Fischell Department of Bioengineering, School of Engineering, University of Maryland College Park, College Park, MD 20742, USA.
J Control Release. 2012 Dec 10;164(2):125-37. doi: 10.1016/j.jconrel.2012.05.052. Epub 2012 Jun 15.
Targeting of therapeutic agents to molecular markers expressed on the surface of cells requiring clinical intervention holds promise to improve specificity of delivery, enhancing therapeutic effects while decreasing potential damage to healthy tissues. Drug targeting to cellular receptors involved in endocytic transport facilitates intracellular delivery, a requirement for a number of therapeutic goals. However, after several decades of experimental design, there is still considerable controversy on the practical outcome of drug targeting strategies. The plethora of factors contributing to the relative efficacy of targeting makes the success of these approaches hardly predictable. Lack of fully specific targets, along with selection of targets with spatial and temporal expression well aligned to interventional requirements, pose difficulties to this process. Selection of adequate sub-molecular target epitopes determines accessibility for anchoring of drug conjugates and bulkier drug carriers, as well as proper signaling for uptake within the cell. Targeting design must adapt to physiological variables of blood flow, disease status, and tissue architecture by accommodating physicochemical parameters such as carrier composition, functionalization, geometry, and avidity. In many cases, opposite features need to meet a balance, e.g., sustained circulation versus efficient targeting, penetration through tissues versus uptake within cells, internalization within endocytic compartment to avoid efflux pumps versus accessibility to molecular targets within the cytosol, etc. Detailed characterization of these complex physiological factors and design parameters, along with a deep understanding of the mechanisms governing the interaction of targeted drugs and carriers with the biological environment, are necessary steps toward achieving efficient drug targeting systems.
将治疗药物靶向作用于需要临床干预的细胞表面表达的分子标志物，有望提高药物递送的特异性，增强治疗效果，同时降低对健康组织的潜在损伤。靶向作用于参与内吞运输的细胞受体的药物靶向作用促进细胞内递送，这是许多治疗目标的要求。然而，经过几十年的实验设计，药物靶向策略的实际效果仍然存在相当大的争议。导致靶向相对疗效的诸多因素使得这些方法的成功难以预测。完全特异性靶标的缺乏，以及与介入要求空间和时间表达相匹配的靶标的选择，给这一过程带来了困难。选择适当的亚分子靶标决定了药物偶联物和更大的药物载体的锚定以及细胞内摄取的适当信号传导的可及性。靶向设计必须通过适应血流、疾病状态和组织结构的生理变量，通过容纳载体组成、功能化、几何形状和亲和力等理化参数来适应生理变量。在许多情况下，相反的特征需要平衡，例如，持续循环与高效靶向、组织穿透与细胞内摄取、内吞体腔内的内化以避免流出泵与细胞溶质内的分子靶标可及性等。对这些复杂生理因素和设计参数进行详细表征，以及深入了解靶向药物和载体与生物环境相互作用的机制，是实现高效药物靶向系统的必要步骤。
