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Cationic alkyl chain length and nanoaggregate form of ionic liquids dominate biocompatibility and toxicity
Yuyuan Xing1,2,3, Yanhui Hu1,2,4,5, Xiao Zhang1,2
1Beijing Key Laboratory of Solid State Battery and Energy Storage Process, State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, P. R. China.
Insights
Ionic liquids (ILs) show promise in medicine, but safety is key. Short-chain ILs (scILs) are safer than long-chain ILs (lcILs), offering potential drug delivery applications.
Area of Science:
- Materials Science
- Nanotechnology
- Biomedical Engineering
Background:
- Ionic liquids (ILs) possess diverse applications but their biomedical potential is limited by a lack of systematic biosafety data.
- Understanding the biocompatibility and toxicity spectrum of ILs is crucial for advancing their clinical use.
Purpose of the Study:
- To establish an ionic liquid library and elucidate the relationship between IL structure and biosafety.
- To investigate the in vitro and in vivo behavior and mechanisms of IL nanoaggregates in biological systems.
- To evaluate the potential of safe ILs as drug delivery carriers.
Main Methods:
- Development of an ionic liquid library with varying cationic alkyl chain lengths.
- In vitro studies using multiple cell lines, cell spheroids, and patient-derived organoids to assess cytotoxicity and cellular uptake.
- In vivo evaluations in murine and canine models, including different administration routes (oral, intramuscular, intravenous).
- Computational analysis integrated with experimental data to understand IL nanoaggregate behavior and mechanisms.
Main Results:
- Biocompatibility of ILs decreases with increasing cationic alkyl chain length, with short-chain ILs (scILs) showing significantly lower toxicity than long-chain ILs (lcILs).
- ILs form nanoaggregates in aqueous environments; scILs are endocytosed into vesicles, while lcILs accumulate in mitochondria, inducing mitophagy and apoptosis.
- In vivo studies confirmed lcILs induce mitophagy and apoptosis, with scILs exhibiting 30-80 times greater tolerance than lcILs across various administration routes.
- scIL nanoaggregates demonstrated feasibility as carriers for insoluble drugs, achieving enhanced bioavailability compared to commercial formulations.
Conclusions:
- Ionic liquid safety is strongly correlated with cationic alkyl chain length, with scILs presenting a favorable safety profile for biomedical applications.
- The mechanism of IL-induced cellular toxicity involves mitochondrial accumulation and subsequent mitophagy/apoptosis for lcILs.
- scILs are promising candidates for drug delivery systems, offering improved bioavailability and enhanced safety over lcILs.
Abstract:
While ionic liquids (ILs) have diverse applications, their potential in biomedical applications remains largely untapped due to gaps in systematic understanding of the spectrum of IL biosafety (biocompatibility/toxicity). Here, we establish an IL library and identify an in vitro reduction in biocompatibility (increased toxicity) with increased ILs' cationic alkyl chain length. Particularly, we present compelling evidence for IL nanoaggregates in aqueous environment, thereby elucidating the mechanisms involved in cell interactions. ILs with short cationic alkyl chains (scILs) are restricted in intracellular vesicles, whereas ILs with long cationic alkyl chains (lcILs) accumulate to the mitochondria for inducing mitophagy and apoptosis. The occurrence of dysfunctional behaviour in lcILs is also observed in vivo, with a positive correlation between the lcIL signal in tissues and mitophagy/apoptotic levels. Irrespective of the administration routes (oral/intramuscular/intravenous), scILs exhibit ~30-80 times greater tolerance than lcILs. The feasibility of scIL nanoaggregates as carriers for insoluble drugs is thus validated, and an enhanced bioavailability over the commercial tablet is acquired. The findings obtained by integrating computational analysis with diverse cell/animal evaluations (from multiple cell lines, cell spheroids, patient-derived organoids to male murine and canine models) offer unique insights into the behaviour, mechanisms, and biomedical application scenarios of IL nanoaggregates.
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