Effect of nanodiamond surface chemistry on adsorption and release of tiopronin
Graphical abstract
Introduction
Tiopronin is a low-molecular-weight thiol drug used for the treatment of rheumatoid arthritis and cystinuria. It has also demonstrated potential benefits in a variety of other conditions, including heavy metal toxicity [1], radiation poisoning [2], and cataract [3]. A primary mechanism of its action in these conditions is the direct scavenging of free radicals and maintenance of healthy levels of glutathione (GSH), a vital antioxidant and the body's most abundant non-protein thiol [4,5]. However, the effectiveness of tiopronin is limited by its bioavailability. Tiopronin is weakly acidic and becomes deprotonated at physiological pH. The negatively charged conjugate base (Fig. 1) cannot easily penetrate the low polarity lipid bilayer of cell membranes. Furthermore, when administered topically, insufficient residence time on physiological barriers such as the skin or cornea can severely curtail its uptake and deeper penetration into tissues [6]. These effects necessitate the administration of higher dosages, increasing the risk and severity of adverse side effects. It is therefore desirable to provide a means by which small hydrophilic molecules such as tiopronin can be transported and released in a controlled manner at their desired site of action. Towards this end, drug delivery vehicles offer a promising alternative to the large systemic doses of neat drug and excipient used currently [7]. For example, it has been shown that poloxamer hydrogels significantly enhanced uptake and effectiveness of tiopronin in a rat model of age-related nuclear cataracts [8].
In addition to providing controlled transport and release of a well-defined and therapeutically consequential payload, drug delivery vehicles must be highly biocompatible and stable under formulation conditions (which may include autoclaving or irradiation). Sustained release is also desirable, given that the conditions mentioned above may be long-term or chronic illnesses. In these respects, hydrogels present many challenges with regard to chemical stability, longevity, and especially sustained and controlled release [9]. Nanodiamonds (NDs), however, are not subject to these limitations. Detonation nanodiamonds, which are inexpensive and commercially available, are nontoxic and are considered the most biocompatible of all carbon nanoparticles [10]. Each ND particle possesses a core of sp3 hybridized carbon that is chemically inert and similar to bulk diamond, while the surface comprises fully exposed, covalently attached functional groups that can be tailored for optimal interaction with the drug payload and environment [10,11]. Modification of surface chemistry affords a high degree of control, specificity, and flexibility with respect to drug-ND interaction [[12], [13], [14]]. Here we investigate the potential of ND as a promising candidate platform for delivery and sustained release of tiopronin.
A critical step in assessing the suitability of a drug delivery platform is to determine its capacity to carry and release the compound of interest. Adsorption/desorption is the simplest and therefore preferred mechanism of loading and release. It requires no chemical modification of the drug, which reduces risks of interfering with its biological activity [13]. The rich surface chemistry of ND allows for a high degree of control over drug-ND interactions, which is exerted through the creation of functional groups such as -COOH, -OH, or -NH2 on the ND surface. Controlling ND surface chemistry can significantly affect loading capacity, strength of binding, and release of the desired drug [14]. Because tiopronin is negatively charged at physiological pH, the electrostatic interaction between adsorbent and adsorbate can be tailored to optimize the drug delivery platform.
Although understanding adsorption and release is essential for development of ND-drug complexes capable of delivering well-defined dosages, these phenomena have been largely unexplored for ND as a carrier of tiopronin or other similar thiol drugs. By understanding the effects of surface functionalization on ζ-potential, adsorption monolayer capacity, and cumulative drug release, we can determine the optimal surface chemistry for ND-mediated delivery of tiopronin for a variety of conditions. Consistent and reliable delivery of tiopronin and related compounds can pave the way for more targeted treatment regimens that produce the same therapeutic effects with significantly lower incidence of side effects.
Section snippets
Materials and reagents
UD90 ND powder was donated by NanoBlox, Inc. Tiopronin, tris(2-carboxyethyl)phosphine (TCEP), N-acetylcysteine (NAC), and K2HPO4 were purchased from MilliporeSigma (St. Louis, MO, USA). ThioGlo-3 was purchased from Covalent Associates Inc. (Bellingham, WA, USA). All other reagents were purchased from Fisher Scientific (Pittsburgh, PA, USA). Type 1 water was prepared in-house using a Millipore Simplicity 185 purification system (MilliporeSigma). Citrate-phosphate buffers were prepared to the
Characterization of functionalized NDs
Representative TEM micrographs of ND-COOH are shown in Fig. 2. Fig. 2A shows a low-resolution image of an ND-COOH sample, which reveals typical morphology of detonation nanodiamonds dried on TEM grid. The sample appears uniform, and although separate single nanodiamond particles were found in the sample, larger clusters were primarily observed. The high resolution TEM image of ND-COOH in Fig. 2B shows 0.206 nm (111) d-spacing of crystalline diamond. The selected-area electron diffraction
Conclusion
Adsorption and release of tiopronin is sensitive to the changes of ND surface chemistry. However, due to the complexity of interactions between surface functional groups, drug molecules, and the environment, this effect cannot be explained by simply examining net surface charges. Our results show that ND-OH provides the best balance between drug capacity and release, making it the best candidate for applications which benefit from prolonged release of large amounts of tiopronin. Furthermore,
Acknowledgments
None.
Funding
This work was supported by the NEI of the National Institutes of Health under award number R15EY029813 and the Richard K. Vitek/FCR Endowment at Missouri University of Science and Technology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author contributions
VM and NE conceived and supervised the project. JB and AP designed and executed adsorption and release experiments and performed data analysis. IA functionalized ND surfaces and performed all ND characterization experiments. AC assisted with adsorption and release experiments. VM provided guidance and supervision during all stages of ND synthesis, characterization, adsorption and release. NE was instrumental in selection of antioxidant drug and oversaw analysis of adsorption and release. All
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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