Luo Y, Prestwich G D
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA.
Curr Cancer Drug Targets. 2002 Sep;2(3):209-26. doi: 10.2174/1568009023333836.
A major challenge in cancer chemotherapy is the selective delivery of small molecule anti cancer agents to tumor cells. Water-soluble polymer-drug conjugates exhibit good water solubility, increased half-life, and potent anti tumor effects. By localizing the drug at the desired site of action, macromolecular therapeutics have improved efficacy and enhanced safety at lower doses. Since small molecule drugs and macromolecular drugs enter cells by different pathways, multi-drug resistance (MDR) can be minimized. Anti-cancer polymer-drug conjugates can be divided into two targeting modalities: passive and active. Tumor tissues have anatomic characteristics that differ from normal tissues. Macromolecules penetrate and accumulate preferentially in tumors relative to normal tissues, leading to extended pharmacological effects. This "enhanced permeability and retention" (EPR) effect is the principal reason for current successes with macromolecular anti-cancer drugs. Both natural and synthetic polymers have been used as drug carriers, and several bioconjugates have been clinically approved or are in human clinical trials. While clinically useful anti-tumor activity has been achieved using passive macromolecular drug delivery systems, further selectivity is possible by active targeting. Attachment of targeting moieties to the polymer backbone can further exploit differences between cancer and normal cells through selective receptor-mediated endocytosis. This strategy would augment the EPR effect, thereby further improving the therapeutic index of the macromolecular drug. This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy. Specific examples are selected to illustrate the basic design principles for soluble polymeric drug delivery systems.
癌症化疗中的一个主要挑战是将小分子抗癌药物选择性地递送至肿瘤细胞。水溶性聚合物 - 药物偶联物具有良好的水溶性、延长的半衰期和强大的抗肿瘤作用。通过将药物定位在所需的作用部位，大分子疗法在较低剂量下具有更高的疗效和更高的安全性。由于小分子药物和大分子药物通过不同途径进入细胞，因此可以将多药耐药性（MDR）降至最低。抗癌聚合物 - 药物偶联物可分为两种靶向方式：被动靶向和主动靶向。肿瘤组织具有与正常组织不同的解剖学特征。相对于正常组织，大分子在肿瘤中优先渗透和积累，从而导致延长的药理作用。这种“增强的渗透和滞留”（EPR）效应是目前大分子抗癌药物取得成功的主要原因。天然和合成聚合物均已用作药物载体，并且几种生物偶联物已获得临床批准或正在进行人体临床试验。虽然使用被动大分子药物递送系统已实现了临床上有用的抗肿瘤活性，但通过主动靶向可以实现进一步的选择性。将靶向部分连接到聚合物主链上可以通过选择性受体介导的内吞作用进一步利用癌细胞与正常细胞之间的差异。这种策略将增强EPR效应，从而进一步提高大分子药物的治疗指数。本综述讨论了用于癌症化疗的原型大分子药物的开发和治疗潜力。选择了具体实例来说明可溶性聚合物药物递送系统的基本设计原则。
