Extending the Bioavailability of Hydrophilic Antioxidants for Metal Ion Detoxification via Crystallization with Polysaccharide Dopamine

Abstract

Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential to have toxic effects on human and environmental health has gained interest with an improved understanding of their mechanisms to promote oxidative stress. Redox control is a major focus of many drug delivery systems and often incorporates an antioxidant as the active pharmaceutical ingredient (API) to neutralize overproduced reactive oxygen species (ROS). Nevertheless, there are still limitations with bioavailability and extended redox control with regard to antioxidant drug delivery. Herein, this study develops a colloidal antioxidant crystal system that dissolves sustainably through polymer stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa). We explore the role of dopamine incorporation into crystal-stabilizing polymers and quantify the balance between drug–polymer interactions and competing polymer–polymer interactions. We propose that this type of analysis is useful in the engineering of and provides insight into the release behavior of polymer–crystal complexes. In developing our crystal complex, N-acetylcysteine (NAC) was used as the model antioxidant to protect against silver ion toxicity. We found that our optimized HA-dopa-stabilized NAC crystals prolong the release time of NAC 5-fold compared to a polymer-free NAC crystal. Therefore, following sublethal exposure to AgNO3, the extended lifetime of NAC was able to maintain normal intracellular ROS levels, modulate metabolic function, mitigate fluctuations in ATP levels and ATP synthase activity, and preserve contraction frequency in engineered cardiac muscle tissue. Furthermore, the protective effects of the HA-dopa-stabilized NAC crystals were extended to a Daphnia magna model where silver-ion-induced change to both cell-level biochemistry and organ function was alleviated. As such, we propose that the packaging of hydrophilic antioxidants as colloidal crystals drastically extends the lifetime of the API, better maintains ROS homeostasis post metal ion exposure, and therefore preserves both intracellular biochemistry and tissue functionality.

In‐Drop Thermal Cycling of Microcrystal Assembly for Senescence Control with Minimal Variation in Efficacy

“…As it was previously reported, the degree of substitution of dopamine (DS dopa ) was controlled by fixing the molar ratio between dopamine to sodium glucuronate of HA at 8:9. [ 20 ] This ratio leads to ≈20% of the carboxylic acids on HA being conjugated with dopamine.…”

“…[15][16][17][18] However, most hydrophilic antioxidants are metabolized within 6 h in media, leaving <5% bioactive. [19,20] The increased and more frequent dosing for compensation leads to antioxidant stress, DNA damage in proliferating MSCs, and large efficacy variation. [18] In addition, even micromolar fluctuations in the ROS levels in MSCs can lead to substantial changes in intracellular transcription and translation of therapeutic paracrine factors, [21][22][23] driving the need for prolonged and sustained antioxidant release.…”

“…Recently, crystallization of antioxidants with stabilizing polymers have illustrated improved release kinetics and efficacy. [19,20] MSC-secretome manufacturing can benefit from these emerging systems by achieving ROS homeostasis, through the careful design and fabrication of an antioxidant crystal platform. In pharmaceutical manufacturing, crystallization is an important step in active pharmaceutical ingredient (API) assembly, and control of the crystal size distribution (CSD) has major implications on API bio-efficacy.…”

“…Previously, we demonstrated that dopamine conjugation to hyaluronate could interface with NAC crystals and is necessary to provide extended stability and release through aggregation. [ 20 ] We anticipate that a reduction in the CSD will further extend NAC release and minimize variation through more uniform aggregation. This microcrystal assembly for senescence control (MASC) can then actively scavenge ROS, alleviate oxidative stress, and reduce the heterogeneity in MSCs in order to improve the therapeutic efficacy of the MSCs secretome (Figure 1d).…”

Recent progress of antibacterial hydrogel materials for biomedical applications

“…The mechanisms of toxicity include the affinity of the released metal ions to cellular components and biomolecules, and oxidative stress caused by the ROS produced on the crystal surface of some NPs. 52 The mechanisms of resistance include electrostatic repulsion, ion efflux pumps, expression of the extracellular matrix, mutation, and biofilm adaptation. 53 The incorporation of metal nanomaterials into hydrogels may control their ion release rate and hamper the generation of drug resistance to reduce their toxicity and resistance.…”