Abstract
Toxicity studies for conventional oral drug formulations are standardized and well documented, as required by the guidelines of administrative agencies such as the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or European Medicines Evaluation Agency (EMEA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Researchers tend to extrapolate these standardized protocols to evaluate nanoformulations (NFs) because standard nanotoxicity protocols are still lacking in nonclinical studies for testing orally delivered NFs. However, such strategies have generated many inconsistent results because they do not account for the specific physicochemical properties of nanomedicines. Due to their tiny size, accumulated surface charge and tension, sizeable surface-area-to-volume ratio, and high chemical/structural complexity, orally delivered NFs may generate severe topical toxicities to the gastrointestinal tract and metabolic organs, including the liver and kidney. Such toxicities involve immune responses that reflect different mechanisms than those triggered by conventional formulations. Herein, we briefly analyze the potential oral toxicity mechanisms of NFs and describe recently reported in vitro and in vivo models that attempt to address the specific oral toxicity of nanomedicines. We also discuss approaches that may be used to develop nontoxic NFs for oral drug delivery.
Highlights
Oral administration is one of the most popular routes for delivering drug formulations due to its convenience of dosing and excellent patient compliance
As we continue to discover the mechanisms through which NFs interact with biological systems, we are learning about their potential toxicity, which may result in serious adverse effects in late-stage trials
This is a serious issue in clinical settings, where NFs are increasingly being used as therapeutics or as drug delivery systems
Summary
Oral administration is one of the most popular routes for delivering drug formulations due to its convenience of dosing and excellent patient compliance. The toxicity of NFs can originate from pristine NFs, partially degraded NFs, nanocomposite chemicals, or premature release of the loaded drug [13,14,15,16]. As scientists tend to employ biocompatible chemicals to construct NFs and the loaded drug is generally present at a much lower dose compared to the conventional formulations [17], current toxicity studies mainly focus on the harmful effects that originate from intact and partially degraded NFs. Intact NFs have unique physicochemical properties, including their size, aspect ratio, microstructure, surface charge, and surface chemistry. Intact NFs have unique physicochemical properties, including their size, aspect ratio, microstructure, surface charge, and surface chemistry These properties determine their in vivo efficacy and toxicity upon oral administration [18,19].
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