Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Control Release. 2011 Dec 10;156(2):265-72. doi: 10.1016/j.jconrel.2011.06.030. Epub 2011 Jul 2.
Hyperthermia, which is heating of tumors above 43°C for about 30min, has been known to modulate vascular permeability for enhanced chemotherapy. However, it is not clear whether a similar effect exists when temperature at tumor sites is elevated above 43°C, such as temperature achieved in laser-induced photothermal ablation (PTA) therapy. Also, the effect of timing of chemotherapeutic drug administration following heating in the efficiency of drug delivery is not established. In this study, we investigated the impact of near infrared (NIR) laser irradiated anti-EGFR monoclonal antibody C225-conjugated hollow gold nanospheres (C225-HAuNS) on vascular permeability and subsequent tumor uptake of a water-soluble polymer using combined MRI, ultrasound and optical imaging approaches. Magnetic temperature imaging showed a maximum temperature of 65.2±0.10 °C in A431 tumor xenograft of mice treated with C225-HAuNS plus laser and 47.0±0.33 °C in tumors of mice treated with saline plus laser at 4 W/cm² for 3 min (control) at 2 mm from the light incident surface. Dynamic contrast enhanced (DCE) MRI demonstrated greater than 2-fold increase of DTPA-Gd in the initial area under the curve (IAUC₉₀) in mice injected with C225-HAuNS and exposed to NIR laser compared with control mice at 3 min after laser treatment. Similarly, Power Doppler (PD) ultrasound revealed a 4- to 6-fold increase in percentage vascularization in mice treated with C225-HAuNS plus NIR laser compared to control mice and confirmed increased vascular perfusion immediately after laser treatment. Twenty-four hours later, the blood perfusion was shut down. On optical imaging, tumor uptake of PG-Gd-NIR813, which is the model polymeric drug used, was significantly higher (p-value<0.05) in mice injected with PG-Gd-NIR813 at 5 min after laser treatment than in mice injected with PG-Gd-NIR813 at 24h after laser treatment and the saline-treated mice. In conclusion, laser irradiation of tumors after intravenous injection of C255-HAuNS induces a thermally mediated modulation of the vascular perfusion, which enhances the delivery of polymeric drugs to the tumors at the time phototherapy is initiated.
热疗是指将肿瘤加热至 43°C 以上 30 分钟，已被证实可调节血管通透性，以增强化疗效果。然而，当肿瘤部位的温度升高至 43°C 以上，例如激光诱导光热消融（PTA）治疗中达到的温度时，是否存在类似的效果尚不清楚。此外，加热后给予化疗药物的时间对药物输送效率的影响也尚未确定。在这项研究中，我们使用磁共振成像（MRI）、超声和光学成像相结合的方法，研究了近红外（NIR）激光照射抗表皮生长因子受体（EGFR）单克隆抗体 C225 偶联的中空金纳米球（C225-HAuNS）对血管通透性的影响，以及随后水凝胶聚合物在肿瘤中的摄取。磁测温显示，在接受 C225-HAuNS 联合激光治疗的 A431 肿瘤异种移植小鼠中，最大温度为 65.2±0.10°C，而在接受生理盐水联合激光治疗（对照组）、激光功率为 4 W/cm²、照射 3 分钟的小鼠中，肿瘤温度为 47.0±0.33°C，激光照射面距离为 2mm。动态对比增强磁共振成像（DCE-MRI）显示，与对照组相比，在激光治疗后 3 分钟，接受 C225-HAuNS 联合 NIR 激光照射的小鼠的初始曲线下面积（IAUC₉₀）中的 DTPA-Gd 增加了两倍以上。同样，在接受 C225-HAuNS 联合 NIR 激光治疗的小鼠中，通过功率多普勒（PD）超声检测到血管化百分比增加了 4-6 倍，与对照组相比，这一结果在激光治疗后立即得到证实，并且证实了血管灌注增加。24 小时后，血流停止。在光学成像上，在激光治疗后 5 分钟注射 PG-Gd-NIR813 的小鼠的肿瘤摄取明显高于（p 值<0.05）激光治疗后 24 小时注射 PG-Gd-NIR813 的小鼠和生理盐水处理的小鼠。综上所述，静脉注射 C255-HAuNS 后激光照射肿瘤会引起热介导的血管灌注调节，从而在启动光疗时增强聚合物药物向肿瘤的输送。
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