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

Abstract

Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany preclinical 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 nanoparticleformulated drugs toward clinical trials. Special attention will be paid to the grandchallenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge.

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

“…Nanoparticles were introduced to decrease some of the challenges of traditional drug delivery, but come with their own difficulties and limitations that will continue to be an important area of research. In vivo bio-distribution and toxicity studies currently guide particle design and clinical trial candidates, but the real world use of nanomedicines need Phase IV post-marketing review after clinical application to show the full benefits and limitations of these technologies (11,20,(83)(84)(85)(86). Several nanomedicine products have undergone clinical trials only to be later withdrawn due to efficacy or safety concerns e.g.…”

“…For nanomedicines it is becoming increasingly important to have a comprehensive understanding of the physicochemical parameters of the material, and the reproducibility and scalability of the manufacturing process. Publications from the Nanotechnology Characterization Laboratory (NCL; established by the National Cancer Institute) are available to guide this process, and researchers have the option to send material for testing and validation at the NCL according to a series of emerging protocols (19)(20)(21). However, significant research is still required to understand and predict how these materials will behave in biological systems, including the development of new assays and readout methods that are not confounded by the presence of the nanoparticle component.…”

Early Development Challenges for Drug Products Containing Nanomaterials

“…Early consideration of the immunological responses elicited from nanomaterial interaction with blood components and immune cells can help avoid a latestage failure of the product over serious immunological toxicities. Many in vitro assays have been developed for evaluation of nanoparticle immunotoxicity, and many have been shown to be reasonably predictive of in vivo responses (40)(41)(42). Table I lists several key in vitro immunology tests that can be critical for derisking early development nanomedicines, as well as their potential associated in vivo consequences (40).…”

“…Many in vitro assays have been developed for evaluation of nanoparticle immunotoxicity, and many have been shown to be reasonably predictive of in vivo responses (40)(41)(42). Table I lists several key in vitro immunology tests that can be critical for derisking early development nanomedicines, as well as their potential associated in vivo consequences (40). A substantial fraction of nanomedicines in early preclinical development are contaminated with endotoxin above allowable levels for parenteral administration to humans (7).…”

Efecto inmunomodulador de nanopartículas usadas en nanomedicina

“…Las NP se clasifican según su composición química en los siguientes dos grupos: A. Nanopartículas inorgánicas como las de sílice, los Quatum Dots, las metálicas, los nanotubos de carbono, las de oro y los fulerenos. B. Nanopartículas orgánicas como los liposomas, las micelas, los dendrímeros, los conjugados de proteínas y las poliméricas es ventajosa para su uso; sin embargo, esas mismas características y propiedades hacen que, cuando una NP se introduce en el organismo, el sistema inmunitario la reconozca como un agente extraño y se produzca una respuesta inmune (19,20). Además, factores como la dosis y la vía de administración, el mecanismo de acción y el sitio de la actividad -que son propiedades extrínsecas al material-también son críticos en el establecimiento de la respuesta inmune (12,21).…”