Liposomes as drug carriers in cancer chemotherapy.
Liposomes as drug carriers in cancer chemotherapy.
复制标题
DOI：
10.1016/0163-7258(84)90035-4
复制
发表时间：
1984
影响因子：
13.5
通讯作者：
J. Weinstein;L. Leserman
中科院分区：
文献类型：
--
作者：
J. Weinstein;L. Leserman
当一个人想要改变时。药物的药理学研究，通常的方法是合成分子本身的大量新衍生物。尽管合理的药物设计取得了进展，但这种方法仍然让人联想到无限数量的化学家坐在无限数量无限长的实验室长凳上，对每种药物产生无限的变化。另一种方法是将药物附着到靶向载体上。选择包括合成聚合物、核酸、免疫球蛋白（单克隆和其他）、白蛋白、蛋白质聚集体、激素、凝集素、微胶囊、纳米颗粒和脂质体。对于治疗，有效负载可以是药物、毒素、生物反应调节剂或放射性同位素；出于诊断目的，它可能是伽马发射器、正电子发射器或核磁共振标记。脂质体的研究比任何其他类型的大分子载体都更广泛。在这里，我们将集中讨论它们作为药物和生物制剂载体的用途，特别强调“靶向”它们的方法。我们还将考虑许多物理化学和细胞生物学问题。最后，脂质体可能更多地通过其在提高我们对基础细胞生物学和免疫学的理解方面的作用而不是作为药物来影响我们治疗癌症的方法。脂质体是由一个或多个包围相同数量的水空间的同心脂质双层组成的微观结构。自 20 世纪 60 年代中期以来，物理化学家、生物学家和医学科学家一直在研究脂质体，当时 Alec Bangham 及其同事 (1964, 1965a, b, c) 证明它们是封闭的、离散的结构，能够捕获水溶性分子。对于许多医学应用，脂质体可以被视为药理学胶囊，可以在其中放入水溶性或脂溶性药物。正如稍后将详细讨论的，使用它们的可能原因包括：（i）由于比非封装药物更长的循环时间而延长药物作用；（ii）脂质体将作为颗粒被隔离在目标位置（即肿瘤）中的可能性；（iii）减少不积累脂质体的那些组织（例如心肌）的毒性；（iv）保护药物在到达目标之前免受代谢和免疫攻击；（v）将脂质体作为颗粒限制定向到选定的解剖室；（vi）通过附着抗体或其他配体将脂质体定向到靶细胞；（vii）将脂质体定向到其天然靶标，即肝脏、脾脏和其他器官的吞噬细胞；（viii）通过在每个定向颗粒中掺入大量药物分子来放大治疗效果；（ix）作为物理因素（例如局部温度或pH）的函数从脂质体选择性局部释放；（x）规避通过胞吞作用或脂质体与细胞的融合来消除渗透性屏障； (xi) 递送设计在内吞后具有活性的药物。
When one wishes to alter the. pharmacology of a drug, the usual approach is to synthesize a large number of new derivatives of the molecule itself. Despite progress in rational drug design, that approach still conjures the image of an infinite number of chemists sitting at an infinite number of infinitely long laboratory benches turning out infinite variations on each agent. An alternative is to attach the drug to a target-directed carrier. Choices include synthetic polymers, nucleic acids, immunoglobulins (monoclonal and otherwise), albumin, protein aggregates, hormones, lectins, microcapsules, nanoparticles, and liposomes. For therapy the payload may be a drug, a toxin, a biological response modifier, or a radioisotope; for diagnostic purposes it will likely be a gammaemitter, a positron-emitter, or a nuclear magnetic resonance marker. Liposomes have been studied more extensively than any other type of macromolecular carrier. Here we will concentrate on their use as carriers of drugs and biological agents, with special emphasis on ways of'targeting'them. We will also consider a number of physico-chemical, and cell biological issues. In the end, liposomes may affect our approach to cancer more by their role in improving our understanding of basic cell biology and immunology than by their use as pharmaceuticals. Liposomes are microscopic structures consisting of one or more concentric lipid bilayers enclosing an equal number of aqueous spaces. They have been studied by physical chemists, biologists, and medical scientists since the mid-1960s when Alec Bangham and co-workers (1964, 1965a, b, c) demonstrated that they are closed, discrete structures capable of trapping water soluble molecules.For many medical applications, liposomes can be viewed as pharmacological capsules into which can be placed either water soluble or lipid soluble drugs. As will be discussed in detail later, the possible reasons for their use include:(i) prolonged drug effect due to longer times of circulation than non-encapsulated drug;(ii) the possibility that liposomes will be sequestered as particles in the target location (ie a tumor);(iii) reduction of toxicity in those tissues (eg cardiac muscle) which do not accumulate liposomes;(iv) protection of a drug from metabolism and immune attack until it reaches the target;(v) confinement of liposomes as particles to a chosen anatomical compartment;(vi) direction of liposomes to target cells by attaching an antibody or other ligand;(vii) direction of liposomes to their natural target, the phagocytic cells of liver, spleen, and other organs;(viii) amplification of therapeutic effect by incorporation of numerous drug molecules in each target-directed particle;(ix) selective local release from liposomes as a function of physical factors such as the local temperature or pH;(x) circumvention of permeability barriers by endocytosis or fusion of liposomes with cells; and (xi) delivery of drugs designed to be active after endocytic uptake.