Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound.
Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound.
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DOI：
10.1093/jnci/djt305
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发表时间：
2013-11-20
期刊：
影响因子：
--
通讯作者：
Seymour LW
中科院分区：
文献类型：
--
作者：
Carlisle R;Choi J;Bazan-Peregrino M;Laga R;Subr V;Kostka L;Ulbrich K;Coussios CC;Seymour LW
溶瘤病毒是正在开发的最有效和最有选择性的癌症治疗药物之一，在临床试验中显示出强劲的活性，特别是当直接给药到肿瘤结节中时。然而，它们用于治疗转移性疾病的静脉给药受到了不利的药代动力学和低效的肿瘤蓄积和渗透的阻碍。用一种新的N-(2-羟丙基)甲基丙烯酰胺聚合物“隐蔽腺病毒”(Ad)，并在荷人ZR-75-1异种移植瘤的Balb/C SCID小鼠(每组8只)上测定循环动力学。然后，为了非侵入性地增加循环聚合物包被的Ad向肿瘤内的渗出，将其与气体微泡共同注射，并用0.5 MHz聚焦超声照射肿瘤，峰值稀释压为1.2 Mpa。这些超声暴露条件旨在触发惯性空化，这是一种会产生冲击波的声学现象，可以进行远程实时监测。当组数大于2时，组间比较采用t检验或采用Tukey校正的单向方差分析。所有的统计检验都是双面的。Ad的聚合物涂层减少了肝脏隔离、感染(>；8000倍；P<；.001)、毒性和改善循环半衰期(>；50倍；P=.001)。聚合物包被的Ad、气泡和聚焦超声的组合将肿瘤感染增强了30倍；(4×106光子/秒/cm2；使用超声波时标准偏差=3×106 vs 1.3×105；不使用超声波时标准偏差=1×105；P=0.03)和穿透性，能够从最近的血管杀死超过100微米的细胞。这导致了大量的和统计上显着的延缓肿瘤生长和提高存活率。结合药物偷取和超声波诱导的空化最终可能会增强一系列强大疗法的疗效，从而改善转移性癌症的治疗。
Oncolytic viruses are among the most powerful and selective cancer therapeutics under development and are showing robust activity in clinical trials, particularly when administered directly into tumor nodules. However, their intravenous administration to treat metastatic disease has been stymied by unfavorable pharmacokinetics and inefficient accumulation in and penetration through tumors. Adenovirus (Ad) was “stealthed” with a new N-(2-hydroxypropyl)methacrylamide polymer, and circulation kinetics were characterized in Balb/C SCID mice (n = 8 per group) bearing human ZR-75-1 xenograft tumors. Then, to noninvasively increase extravasation of the circulating polymer-coated Ad into the tumor, it was coinjected with gas microbubbles and the tumor was exposed to 0.5 MHz focused ultrasound at peak rarefactional pressure of 1.2MPa. These ultrasound exposure conditions were designed to trigger inertial cavitation, an acoustic phenomenon that produces shock waves and can be remotely monitored in real-time. Groups were compared with Student t test or one-way analysis of variance with Tukey correction where groups were greater than two. All statistical tests were two-sided. Polymer-coating of Ad reduced hepatic sequestration, infection (>8000-fold; P < .001), and toxicity and improved circulation half-life (>50-fold; P = .001). Combination of polymer-coated Ad, gas bubbles, and focused ultrasound enhanced tumor infection >30-fold; (4×106 photons/sec/cm2; standard deviation = 3×106 with ultrasound vs 1.3×105; standard deviation = 1×105 without ultrasound; P = .03) and penetration, enabling kill of cells more than 100 microns from the nearest blood vessel. This led to substantial and statistically significant retardation of tumor growth and increased survival. Combining drug stealthing and ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of metastatic cancer.
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影响因子：
17.4
作者：
Gormley AJ;Larson N;Sadekar S;Robinson R;Ray A;Ghandehari H
通讯作者：
Ghandehari H
影响因子：
10.8
作者：
Bazan-Peregrino, Miriam;Arvanitis, Costas D.;Coussios, Constantin-C.
通讯作者：
Coussios, Constantin-C.
影响因子：
5.1
作者：
Cichon, G;Boeckh-Herwig, S;Burger, R
通讯作者：
Burger, R
影响因子：
4.2
作者：
Doronin, Konstantin;Shashkova, Elena V.;Barry, Michael A.
通讯作者：
Barry, Michael A.
影响因子：
46.9
作者：
通讯作者：
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