Mixed backbone antisense glucosylceramide synthase oligonucleotide (MBO-asGCS) loaded solid lipid nanoparticles: in vitro characterization and reversal of multidrug resistance in NCI/ADR-RES cells.
In this study, solid lipid nanoparticles (SLN) loaded with MBO-asGCS oligonucleotide were prepared, characterized and evaluated for cytotoxicity against NCI/ADR-RES human ovary cancer cells. Two types of cetyltrimethyl ammonium bromide (CTAB) stabilized SLN, with or without ceramide VI, were prepared by mixed homogenization/ultrasonication technique. Complexes were characterized for size, zeta-potential, and stability in biorelevant media and against DNaseI activity. Binding and release studies were further confirmed by gel electrophoresis. Cytotoxicity of the SLN against NCI/ADR-RES cells was evaluated by quantizing ATP. SLN with ceramide VI had lower particle size (74.6 nm) with improved stability in RPMI media when compared to reference SLN without ceramide VI (167.16 nm). Both SLN however had similar cytotoxicity profile with an optimum binding at CTAB to MBO-asGCS ratio of 6:1. Blank SLN, and free MBO-asGCS in the presence and absence of free doxorubicin had insignificant effect on the viability of NCI/ADR-RES cells. However, when cells were concurrently treated with MBO-asGCS loaded SLN and free doxorubicin, cell viability significantly decreased to approximately 12%. These results suggested that SLN enhanced internalization and uptake of MBO-asGCS oligonucleotide, which led to the downregulation of GCS and subsequently reversing the resistance of the cells to doxorubicin.
Siddiqui
Akhtar
A
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, United States.
Patwardhan
Gauri Anand
GA
Liu
Yong-Yu
YY
Nazzal
Sami
S
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005964:Glucosyltransferases / Q000235:genetics*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D010051:Ovarian Neoplasms; D010316:Particle Size
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008055:Lipids; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
J Biol Chem. 2000 Mar 10;275(10):7138-43
10702281
Mol Cancer Ther. 2004 May;3(5):633-9
15141021
Eur J Pharm Biopharm. 2006 May;63(1):1-10
16364618
Am J Clin Nutr. 1989 Dec;50(6):1370-81
2596427
J Control Release. 2002 May 17;81(1-2):173-84
11992690
Cancer Res. 1999 Feb 15;59(4):880-5
10029079
J Control Release. 2005 Mar 2;103(1):99-111
15710504
Biochim Biophys Acta. 2006 Dec;1758(12):2096-103
17010304
Cancer Res. 2005 May 1;65(9):3861-7
15867385
J Lipid Res. 2004 May;45(5):933-40
14967819
Pharm Res. 2007 Jun;24(6):1098-107
17385021
Int J Pharm. 2007 Jul 18;339(1-2):261-8
17467205
Biochim Biophys Acta. 2002 Dec 30;1585(2-3):172-8
12531551
J Biol Chem. 2004 Sep 24;279(39):40412-8
15263008
J Control Release. 2004 Jun 18;97(2):321-32
15196759
J Pharmacol Exp Ther. 2002 Aug;302(2):619-26
12130724
Bioconjug Chem. 2007 Mar-Apr;18(2):302-8
17253655
FASEB J. 2001 Mar;15(3):719-30
11259390
Eur J Pharm Biopharm. 1999 Mar;47(2):125-32
10234536
FASEB J. 2008 Jul;22(7):2541-51
18245173
J Biol Chem. 1999 Jan 8;274(2):1140-6
9873062
Oligonucleotides. 2003;13(5):345-52
15000825
Micron. 2007;38(8):819-23
17693092
PLoS One. 2009 Sep 09;4(9):e6938
19742320
Eur J Pharm Biopharm. 2007 Sep;67(2):320-8
17368876
J Drug Target. 2007 May;15(4):295-301
17487698
Pharm Res. 2002 Jul;19(7):939-46
12180545
Cancer. 1999 Jul 15;86(2):300-11
10421266
Cancer Gene Ther. 2001 Jun;8(6):459-68
11498766
Eur J Pharm Biopharm. 2004 Mar;57(2):155-62
15018970
Clin Cancer Res. 2005 May 1;11(9):3465-74
15867249
J Control Release. 2001 Dec 13;77(3):345-55
11733101
J Control Release. 2004 Dec 10;100(3):411-23
15567506