Resveratrol-Loaded Lipid Nanocarriers Are Internalized By Endocytosis in Yeast

Abstract

Different positive pharmacological effects have been attributed to the natural product resveratrol (RSV), including antioxidant, antiaging, and cancer chemopreventive properties. However, its low bioavailability and rapid metabolic degradation has led to the suspicion that many of the biological activities of this compound observed in vitro may not be attainable in humans. To improve its bioavailability and pharmacokinetic profile, attempts have been made to encapsulate RSV into lipid-based nanocarrier systems. Here, the dioctadecyldimethylammonium bromide (DODAB):monoolein (MO) liposomal system (1:2) loaded with RSV revealed appropriate characteristics for drug release purposes: reduced size for cellular uptake (157 ± 23 nm), stability up to 80 days, positive surface charge (ζ ≈ +40 mV), and a controlled biphasic release of RSV from the lipid nanocarriers over a period of almost 50 h at pH 5.0 and 7.4. Moreover, the encapsulation efficiency of the nanocarrier ranged from 70% to 92% and its RSV loading capacity from 9% to 14%, when [RSV] was between 100 and 200 μM. The partition coefficient (K p) of RSV between lipid and aqueous phase was log K p = 3.37 ± 0.10, suggesting moderate to high lipophilicity of this natural compound and reinforcing the lipid nanocarriers’ suitability for RSV incorporation. The thermodynamic parameters of RSV partitioning in the lipid nanocarriers at 37 °C (ΔH = 43.76 ± 5.68 kJ mol–1; ΔS = 0.20 ± 0.005 kJ mol–1; and ΔG = −18.46 ± 3.48 kJ mol–1) reflected the spontaneity of the process and the establishment of hydrophobic interactions. The cellular uptake mechanism of the RSV-loaded nanocarriers labeled with the lipophilic fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was studied in the eukaryotic model system Saccharomyces cerevisiae. Thirty minutes after incubation, yeast cells readily internalized nanocarriers and the spots of blue fluorescence of DPH clustered around the central vacuole in lipid droplets colocalized with the green fluorescence of the lipophilic endocytosis probe FM1-43. Subsequent studies with the endocytosis defective yeast deletion mutant (end3Δ) and with the endocytosis inhibitor methyl-β-cyclodextrin supported the involvement of an endocytic pathway. This novel nanotechnology approach opens good perspectives for medical applications.

Development and Characterization of Monoolein-Based Liposomes of Carvacrol, Cinnamaldehyde, Citral, or Thymol with Anti- Candida Activities

“…The DODAB:MO system has been described as an efficient delivery system because of its high interaction with mammalian cells and their internalized formulations by endocytosis into fungal cells (19,44). These features could be responsible for the improved bioavailability of these phytocompounds within the macrophage and the subsequent interaction with Candida cells, enabling their antifungal activity.…”

Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR

“…Numerous phytochemicals were found to defeat cancer cells without disturbing normal cells, exert chemoprophylaxis activities, support cancer cells' sensitivity to DXR (An et al, 2017), and improve chemotherapy-associated side effects (Choudhari et al, 2020). Resv has attracted growing interest due to its diverse, health benefits, including antioxidant activity and nephroprotection against several toxicants (Novelle et al, 2015;Rajagopal et al, 2018), specifically if used in its nanoformulation (Barbosa et al, 2019;Sharifi-Rad et al, 2021). More recently, Sharifi-Rad and others emphasized the distinctive role of N-Resv in cancer treatment as it contributes to autophagy induction in cancer cells and inhibits angiogenesis and metastasis, thus adding to other chemotherapy actions and minimizing their side effects (Sharifi-Rad et al, 2021).…”

Incorporation of lipid nanosystems containing omega-3 fatty acids and resveratrol in textile substrates for wound healing and anti-inflammatory applications

“…Liposomes containing DSPC (0.4 wt%), DOPE (0.2 wt%) and omega-3 (0.1 wt%) were prepared by the lipid film hydration method using ultrapure water (99.3 wt%) followed by extrusion [8,9]. RSV (200 µM final concentration, regarded as suitable for obtaining anti-inflammatory effect [10,11]) was incorporated in the preformed liposomes by an incubation method as previously reported [8,9]. For sake of clarity the lipid nanosystems will be simply referred as NLCs (designating NLCs containing omega-3 fatty acid) and Liposomes (designating liposomes containing omega-3 fatty acid and RSV).…”

“…The release medium was chosen to provide the necessary chemical affinity for bioactives, so that release is simulated. RSV has moderate lipophilic character [9] and its solubilization is favored in amphiphilic media. Hence, RSV will only be released from liposomes if it has chemical affinity to the surrounding medium.…”

“…One of RSV's limitations is its rapid metabolization by the human body [7] and also its propensity to suffer oxidation and produce the inactive cis-isomer. To overcome this drawback, the encapsulation of RSV in liposomes, that might provide protection against early degradation and metabolism, is a strategy that has been investigated [8,9]. Based on the galenic (i.e.…”