Optimizing delivery of multivalent targeting constructs for detection of secondary tumors.
Optimizing delivery of multivalent targeting constructs for detection of secondary tumors.
复制标题
优化多价靶向构建体的递送以检测继发性肿瘤。
DOI：
10.1007/s10439-008-9498-8
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发表时间：
2008
影响因子：
3.8
通讯作者：
Caplan,MichaelR
中科院分区：
文献类型：
--
作者：
Stukel,JillM;Heys,JeffreyJ;Caplan,MichaelR
通过将药物或成像分子与细胞表面受体的抗体或配体结合，将其靶向特定细胞，可以更早地检测病理，更好地定位干预，以及更少的副作用。将这些分子递送至靶标因构建体尺寸而复杂化，所述构建体尺寸不能穿过典型的内皮屏障如血管壁，并且缺乏构建体所靶向的继发性肿瘤部位的位置的先验知识。在这里，我们开发了三价结构的扩散和对流增强递送的数学模型。结果显示，将构建体递送至组织不会产生可接受的对比度或特异性;因此，必须通过允许扩散出该区域或后续注射不含构建体的流体（例如，盐水）。对于该附加步骤的需要，扩散递送需要数周至数月以产生可接受的对比度，但对流增强递送可能能够在数天内实现可接受的对比度。因此，多价构建体的对流增强递送可以提供定位继发性肿瘤位点而无需事先知道其位置的机制，这将大大增强检测和治疗癌症的能力。
Targeting drugs or imaging molecules to specific cells by conjugating them to antibodies or ligands for cell surface receptors may allow earlier detection of pathology, better localization for intervention, and fewer side effects. Delivery of these molecules to the target is complicated by construct size, which cannot cross typical endothelial barriers such as the vascular wall, and lack of a priori knowledge of the location of secondary tumor sites to which the construct is targeted. Here we develop mathematical models for diffusive and convection-enhanced delivery of a trivalent construct. Results show that delivery of the construct to the tissue does not yield acceptable contrast or specificity; therefore, unbound construct must be removed from the area of interest by allowing diffusion out of the area or a follow-up injection of fluid containing no construct (e.g., saline). The need for this additional step requires weeks to months for diffusive delivery to yield acceptable contrast, but convection-enhanced delivery may be able to achieve acceptable contrast within several days. Thus, convection-enhanced delivery of multivalent constructs may provide a mechanism to locate secondary tumor sites without prior knowledge of their location which would greatly enhance the ability to detect and treat cancer.