靶向药物与纳米医学:现状与未来。
Targeted drugs and nanomedicine: present and future.
作者信息
Debbage Paul
机构信息
Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Muellerstrasse 59, Innsbruck, Austria.
出版信息
Curr Pharm Des. 2009;15(2):153-72. doi: 10.2174/138161209787002870.
Packaging small-molecule drugs into nanoparticles improves their bio-availability, bio-compatibility and safety profiles. Multifunctional particles carrying large drug payloads for targeted transport, immune evasion and favourable drug release kinetics at the target site, require a certain minimum size usually 30-300 nm diameter, so are nanoparticles. Targeting particles to a disease site can signal the presence of the disease site, block a function there, or deliver a drug to it. Targeted nanocarriers must navigate through blood-tissue barriers, varying in strength between organs and highest in the brain, to reach target cells. They must enter target cells to contact cytoplasmic targets; specific endocytotic and transcytotic transport mechanisms can be used as trojan horses to ferry nanoparticles across cellular barriers. Specific ligands to cell surface receptors, antibodies and antibody fragments, and aptamers can all access such transport mechanisms to ferry nanoparticles to their targets. The pharmacokinetics and pharmacodynamics of the targeted drug-bearing particle depend critically on particle size, chemistry, surface charge and other parameters. Particle types for targeting include liposomes, polymer and protein nanoparticles, dendrimers, carbon-based nanoparticles e.g. fullerenes, and others. Immunotargeting by use of monoclonal antibodies, chimeric antibodies and humanized antibodies has now reached the stage of clinical application. High-quality targeting groups are emerging: antibody engineering enables generation of human/like antibody (fragments) and facilitates the search for clinically relevant biomarkers; conjugation of nanocarriers to specific ligands and to aptamers enables specific targeting with improved clinical efficacy. Future developments depend on identification of clinically relevant targets and on raising targeting efficiency of the multifunctional nanocarriers.
将小分子药物包装成纳米颗粒可改善其生物利用度、生物相容性和安全性。携带大量药物用于靶向运输、免疫逃逸以及在靶位点具有良好药物释放动力学的多功能颗粒,通常需要一定的最小尺寸,直径一般为30 - 300纳米,因此属于纳米颗粒。将颗粒靶向疾病部位可以表明疾病部位的存在、阻断该部位的功能或向其递送药物。靶向纳米载体必须穿过血组织屏障,不同器官的血组织屏障强度不同,其中大脑中的最强,以到达靶细胞。它们必须进入靶细胞以接触细胞质靶点;特定的内吞和转胞吞运输机制可被用作特洛伊木马,将纳米颗粒运送穿过细胞屏障。细胞表面受体的特异性配体、抗体和抗体片段以及适体都可以利用这种运输机制将纳米颗粒运送到其靶点。靶向载药颗粒的药代动力学和药效学关键取决于颗粒大小、化学性质、表面电荷和其他参数。用于靶向的颗粒类型包括脂质体、聚合物和蛋白质纳米颗粒、树枝状大分子、碳基纳米颗粒(如富勒烯)等。利用单克隆抗体、嵌合抗体和人源化抗体进行免疫靶向现已进入临床应用阶段。高质量的靶向基团正在涌现:抗体工程能够产生人源化抗体(片段),并有助于寻找临床相关生物标志物;将纳米载体与特定配体和适体偶联能够实现特异性靶向,提高临床疗效。未来的发展取决于临床相关靶点的识别以及提高多功能纳米载体的靶向效率。