Functionalization of Platinum Complexes for Biomedical Applications

CONSPECTUS: Platinum-based anticancer drugs are the mainstay of chemotherapy regimens in clinic. Nevertheless, the efficacy of platinum drugs is badly affected by serious systemic toxicities and drug resistance, and the pharmacokinetics of most platinum drugs is largely unknown. In recent years, a keen interest in functionalizing platinum complexes with bioactive molecules, targeting groups, photosensitizers, fluorophores, or nanomaterials has been sparked among chemical and biomedical researchers. The motivation for functionalization comes from some of the following demands: to improve the tumor selectivity or minimize the systemic toxicity of the drugs, to enhance the cellular accumulation of the drugs, to overcome the tumor resistance to the drugs, to visualize the drug molecules in vitro or in vivo, to achieve a synergistic anticancer effect between different therapeutic modalities, or to add extra functionality to the drugs. In this Account, we present different strategies being used for functionalizing platinum complexes, including conjugation with bisphosphonates, peptides, receptor-specific ligands, polymers, nanoparticles, magnetic resonance imaging contrast agents, metal chelators, or photosensitizers. Among them, bisphosphonates, peptides, and receptor-specific ligands are used for actively targeted drug delivery, polymers and nanoparticles are for passively targeted drug delivery, magnetic resonance imaging contrast agents are for theranostic purposes, metal chelators are for the treatment or prevention of Alzheimer's disease (AD), and photosensitizers are for photodynamic therapy of cancers. The rationales behind these designs are explained and justified at the molecular or cellular level, associating with the requirements for diagnosis, therapy, and visualization of biological processes. To illustrate the wide range of opportunities and challenges that are emerging in this realm, representative examples of targeted drug delivery systems, anticancer conjugates, anticancer theranostic agents, and anti-AD compounds relevant to functionalized platinum complexes are provided. All the examples exhibit new potential of platinum complexes for future applications in biomedical areas. The emphases of this Account are placed on the functionalization for targeted drug delivery and theranostic agents. In the end, a general assessment of various strategies has been made according to their major shortcomings and defects. The original information in this Account comes entirely from literature appearing since 2010.

概述：铂类抗癌药物是临床上化疗方案的主要支柱。然而，铂类药物的疗效受到严重的全身毒性和耐药性的严重影响，而且大多数铂类药物的药代动力学在很大程度上是未知的。近年来，化学和生物医学研究人员对用生物活性分子、靶向基团、光敏剂、荧光团或纳米材料对铂配合物进行功能化产生了浓厚的兴趣。功能化的动机源于以下一些需求：提高药物的肿瘤选择性或最大限度地降低全身毒性，增强药物在细胞内的积累，克服肿瘤对药物的耐药性，在体外或体内对药物分子进行可视化，实现不同治疗方式之间的协同抗癌效果，或者为药物增加额外的功能。在本文中，我们介绍了用于对铂配合物进行功能化的不同策略，包括与双膦酸盐、肽、受体特异性配体、聚合物、纳米粒子、磁共振成像造影剂、金属螯合剂或光敏剂结合。其中，双膦酸盐、肽和受体特异性配体用于主动靶向给药，聚合物和纳米粒子用于被动靶向给药，磁共振成像造影剂用于诊疗一体化目的，金属螯合剂用于治疗或预防阿尔茨海默病（AD），光敏剂用于癌症的光动力治疗。在分子或细胞水平上对这些设计背后的原理进行了解释和论证，并与生物过程的诊断、治疗和可视化要求相关联。为了说明在这一领域中出现的广泛机遇和挑战，提供了与功能化铂配合物相关的靶向给药系统、抗癌偶联物、抗癌诊疗剂和抗AD化合物的代表性例子。所有这些例子都展示了铂配合物在生物医学领域未来应用的新潜力。本文的重点放在靶向给药和诊疗剂的功能化上。最后，根据各种策略的主要缺点和缺陷对其进行了总体评估。本文的原始信息完全来自2010年以来出现的文献。