Multifunctional nanoparticles delivering small interfering RNA and doxorubicin overcome drug resistance in cancer.
Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations, cationic liposome-polycation-DNA (LPD) and anionic liposome-polycation-DNA (LPD-II), for systemic co-delivery of doxorubicin (Dox) and a therapeutic small interfering RNA (siRNA) to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium-containing cationic lipid, i.e. N,N-distearyl-N-methyl-N-2-(N'-arginyl) aminoethyl ammonium chloride, which can induce reactive oxygen species, down-regulate MDR transporter expression, and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co-deliver vascular endothelial growth factor siRNA and Dox. An enhanced Dox uptake and a therapeutic effect were observed when combined with vascular endothelial growth factor siRNA in the nanoparticles. Third, to avoid P-glycoprotein-mediated drug efflux, we further designed another delivery vehicle, LPD-II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c-Myc siRNA delivered by the LPD-II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) co-formulated in either LPD or LPD-II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPD- and LPD-II-mediated therapy are compared.
Chen
Yunching
Y
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. yunching@email.unc.edu
Bathula
Surendar Reddy
SR
Li
Jun
J
Huang
Leaf
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002412:Cations; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry* / Q000648:ultrastructure; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002412:Cations; D008055:Lipids; D008081:Liposomes; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D004247:DNA; D019791:Guanidine
Cell Mol Biol. 1992 Sep;38(6):561-70
1363885
J Antibiot (Tokyo). 1981 Sep;34(9):1206-9
7328059
Pharmazie. 2008 Sep;63(9):646-9
18819516
Br J Cancer. 2007 Sep 17;97(6):735-40
17712313
Mol Immunol. 2007 Jul;44(15):3672-81
17521728
Cancer Gene Ther. 2006 Sep;13(9):819-29
16424918
Int J Cancer. 2006 May 15;118(10):2448-54
16353156
J Biol Chem. 2001 May 18;276(20):17420-8
11279018
Clin Cancer Res. 2000 May;6(5):1949-57
10815920
Cancer Res. 2006 Feb 1;66(3):1434-45
16452199
J Drug Target. 2009 Aug;17(7):533-42
19530913
J Oncol. 2008;2008:942618
19259336
Mol Pharm. 2009 May-Jun;6(3):696-705
19267451
Cancer Biol Ther. 2007 Nov;6(11):1794-9
18032928
J Biol Chem. 1998 Jun 19;273(25):15540-5
9624143
J Biol Chem. 1996 Apr 5;271(14):8481-7
8626549
Chin Med J (Engl). 2000 Sep;113(9):848-51
11776085
Cancer Res. 2004 Jun 1;64(11):3731-6
15172975
Mol Pharm. 2005 Jan-Feb;2(1):22-8
15804174
Mol Ther. 2010 Apr;18(4):828-34
20068551
J Pharmacol Exp Ther. 2005 Jan;312(1):346-54
15501994
Nat Biotechnol. 2005 Jun;23(6):709-17
15908939
Cancer Res. 1991 Sep 15;51(18):4955-63
1680024
Mol Cell Biochem. 2003 Feb;244(1-2):57-62
12701810
Pavlov J Biol Sci. 1987 Jul-Sep;22(3):85-94
2821470
J Natl Cancer Inst. 2002 Jul 3;94(13):1020-8
12096087
Histochem J. 2000 Oct;32(10):599-606
11202156
IDrugs. 2008 Aug;11(8):572-8
18683092
FEBS Lett. 1996 Mar 25;383(1-2):99-104
8612802