Development of S75:R25 bupivacaine-loaded lipid nanoparticles functionalized with essential oils for treating melanoma

BACKGROUND: A new role as an antitumoral agent has been proposed for the local anesthetic bupivacaine (BVC), considering its toxic effects on cancer cells. However, such drug repositioning requires an improvement in drug available concentrations and sustained release profiles to surpass BVC short action and narrow therapeutic window. Nanostructured lipid carriers (NLC) may provide bupivacaine with sustained release, and they can be formulated with essential oils, whose intrinsic therapeutic properties may act synergistically with BVC. This study reports the development of two NLC formulations prepared with lavender or melaleuca oils and enantiomeric excess S(-)75:R(+)25 bupivacaine (BVCS75). The nanoparticles were characterized by dynamic light scattering, nanotracking analysis, transmission electron microscopy, differential scanning calorimetry and X-ray diffraction, and their stability was followed for 1 year. Encapsulation efficiency and in vitro BVCS75 release profile were also measured. Additionally, the effect on the viability of mice (B16-F10) and human (SK-MEL-25) melanoma cells was determined, as was in vivo anesthesia assessed by the tail flick test in mice. RESULTS: The two formulations optimized by factorial design (NLC-L-B and NLC-M-B) showed robust physical and chemical properties, 1-year stability and sustained release in vitro. Cytotoxicity tests revealed a decrease in IC50 values, relative to free BVCS75, of similar to 80% and 62% (NLC-L-B) and 80% and 25% (NLC-M-B) in mice and human melanoma cells, respectively. Encapsulation in both formulations doubled the anesthesia time of BVCS75. CONCLUSION: Combining the effects of bupivacaine and NLC excipients, the two optimized NLC formulations containing BVCS75 may be interesting nanosystems for the treatment of melanomas after further in vivo tests. (C) 2021 Society of Chemical Industry (SCI).