Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia.
Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia.
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DOI：
10.1158/1078-0432.ccr-12-3191
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Marcucci G
中科院分区：
文献类型：
--
作者：
Huang X;Schwind S;Yu B;Santhanam R;Wang H;Hoellerbauer P;Mims A;Klisovic R;Walker AR;Chan KK;Blum W;Perrotti D;Byrd JC;Bloomfield CD;Caligiuri MA;Lee RJ;Garzon R;Muthusamy N;Lee LJ;Marcucci G
miR-29b directly or indirectly targets genes involved in acute myeloid leukemia (AML) i.e., DNMTs, CDK6, SP1, KIT and FLT3. Higher miR-29b pretreatment expression is associated with improved response to decitabine and better outcome in AML. Thus designing a strategy to increase miR-29b levels in AML blasts may be of therapeutic value. However, free synthetic miRs are easily degraded in bio-fluids and have limited cellular uptake. To overcome these limitations, we developed a novel transferrin-conjugated nanoparticle delivery system for synthetic miR-29b (Tf-NP-miR-29b). Delivery efficiency was investigated by flow-cytometry, confocal microscopy and quantitative-PCR. The expression of miR-29b targets was measured by immunoblotting. The anti-leukemic activity of Tf-NP-miR-29b was evaluated by measuring cell proliferation and colony formation ability and in a leukemia mouse model. Tf-NP-miR-29b treatment resulted in >200-fold increase of mature miR-29b compared to free miR-29b and was about twice as efficient as treatment with non-Tf-conjugated NP-miR-29b. Tf-NP-miR-29b treatment significantly downregulated DNMTs, CDK6, SP1, KIT and FLT3 and decreased AML cell growth by 30–50% and impaired colony formation by approximately 50%. Mice engrafted with AML cells and then treated with Tf-NP-miR-29b had significantly longer survival compared to Tf-NP-scramble (P=0.015) or free miR-29b (P=0.003). Furthermore, priming AML cell with Tf-NP-miR-29b before decitabine resulted in strong cell viability decrease in vitro and showed improved anti-leukemic activity compared with decitabine alone (P=0.001) in vivo. Tf-NP effectively delivered functional miR-29b, resulting in target downregulation and anti-leukemic activity, and warrants further investigation as a novel therapeutic approach in AML.
