcl1 and PD0325901 reduced expression of Mcl1 and pERK1/2 proteins and more effectively reduced tumor cell survival than other treatments. In mice, siMcl1 and PD0325901 co-delivered by PDGL inhibited growth of tumors 79%. Substantial apoptosis of tumor cells was observed following PDGL-mediated co-delivery of siMcl1, but not in other groups.

Conclusions

PDGL-mediated co-delivery of siMcl1 and MEK inhibitor, PD0325901, could serve as a potential strategy for combination chemogene anticancer therapy.

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Abbreviations

DG:

N’,N”-dioleylglutamide

DGL:

DG-based cationic liposomes

DOPE:

dioleyl-sn-glycero-3-phosphoethanolamine

dsRNA:

double-stranded RNA

ERK:

extracellular signal-related kinase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

L2K:

Lipofectamine 2000

Mcl1:

myeloid cell leukemia sequence 1

MEK:

mitogen-activated protein/extracellular signal-regulated kinase kinase

MTT:

3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide

PCR:

polymerase chain reaction

PDGL:

PD0325901-loaded cationic liposomes

pERK1/2:

phospho-ERK1/2

siGL2:

luciferase-specific siRNA

siMcl1:

Mcl1-specific siRNA

siRNA:

small interfering RNA

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ACKNOWLEDGMENTS & DISCLOSURES

This study was financially supported by a grant of the Korean Health Technology R&D Project (Grant No. A090945), Ministry for Health, Welfare & Family Affairs, Republic of Korea.

Author information

Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul, 136-713, South Korea

    Seung Hee Kang, Gayong Shim, Sangbin Lee, Su-Hyeon Kim & Chan-Wha Kim

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Daehak-dong, Gwanank-gu, Seoul, 151-742, South Korea

    Hee-Jeong Cho & Yu-Kyoung Oh

  3. College of Pharmacy, Hanyang University, Ansan, 426-791, South Korea

    Han-Gon Choi

Authors
  1. Seung Hee Kang
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  2. Hee-Jeong Cho
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Corresponding author

Correspondence to Yu-Kyoung Oh.

Additional information

Seung Hee Kang and Hee-Jeong Cho contributed equally to this manuscript.

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Fig S1

Effect of N/P ratios on cellular uptake of fluorescent dsRNA/PDGL complexes. (PPT 364 kb)

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Kang, S.H., Cho, HJ., Shim, G. et al. Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy. Pharm Res 28, 3069–3078 (2011). https://doi.org/10.1007/s11095-011-0569-4

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  • DOI: https://doi.org/10.1007/s11095-011-0569-4

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