Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity

Abstract

Background Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods LEU–fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films

“…While applying LON-or d-LON-loaded MBF in buccal mucosa, the nanoparticles diffused out and then experienced extensive hydrolysis by esterase in saliva or blood, liberating active LEU, as reported previously by our group [47]. It is well known that human saliva presents esterase activity, in addition to blood having abundant amounts of esterase [48].…”

“…It is worth mentioning that interactions between NPs and biological membranes are also among the most important phenomena for developing NP-based therapeutics and overcoming nanotoxicology in drug delivery, cancer targeting, and immune modulation [46]. While applying LON-or d-LON-loaded MBF in buccal mucosa, the nanoparticles diffused out and then experienced extensive hydrolysis by esterase in saliva or blood, liberating active LEU, as reported previously by our group [47]. It is well known that human saliva presents esterase activity, in addition to blood having abundant amounts of esterase [48].…”

Thymol-Modified Oleic and Linoleic Acids Encapsulated in Polymeric Nanoparticles: Enhanced Bioactivity, Stability, and Biomedical Potential

“…Tumor cells ingest fatty acids to use them as biochemical precursors and energy sources. Studies of docosahexaenoic acid and paclitaxel [ 59 ], oleic acid and chlorin e6 [ 60 ], and leuprolide acetate and lauric acid [ 61 ] revealed beneficial effects, like enhanced stability, cytotoxic efficacy, and pharmacokinetics.…”

Chemical modification of sesame protein by acylation reactions: characterisation and evaluation of functional properties

“…The emulsifying activity (EA) and emulsion stability (ES) were determined using the method described by Morales-Santiago et al (2023), with some adaptations.…”