Nelson Jared L, Roeder Beverly L, Carmen John C, Roloff Friederike, Pitt William G
Chemical Engineering, Brigham Young University, Provo, Utah 84602, USA.
Cancer Res. 2002 Dec 15;62(24):7280-3.
Systemic delivery of anticancer agents is accompanied by many unwanted side effects that can be mitigated by encapsulation of antineoplastic agents. However, encapsulation necessitates a technique for controlled delivery to the cancerous tissue. We have developed a novel drug delivery system that releases drug from stabilized micelles upon application of low-frequency ultrasound and that demonstrates efficacy using doxorubicin (Dox) to treat tumors in vivo. Forty-two BDIX rats were inoculated in each hind leg with a DHD/K12/TRb tumor cell line. Dox was encapsulated within stabilized Pluronic micelles and administered weekly i.v. to the rats starting 6 weeks after the tumor inoculations. One of the two tumors was exposed to low-frequency ultrasound for 1 h. Dox concentrations of 1.33, 2.67, and 8 mg/kg and ultrasound frequencies of 20 and 70 kHz were used for treatment. Tumor volume was measured with calipers and observed over the treatment time. Administration of encapsulated Dox at concentrations of 1.33 and 2.67 mg/kg was not lethal to the rats. Application of low-frequency ultrasound (both 20 and 70 kHz) significantly reduced the tumor size when compared with noninsonated controls (P = 0.0062) in the other leg for rats receiving encapsulated Dox. Significant tumor reduction was also noted for those rats receiving ultrasound and encapsulated Dox at 2.67 mg/kg (P = 0.017) and rats receiving Dox and ultrasound at 70 kHz (P = 0.029). We postulate that ultrasound releases the Dox from the micelles as they enter the insonated volume, and ultrasound could also assist the drug and/or carriers to extravasate and enter the tumor cells. Encapsulation of Dox using stabilized Pluronic micelles and localized release using low-frequency ultrasound show promise in offering controlled drug delivery in the treatment of tumors in a rat model.
抗癌药物的全身给药伴随着许多不良副作用，而将抗肿瘤药物封装起来可以减轻这些副作用。然而，封装需要一种将药物可控地递送至癌组织的技术。我们开发了一种新型药物递送系统，该系统在施加低频超声时能从稳定的胶束中释放药物，并且使用阿霉素（Dox）在体内治疗肿瘤时显示出疗效。42只BDIX大鼠的每条后腿均接种DHD/K12/TRb肿瘤细胞系。将Dox封装在稳定的普朗尼克胶束中，并在肿瘤接种6周后开始每周一次静脉注射给大鼠。将两只肿瘤中的一只暴露于低频超声下1小时。使用1.33、2.67和8mg/kg的Dox浓度以及20和70kHz的超声频率进行治疗。用卡尺测量肿瘤体积并在治疗期间进行观察。以1.33和2.67mg/kg浓度封装的Dox给药对大鼠没有致死性。对于接受封装Dox的大鼠，与另一条腿未接受超声照射的对照相比，施加低频超声（20kHz和70kHz）均显著减小了肿瘤大小（P = 0.0062）。对于接受2.67mg/kg超声和封装Dox的大鼠（P = 0.017）以及接受70kHz Dox和超声的大鼠（P = 0.029），也观察到肿瘤显著缩小。我们推测，当胶束进入超声照射区域时，超声会使Dox从胶束中释放出来，并且超声还可以协助药物和/或载体渗出并进入肿瘤细胞。使用稳定的普朗尼克胶束封装Dox并通过低频超声进行局部释放，在大鼠模型的肿瘤治疗中显示出在提供可控药物递送方面的前景。
