Sarin Hemant
National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
J Transl Med. 2009 Sep 1;7:77. doi: 10.1186/1479-5876-7-77.
Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof.
尽管全身化疗药物是小分子，能够轻易透过恶性脑肿瘤微脉管系统的多孔血脑肿瘤屏障，但全身化疗在恶性脑肿瘤的治疗中一直相对无效。小分子全身化疗药物仅在数分钟内维持血药峰值浓度，因此，无法在单个脑肿瘤细胞内蓄积至治疗浓度。恶性脑肿瘤微脉管系统血脑肿瘤屏障的孔径生理上限约为12纳米。直径在7纳米至10纳米之间的球形纳米颗粒可维持数小时的血药峰值浓度，且其尺寸远小于血脑肿瘤屏障孔径12纳米的生理上限，能够在单个脑肿瘤细胞内蓄积至治疗浓度。因此，尺寸在7至10纳米范围内的载化疗药物纳米颗粒可用于将治疗浓度的小分子化疗药物透过血脑肿瘤屏障输送至单个脑肿瘤细胞。Gd-G5-阿霉素树枝状大分子是一种尺寸在7至10纳米范围内的可成像载化疗药物纳米颗粒，其初步治疗效果已在原位RG-2啮齿动物恶性胶质瘤模型中得到证实。在此，我将讨论这种提高全身化疗治疗恶性脑肿瘤有效性的新策略及其治疗意义。
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