Soluble polymer carriers for the treatment of cancer: the importance of molecular architecture.
Soluble polymer carriers for the treatment of cancer: the importance of molecular architecture.
复制标题
用于治疗癌症的可溶性聚合物载体：分子结构的重要性。
DOI：
10.1021/ar900035f
复制
发表时间：
2009-08-18
影响因子：
18.3
通讯作者：
Frechet, Jean M. J.
中科院分区：
文献类型：
--
作者：
Fox, Megan E.;Szoka, Francis C.;Frechet, Jean M. J.
化疗可以摧毁肿瘤，阻止癌症的发展。不幸的是，严重的副作用——治疗通常是注射一系列剧毒药物——往往限制了剂量的频率和大小，严重损害了肿瘤抑制作用。大多数化疗药物的药代动力学特征具有巨大的改善潜力。水溶性聚合物具有增加药物循环时间、改善药物溶解度、延长药物在肿瘤中的停留时间和降低毒性的潜力。通过可逆键与水溶性聚合物共价结合的细胞毒性药物比单独使用药物更有效地靶向肿瘤组织。大分子通过降低肾脏清除率和利用增强渗透和保留（EPR）效应的组合来被动靶向实体肿瘤组织，这种效应在快速生长的肿瘤中普遍存在。有效的药物递送包括以下两方面的平衡：(i)肾脏、肝脏和其他器官从血液中消除聚合物药物偶联物和（ii）药物从血管中进入肿瘤（即外渗）。聚合物通过与聚合物的流体动力学直径相当的孔径过滤在肾脏中被消除；相反，穿过肿瘤的血管结构的开口比聚合物的直径大一个数量级。因此，聚合物的“分子结构”特征——如其流体动力学体积（或分子量）、分子构象、链柔顺性、分支和附着药物的位置——可以极大地影响聚合物通过肾脏从体内排出，但对聚合物向肿瘤外渗的影响要小得多。从理论上讲，分子结构可以调整，以保证对消除和外渗的基本独立控制。因此，了解分子结构如何影响聚合物通过孔的通道对于设计聚合物药物载体至关重要，这些载体可以有效地被动递送药物载荷，同时符合聚合物必须最终从体内消除的要求。在这篇文章中，我们讨论了来自体内研究的例子，这些研究证明了聚合物的结构特征如何影响聚合物的肾脏滤过以及肿瘤的渗透和肿瘤的积累。简而言之，抑制聚合物通过孔的特征，如分子量较高、柔韧性降低和聚合物链末端数量增加，有助于防止聚合物被肾脏清除，并可以改善血液循环时间和肿瘤积累，从而提高治疗效果。
Chemotherapy can destroy tumors and arrest cancer progress. Unfortunately, severe side effects—treatment is usually a series of injections of highly toxic drugs—often restrict the frequency and size of dosages, much to the detriment of tumor inhibition. Most chemotherapeutic drugs have pharmacokinetic profiles with tremendous potential for improvement. Water-soluble polymers offer the potential to increase drug circulation time, improve drug solubility, prolong drug residence time in a tumor, and reduce toxicity. Cytotoxic drugs that are covalently attached to water-soluble polymers via reversible linkages more effectively target tumor tissue than the drugs alone. Macromolecules passively target solid tumor tissue through a combination of reduced renal clearance and exploitation of the enhanced permeation and retention (EPR) effect, which prevails for fast-growing tumors. Effective drug delivery involves a balance between (i) elimination of the polymeric drug conjugate from the bloodstream by the kidneys, liver, and other organs and (ii) movement of the drug out of the blood vasculature and into the tumor (that is, extravasation). Polymers are eliminated in the kidney by filtration through pores with a size comparable to the hydrodynamic diameter of the polymer; in contrast, the openings in the blood vessel structures that traverse tumors are an order of magnitude greater than the diameter of the polymer. Thus, features that may broadly be grouped as the “molecular architecture” of the polymer—such as its hydrodynamic volume (or molecular weight), molecular conformation, chain flexibility, branching, and location of the attached drug—can greatly impact elimination of the polymer from the body through the kidney but have a much smaller effect on the extravasation of the polymer into the tumor. Molecular architecture can in theory be adjusted to assert essentially independent control over elimination and extravasation. Understanding how molecular architecture affects passage of a polymer through a pore is therefore essential for designing polymer drug carriers that are effective in passively delivering a drug payload while conforming to the requirement that the polymers must eventually be eliminated from the body. In this Account, we discuss examples from in vivo studies that demonstrate how polymer architectural features impact the renal filtration of a polymer as well as tumor penetration and tumor accumulation. In brief, features that inhibit passage of a polymer through a pore—such as higher molecular weight, decreased flexibility, and an increased number of polymer chain ends—help prevent elimination of the polymer by the kidneys and can improve blood circulation times and tumor accumulation, thus improving therapeutic effectiveness.
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影响因子：
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Fréchet, JMJ