Dobrovolskaia Marina A
Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI at Frederick, Frederick, MD 21702, United States.
J Control Release. 2015 Dec 28;220(Pt B):571-83. doi: 10.1016/j.jconrel.2015.08.056. Epub 2015 Sep 5.
Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany pre-clinical development of nanotechnology-formulated drugs. Some of these challenges are not unique to nanotechnology and are common in the development of other pharmaceutical products. However, nanoparticle-formulated drugs are biochemically sophisticated, which causes their translation into the clinic to be particularly complex. An understanding of both the immune compatibility of nanoformulations and their effects on hematological parameters is now recognized as an important step in the (pre)clinical development of nanomedicines. An evaluation of nanoparticle immunotoxicity is usually performed as a part of a traditional toxicological assessment; however, it often requires additional in vitro and in vivo specialized immuno- and hematotoxicity tests. Herein, I review literature examples and share the experience with the NCI Nanotechnology Characterization Laboratory assay cascade used in the early (discovery-level) phase of pre-clinical development to summarize common challenges in the immunotoxicological assessment of nanomaterials, highlight considerations and discuss solutions to overcome problems that commonly slow or halt the translation of nanoparticle-formulated drugs toward clinical trials. Special attention will be paid to the grand-challenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge.
纳米技术制剂药物的临床前开发伴随着物理化学表征、灭菌、去热原以及药理学、安全性和有效性评估等方面的各种挑战。其中一些挑战并非纳米技术所独有，在其他药品的开发中也很常见。然而，纳米颗粒制剂药物在生物化学方面较为复杂，这使得它们向临床转化的过程格外复杂。如今，了解纳米制剂的免疫相容性及其对血液学参数的影响已被视为纳米药物临床前（及临床）开发的重要一步。纳米颗粒免疫毒性评估通常作为传统毒理学评估的一部分进行；然而，这往往需要额外的体外和体内专门免疫及血液毒性测试。在此，我回顾文献实例，并分享美国国立癌症研究所纳米技术表征实验室在临床前开发早期（发现阶段）使用的检测方法流程的经验，以总结纳米材料免疫毒理学评估中的常见挑战，强调注意事项并讨论克服那些通常会延缓或阻碍纳米颗粒制剂药物向临床试验转化的问题的解决方案。将特别关注与纳米制剂中内毒素的检测、定量和去除相关的重大挑战，以及与此挑战相关的实际考量。
