Hussain Sajid, Rodriguez-Fernandez Maria, Braun Gary B, Doyle Francis J, Ruoslahti Erkki
1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Center for Nanomedicine, and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA.
Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106-5080, US.
Sci Rep. 2014 Jun 10;4:5232. doi: 10.1038/srep05232.
Synaphic (ligand-directed) targeting of drugs is an important potential new approach to drug delivery, particularly in oncology. Considerable success with this approach has been achieved in the treatment of blood-borne cancers, but the advances with solid tumours have been modest. Here, we have studied the number and availability for ligand binding of the receptors for two targeting ligands. The results show that both paucity of total receptors and their poor availability are major bottlenecks in drug targeting. A tumour-penetrating peptide greatly increases the availability of receptors by promoting transport of the drug to the extravascular tumour tissue, but the number of available receptors still remains low, severely limiting the utility of the approach. Our results emphasize the importance of using drugs with high specific activity to avoid exceeding receptor capacity because any excess drug conjugate would lose the targeting advantage. The mathematical models we describe make it possible to focus on those aspects of the targeting mechanism that are most likely to have a substantial effect on the overall efficacy of the targeting.
药物的亲和性（配体导向）靶向是药物递送的一种重要潜在新方法，尤其是在肿瘤学领域。这种方法在治疗血源性癌症方面已取得相当大的成功，但在实体瘤方面进展不大。在此，我们研究了两种靶向配体的受体数量及其与配体结合的可及性。结果表明，总受体数量不足及其可及性差是药物靶向的主要瓶颈。一种肿瘤穿透肽通过促进药物向血管外肿瘤组织的转运，极大地提高了受体的可及性，但可用受体数量仍然很低，严重限制了该方法的效用。我们的结果强调了使用高比活性药物以避免超过受体容量的重要性，因为任何过量的药物偶联物都会失去靶向优势。我们描述的数学模型使得能够专注于靶向机制中最有可能对靶向的整体疗效产生实质性影响的那些方面。
