Affiliations of authors: Institute of Biomedical Engineering, Department of Engineering Science(RC, JC, C-CC) and Department of Oncology (RL, LWS), University of Oxford, Oxford, UK; Institut d'Investigacio Biomedica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain (MB-P); Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic (VS, LK, KU).
J Natl Cancer Inst. 2013 Nov 20;105(22):1701-10. doi: 10.1093/jnci/djt305. Epub 2013 Oct 29.
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 1.2 MPa. 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 × 10(6) photons/sec/cm(2); standard deviation = 3 × 10(6) with ultrasound vs 1.3 × 10(5); standard deviation = 1 × 10(5) 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.
溶瘤病毒是目前最强大和最具选择性的癌症治疗方法之一，在临床试验中表现出强大的活性，特别是当直接注射到肿瘤结节中时。然而，它们的静脉给药治疗转移性疾病受到不利的药代动力学和在肿瘤中积累和渗透效率低下的阻碍。
腺病毒（Ad）被一种新的 N-(2-羟丙基)甲基丙烯酰胺聚合物“隐身”，并在携带人 ZR-75-1 异种移植肿瘤的 Balb/C SCID 小鼠（每组 8 只）中描述其循环动力学。然后，为了非侵入性地增加循环聚合物包裹的 Ad 进入肿瘤的渗出，将其与气体微泡一起注射，并将肿瘤暴露于 0.5 MHz 聚焦超声，峰值稀疏压力为 1.2 MPa。这些超声暴露条件旨在引发惯性空化，这是一种产生冲击波的声学现象，可以实时进行远程监测。使用学生 t 检验或单向方差分析与 Tukey 校正比较组，当组大于两个时。所有统计检验均为双侧检验。
Ad 的聚合物涂层减少了肝脏的隔离、感染（>8000 倍；P <.001）和毒性，并延长了循环半衰期（>50 倍；P =.001）。聚合物包裹的 Ad、气体微泡和聚焦超声的组合增强了肿瘤感染>30 倍；（4×10(6) 光子/秒/cm(2)；标准偏差=3×10(6) 有超声 vs 1.3×10(5)；标准偏差=1×10(5) 无超声；P =.03）和渗透，使距离最近血管超过 100 微米的细胞死亡。这导致肿瘤生长显著且具有统计学意义的延迟，并提高了存活率。
结合药物隐身和超声诱导的空化作用可能最终增强一系列强大治疗药物的疗效，从而改善转移性癌症的治疗效果。
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