Curcumin is a polyphenol extracted from the roots of the Curcuma longa plant, native to India [1–4]. It is a yellow-orange solid that has diverse applications, with a broad spectrum of action depending on both its concentration and the time of administration [5–12]. It has been reported that low doses of curcumin are related to anti-inflammatory [13, 14], antioxidant [9, 15–17], and neuroprotective effects [10, 11, 18, 19]; whereas, at high concentrations, it has lethal effects, which is why it is used as a potent anti-tumor agent [5–8, 20, 21]. This diversity of behaviors allows us to understand curcumin as a hormetic compound. Thus, at low doses it has cellular effects that promote cell development, while at high doses it promotes cell death, being used for its anti-tumor properties [22–24].
Due to its hydrophobic character, curcumin needs to be solubilized in organic solvents, the most conventionally used being ethanol and dimethyl sulfoxide (DMSO) [20, 21, 25–28]. Unfortunately, these vehicles present effects by themselves (especially visible at prolonged exposure times), more or less detectable depending on the biological models used [29–32]. Recently, we have reported effects on the viability and proliferation of primary Schwann cell cultures of both ethanol and DMSO, irreversible in a pathological context, after 6 days of treatment [30].
Given the great versatility of curcumin, the limitations of its conventional vehicles, and its low bioavailability, several strategies have emerged to improve its delivery. The use of cyclodextrin/cellulose nanocrystals coated with curcumin [33, 34], curcumin in polyethylene glycol [35, 36], curcumin nanosuspension in tween-80 [37], curcumin in chitosan/aloe film [38], curcumin conjugated to polyacetal [39], among others [40–42].
Among other alternative approaches, the use of nanoparticles as delivery systems is a successful strategy for many compounds [43–45]. Recently, polydopamine (PDA) nanoparticles have been used not only as coatings and surface functionalization [46, 47] but also as vehicles [48–52].
Some studies have used PDA to vehicle curcumin through different approaches. Pan et al. 2020 created carrier-free curcumin nanoparticles of different concentrations between 4 and 50 µg/ml (approximately between 11 µM and 136 µM), which they subsequently coated with PDA, demonstrating that these curcumin-loaded nanoparticles are stable structures, with curcumin release dependent on pH variations [49]. In 2021, Su et al. synthesized PDA nanoparticles, and then exposed them to curcumin (around 1.13 mM curcumin), demonstrating their antioxidant and antibacterial properties in yeast cultures [50]. Zhao et al., 2022 use PDA nanoparticles coating curcumin loaded with poly L-lactic acid for chemo-photo thermal therapy of osteosarcoma. The work demonstrates that by thermo-activation of nanoparticles loaded with approximately 1 mg/ml curcumin (⋍ 2.72 mM), their release in human osteosarcoma cultures (MG-63) is possible, depending on the pH of the intracellular medium [51]. Recently, Lei et al., 2023 coated a rabies virus glycoprotein (RVG29 peptide) to PDA nanoparticles with 0.3 mmol curcumin previously dissolved in PEG and DMSO (approximately 2.24 mM), to target the nanoparticles to the murine brain. The work explores the antiaggregatory effects of curcumin on α-synuclein in different experimental models (Balb/c mice, C. elegans, and PC12 cell culture). The results further demonstrate a decrease in oxidative stress levels and apoptosis upon delivery of curcumin through these nanoparticles [52]. The literature thus points to the sensitivity and dependence of curcumin release from PDA nanoparticles in response to the pH of the medium. Likewise, the different effects of curcumin on the dose used, evidence its hormetic action, especially when considering the use of these nanoparticles at the biological level.
In the present work, we propose a new synthesis and loading protocol, using equal concentrations of PDA and curcumin to produce PDA nanoparticles. This protocol incorporates a key dialysis step to eliminate possible pH variations outside the physiological range. We describe the structure of PDA nanoparticles, loaded or not with curcumin, by transmission and scanning electron microscopy. We analyze their loading and unloading dynamics with curcumin, characterizing, the released compounds by UHPLC-MS. Finally, we tested the safety of PDA as a vehicle (without curcumin) and the functional dynamics of nanoparticles loaded with low doses of curcumin in endoneurial fibroblast cultures, evaluating their impact on cell viability and proliferation for prolonged periods of time.