Dipartimento di Scienze dell'Ambiente e della Vita, Universită del Piemonte Orientale A Avogadro, Viale T Michel 11, 15121 Alessandria, Italy.
Curr Med Chem. 2009;16(34):4544-80. doi: 10.2174/092986709789760661.
Platinum-based anticancer chemotherapy is associated to severe side effects because of its poor specificity. In particular, the hydrolysis of Pt-based drugs generates cationic complexes with electrophylic properties able to target DNA. The effectiveness of this kind of chemotherapy relies solely on the proliferation index of tumour cells, which is higher than in healthy cells. In recent years, the "drug targeting and delivery" approach has been developed in an attempt to reduce chemotherapy-related systemic side effects by using vectors that selectively deliver the cytotoxic agent to tumour cells, thus sparing healthy cells. These vectors include bioactive substances, such as nutrients, that more readily enter metabolically active tumour cells, or hormones, folates and bile acids, that are selectively conveyed by receptors/transporters often over-expressed in cancer cells (active targeting). Alternatively, macromolecular vectors, exploiting the so-called EPR (enhanced permeability and retention) effect, can be used (passive targeting). The bioactive or macromolecular vector must contain a coordinating arm capable of binding the PtX(2)-unit, acting either as carrier or leaving group for the cytotoxic Pt-moiety. In both cases, the Pt-vector conjugate should be promptly cleaved to generate the active species. The release of platinum drugs from the pharmacophore is crucial for fine-tuning of the overall cytotoxic properties of the conjugates. The "drug targeting and delivery" method represents an exciting field of research for improving the therapeutic potential of the long established, very efficient, but intrinsically non-specific Pt-based drugs.
铂类抗癌化疗药物由于其特异性差而与严重的副作用相关。特别是，铂类药物的水解会产生具有亲电性的阳离子配合物，能够靶向 DNA。这种化疗的有效性完全依赖于肿瘤细胞的增殖指数，其增殖指数高于健康细胞。近年来，已经开发了“药物靶向和递药”方法，试图通过使用选择性地将细胞毒性剂递送到肿瘤细胞的载体来减少与化疗相关的全身副作用，从而使健康细胞免受影响。这些载体包括生物活性物质，例如更容易进入代谢活跃的肿瘤细胞的营养素，或激素、叶酸和胆酸，它们被癌细胞中经常过度表达的受体/转运体选择性携带（主动靶向）。或者，可以使用利用所谓的 EPR（增强的通透性和保留）效应的大分子载体（被动靶向）。生物活性或大分子载体必须包含一个能够结合 PtX(2)-单元的配位臂，该配位臂可以作为载体或细胞毒性 Pt 部分的离去基团。在这两种情况下，Pt-载体缀合物都应该被迅速切割以生成活性物质。从药效团中释放铂类药物对于精细调整缀合物的整体细胞毒性特性至关重要。“药物靶向和递药”方法代表了一个令人兴奋的研究领域，可以提高长期确立的、非常有效但内在非特异性的铂类药物的治疗潜力。
