Immunotoxicity Considerations for Next Generation Cancer Nanomedicines

Abstract

Although interest and funding in nanotechnology for oncological applications is thriving, translating these novel therapeutics through the earliest stages of preclinical assessment remains challenging. Upon intravenous administration, nanomaterials interact with constituents of the blood inducing a wide range of associated immunotoxic effects. The literature on the immunological interactions of nanomaterials is vast and complicated. A small change in a particular characteristic of a nanomaterial (e.g., size, shape, or charge) can have a significant effect on its immunological profile in vivo, and poor selection of specific assays for establishing these undesirable effects can overlook this issue until the latest stages of preclinical assessment. This work describes the current literature on unintentional immunological effects associated with promising cancer nanomaterials (liposomes, dendrimers, mesoporous silica, iron oxide, gold, and quantum dots) and puts focus on what is missing in current preclinical evaluations. Opportunities for avoiding or limiting immunotoxicity through efficient preclinical assessment are discussed, with an emphasis placed on current regulatory views and requirements. Careful consideration of these issues will ensure a more efficient preclinical assessment of cancer nanomedicines, enabling a smoother clinical translation with less failures in the future.

Challenges in Tracking of Fluorochrome-Labelled Nanoparticles in Mice via Whole Body NIRF Imaging

“…The fluorescence of the core-bound dye (DY-730) in the liver and spleen of mice was in agreement with the increase of iron only at the early time point of examination. Based on the facts that i) MNP are opsonized and recognized by MPS [17], ii) that they are mainly taken up by Kupffer cells of the liver and spleen (our data and from other groups [10]), and iii) that the MNP degradation takes place in their lysosomal environment, our examinations (in vitro) show that there was a transient fluorescence increase of the core-bound dye DY-730 in the lysosomal environment. Moreover, citrate-iron chelating seems to favor core dye fluorescence, whereas excess of free Fe 3+ is controversial to it.…”

A Step-by-Step Approach to Improve Clinical Translation of Liposome-Based Nanomaterials, a Focus on Innate Immune and Inflammatory Responses

“…Among them, IL-1β, TNF-α, IL-6, IL-12, which are involved in inflammatory response [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Thus, nanoimmunotoxicity studies that do not consider the accidental presence of endotoxin in particle samples risk attributing to particles the inflammatory effects caused by contaminating endotoxin [ 10 ].…”

“…From a regulatory perspective, immunotoxic effects are not properly examined in the current immunotoxicological studies for human pharmaceuticals (ICH-S8) testing guidelines [ 9 ] and, despite the need for standardized approaches, currently there are no regulatory guidelines for immunotoxicity evaluation that are specific for nanomedicines [ 10 ]. In this regard, the National Cancer Institute-Nanotechnology Characterization Laboratory (USNCL) and the European Union Nanomedicine Characterization Laboratory (EUNCL), working alongside the US Food and Drug Administration (FDA) and the European Medicinal Agency (EMA), have validated protocols for assessing in vitro the capacity of NM to induce cytokine release, which have the advantage of avoiding animal experimentation and overcoming the limitations that animal models have in predicting human responses to challenges [ 11 , 12 , 13 , 14 ].…”

Risk Management Framework for Nano-Biomaterials Used in Medical Devices and Advanced Therapy Medicinal Products

“…For any biomaterial or NBM intended for clinical use, the issue of testing for endotoxin content is of paramount importance [ 60 ]. The BIORIMA project has focused considerable efforts on the evaluation of assays for endotoxin testing, including the conventional Limulus amebocyte lysate (LAL) assay.…”