siRNA-Mediated Down-Regulation of P-glycoprotein in a Xenograft Tumor Model in NOD-SCID Mice

被引：19

作者：

Abbasi, Meysam ^{[2
]}

Aliabadi, Hamidreza Montazeri ^{[1
]}

Moase, Elaine H. ^{[3
]}

Lavasanifar, Afsaneh ^{[1
,3
]}

Kaur, Kamaljit ^{[3
]}

Lai, Raymond ^{[4
]}

Doillon, Charles ^{[5
]}

Uludag, Hasan ^{[1
,2
,3
]}

机构：

[1] Univ Alberta, Fac Engn, Dept Chem & Mat Engn, Edmonton, AB T6G 2G6, Canada

[2] Univ Alberta, Fac Med, Dept Biomed Engn, Edmonton, AB T6G 2G6, Canada

[3] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2G6, Canada

[4] Univ Alberta, Dept Lab Med & Pathol, Fac Med, Edmonton, AB T6G 2G6, Canada

[5] CHUQ Laval Univ, CHULs Res Ctr, Sillery, PQ, Canada

来源：

PHARMACEUTICAL RESEARCH | 2011年 / 28卷 / 10期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

multidrug resistance; non-viral siRNA delivery; P-glycoprotein; polymeric biomaterials; xenograft; SMALL INTERFERING RNA; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; DRUG-RESISTANCE; IN-VIVO; DELIVERY; CANCER; REVERSAL; CELLS; MODULATION;

D O I：

10.1007/s11095-011-0480-z

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The efficacy of chemotherapy is decreased due to over-expression of the drug transporter P-glycoprotein (P-gp). This study was conducted to determine the feasibility of down-regulating tumor P-gp levels with non-viral siRNA delivery in order to sensitize the tumors to drug therapy. P-gp over-expressing MDA435/LCC6 MDR1 cells were used to establish xenografts in NOD-SCID mouse. Cationic polymers polyethylenimine (PEI) and stearic acid-substituted poly-L-lysine (PLL-StA) were formulated with P-gp- specific siRNAs and delivered intratumorally to explore the feasibility of P-gp down-regulation in tumors. Intravenous Doxil (TM) was administered to investigate tumor growth. PEI and PLL-StA effectively delivered siRNA to MDA435/LCC6 MDR1 cells in vitro to reduce P-gp expression for 3 days. Intratumoral injection of siRNA with the carriers resulted in 60-80% and 20-32% of siRNA retention in tumors after 24 and 96 hr, respectively. This led to similar to 29.0% and similar to 61.5% P-gp down-regulation with PEI- and PLL-StA-mediated siRNA delivery, respectively. The P-gp down-regulation by intratumoral siRNA injection led to better response to systemic Doxil (TM) treatment, resulting in slowed tumor growth in originally doxorubicin-resistant tumors. Effective P-gp down-regulation was feasible with polymeric siRNA delivery in a xenograft model, resulting in an enhanced response to the drug therapy.

引用

页码：2516 / 2529

页数：14