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.