Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors.
Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors.
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DOI：
10.1016/j.jconrel.2011.09.071
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发表时间：
2012-01-30
期刊：
影响因子：
--
通讯作者：
Borden MA
中科院分区：
文献类型：
--
作者：
Sirsi SR;Hernandez SL;Zielinski L;Blomback H;Koubaa A;Synder M;Homma S;Kandel JJ;Yamashiro DJ;Borden MA
微泡超声造影剂正被开发为图像引导的基因载体，用于体内靶向传递。在本研究中，我们合成了新型复合微泡，对其进行了表征，并对其进行了体循环和肿瘤转染性评价。用聚乙二醇改性支化聚乙烯亚胺(PEI；25 kDa)，将聚乙二醇硫醇化并共价连接到马来酰亚胺基团上形成脂膜微泡。随着马来酰亚胺含量的增加，PEI-微泡的表面电荷和DNA负载量逐渐增加。测量了PEI微泡在健康小鼠肾脏内的超声造影剂持续时间，并建立了考虑游离型和粘附型微泡的二室药动学模型来描述异常的时间-强度曲线。该模型表明，PEI负荷显著减少了自由循环，增加了与血管系统的非特异性黏附。然而，DNA负载形成复合微泡增加了血液中的循环，减少了非特异性黏附。PEI-微泡与荧光素酶生物发光报告质粒DNA偶联，被证明可以转染植入小鼠肾脏的肿瘤。在团注DNA/PEI-微泡后，通过在肿瘤区域应用超声波，实现了局部特异性给药。体内成像显示，与未经治疗的组织相比，肿瘤区域的生物发光强度高出10倍以上。对切除的肿瘤的体外分析显示，肿瘤组织中的表达比非超声对照(心脏)组织中的高40倍以上。这些结果表明，复合微泡平台提供了更好的DNA装载和包装的控制，适合于超声引导的组织转染。
Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.
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DOI：
10.1109/tbme.2009.2034533
发表时间：
2010-01
期刊：
IEEE transactions on bio-medical engineering
影响因子：
--
作者：
Choi JJ;Feshitan JA;Baseri B;Wang S;Tung YS;Borden MA;Konofagou EE
通讯作者：
Konofagou EE
DOI：
10.1186/1756-9966-29-152
发表时间：
2010-11-23
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen ZY;Liang K;Qiu RX
通讯作者：
Qiu RX
影响因子：
3.9
作者：
Lentacker, Ine;De Geest, Bruno G.;Sanders, Niek N.
通讯作者：
Sanders, Niek N.
影响因子：
18.3
作者：
Ferrara, Katherine W.;Borden, Mark A.;Zhang, Hua
通讯作者：
Zhang, Hua
影响因子：
10.8
作者：
Deckers, Roel;Moonen, Chrit T. W.
通讯作者：
Moonen, Chrit T. W.