Safety and efficacy constitute the major criteria governing regulatory approval of any new drug. The best method to maximize safety and efficacy is to deliver a proven therapeutic agent with a targeting ligand that exhibits little affinity for healthy cells but high affinity for pathologic cells. The probability of regulatory approval can conceivably be further enhanced by exploiting the same targeting ligand, conjugated to an imaging agent, to select patients whose diseased tissues display sufficient targeted receptors for therapeutic efficacy. The focus of this Review is to summarize criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity. Because most LTDs are composed of a targeting ligand (e.g., organic molecule, aptamer, protein scaffold, or antibody), spacer, cleavable linker, and therapeutic warhead, criteria for successful design of each component will be described. Moreover, because obstacles to successful drug design can differ among human pathologies, limitations to drug delivery imposed by the unique characteristics of different diseases will be considered. With the explosion of genomic and transcriptomic data providing an ever-expanding selection of disease-specific targets, and with tools for high-throughput chemistry offering an escalating diversity of warheads, opportunities for innovating safe and effective LTDs has never been greater.

中文翻译：

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配体靶向药物递送

安全性和有效性是管理任何新药监管批准的主要标准。最大化安全性和功效的最佳方法是提供一种经过验证的具有靶向配体的治疗药物，该靶向配体对健康细胞几乎没有亲和力，但对病理细胞却具有很高的亲和力。通过利用与显像剂缀合的相同靶向配体，选择患病组织显示出足够的靶向受体以达到治疗功效的患者，可以进一步提高监管批准的可能性。这篇综述的重点是总结在设计配体靶向药物（LTDs）时必须达到的标准，以实现所需的治疗功效且毒性最小。由于大多数LTD由靶向配体（例如有机分子，适体，蛋白质支架或抗体），间隔基组成，将描述可裂解的接头和治疗性战斗部，以成功设计每个组件的标准。此外，由于成功的药物设计障碍可能因人而异，因此，将考虑到由不同疾病的独特特征所带来的药物输送限制。随着基因组和转录组数据的爆炸式增长，提供了针对特定疾病的目标的不断扩展的选择，以及高通量化学的工具提供了越来越多的弹头，创新安全有效的LTDs的机会从未如此之多。将考虑由不同疾病的独特特征对药物输送的限制。随着基因组和转录组数据的爆炸式增长，提供了针对特定疾病的目标的不断扩展的选择，以及高通量化学的工具提供了越来越多的弹头，创新安全有效的LTDs的机会从未如此之多。将考虑由不同疾病的独特特征对药物输送的限制。随着基因组和转录组数据的爆炸式增长，提供了针对特定疾病的目标的不断扩展的选择，以及借助高通量化学工具提供弹头的多样化，创新安全有效的LTDs的机会从未如此之多。