Designing polymer conjugates as lysosomotropic nanomedicines
Designing polymer conjugates as lysosomotropic nanomedicines
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DOI：
10.1042/bst0350056
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发表时间：
2007-02-01
影响因子：
3.9
通讯作者：
Duncan, R.
中科院分区：
文献类型：
--
作者：
Duncan, R.
细胞生物学（“溶酶体药物递送”的概念）的结合以及水溶性合成聚合物可能为靶向药物递送提供理想平台的认识导致了第一个作为抗癌药物进入临床试验的合成聚合物-药物缀合物。从概念上讲，聚合物缀合物与其他大分子药物具有许多共同特征，但它们具有合成化学多功能性的额外优势，允许定制分子量和添加仿生特征。必须仔细优化缀合物特性，以确保聚合物载体具有生物相容性，并且聚合物分子量能够实现肿瘤选择性靶向，然后进行内吞内化。聚合物-药物连接体在运输过程中必须稳定，但在细胞内以最佳速率降解以释放活性药物。我们的早期研究设计了两种含有阿霉素的 HPMA [N-(2-羟丙基)甲基丙烯酰胺] 共聚物缀合物，成为第一个在 I/II 期临床试验中进行测试的合成聚合物-药物缀合物。此后，又出现了四种 HPMA 共聚物-抗癌药物缀合物（最近的是聚合物铂酸盐）和第一种基于聚合物的伽马相机成像剂。由溶酶体硫醇依赖性蛋白酶裂解的聚合物-药物连接体以及降低内体和溶酶体的pH值已被广泛用于促进药物释放。越来越明显的是，不适当的运输和/或酶激活故障可能导致新的临床耐药机制。最近的研究描述了携带内分泌和化疗组合的 HPMA 共聚物缀合物，其活性明显比携带单一药物的单个缀合物更活跃。此外，目前的研究正在研究新型树枝状聚合物结构和新型可生物降解聚合物作为药物载体，这将在未来提供改进的药物输送和成像探针。本文回顾了聚合物抗癌药物的临床现状、聚合物疗法设计的基本原理，并讨论了溶酶体递送的好处和挑战。
Marriage of cell biology (the concept of 'lysosomotropic drug delivery') and the realization that water-soluble synthetic polymers might provide an ideal platform for targeted drug delivery led to the first synthetic polymer-drug conjugates that entered clinical trials as anticancer agents. Conceptually, polymer conjugates share many features with other macromolecular drugs, but they have the added advantage of the versatility of synthetic chemistry that allows tailoring of molecular mass and addition of biomimetic features. Conjugate characteristics must be optimized carefully to ensure that the polymeric carrier is biocompatible and that the polymer molecular mass enables tumour-selective targeting followed by endocytic internalization. The polymer-drug linker must be stable in transit, but be degraded at an optimal rate intracellularly to liberate active drug. our early studies designed two HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer conjugates containing doxorubicin that became the first synthetic polymer-drug conjugates to be tested in phase I/II clinical trials. Since, a further four HPMA copolymer-anticancer drug conjugates (most recently polymer platinates) and the first polymer-based gamma-camera imaging agents followed. Polymer-drug linkers cleaved by lysosomal thiol-dependent proteases and the reduced pH of endosomes and lysosomes have been used widely to facilitate drug liberation. it is becoming clear that inappropriate trafficking and/or malfunction of enzymatic activation can lead to new mechanisms of clinical resistance. Recent studies have described HPMA copolymer conjugates carrying a combination of both endocrine and chemotherapy that are markedly more active than individual conjugates carrying a single drug. Moreover, current research is investigating novel dendritic polymer architectures and novel biodegradable polymers as drug carriers that will provide improved drug delivery and imaging probes in the future. The present paper reviews the clinical status of polymeric anticancer agents, the rationale for the design of polymer therapeutics and discusses the benefits and challenges of lysosomotropic delivery.