Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: Challenges, considerations and strategy

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• 作者：Marina A. Dobrovolskaia ; ^{marina@mail.nih.gov" class="auth_mail" title="E-mail the corresponding author}
• 关键词：5-FU ; 5-fluorouracil ; API ; active pharmaceutical ingredient ; ADA ; anti-drug antibodies ; CSE ; control standard endotoxin ; CTL ; cytotoxic T lymphocytes ; CARPA ; complement activation&ndash ; related pseudoallergy ; CHAPS ; 3-[(3-Cholamidopropyl)dimethylammonio]-1- ; DIC ; disseminated intravascular coagulation ; EDTA ; ethylenediaminetetraacetic acid ; GLP ; good laboratory practices ; IEC ; inhibition/enhancement control ; ICH S8 ; International Conference on Harmonization Safety Guidelines Section 8 ; IDE ; Inve
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 December 2015
• 年：2015
• 卷：220
• 期：part_PB
• 页码：571-583
• 全文大小：1380 K

文摘

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.