PEG‐PLA nanoparticles decorated with small‐molecule PSMA ligand for targeted delivery of galbanic acid and docetaxel to prostate cancer cells

Abstract

Prostate cancer (PCa) is one of the most prevalent non-drug delivery system cutaneous malignancies. Undoubtedly, introducing novel treatment options to achieve higher therapeutic index will be worthwhile. In this study, we report for the first time, a novel targeted self-assembled based on PEG-PLA nanoparticles (PEG-PLA NPs) containing galbanic acid (GBA) and docetaxel, which was targeted using ((S)-2-(3-((S)-5-amino-1-carboxypentyl) ureido) pentanedioic acid (ACUPA), a small molecule inhibitor targeting prostate-specific membrane antigen (PSMA), in prostate cancer cell line. The prepared NPs were characterized by different analytical methods. The MTT assay was used to compare the anti-proliferation of drugs-loaded PEG-PLA NPs and ACUPA-PEG-PLA against LNCaP (PSMA + ) and PC3 (PSMA − ) cells. PEG-PLA NPs with an average size of 130-140 nm had an enhanced release of GBA and docetaxel at pH 5.5 compared with pH 7.5.Spectrofluorometric analysis suggested that ACUPA-modified PEG-PLA could effectively enhance the drug uptake in PSMA + prostate cancer cells. Cytotoxicity studies showed that the targeted NPs loaded with different concentrations of GBA and fixed concentration of docetaxel (4 nM) have shown higher toxicity (IC 50 30 ± 3 µM) than both free GBA (80 ± 4.5 µM) and nontargeted NPs (IC 50 40 ± 4.6 µM) in LNCaP cells. Collectively, these findings suggest that ACUPAconjugated PEG-PLA nanosystem containing GBA and docetaxel is a viable delivery carrier for various cancer-targeting PSMA that suffer from short circulation half-life and limited therapeutic efficacy.

Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

“…PLA has a longer degradation time and better stability than PLGA and is often used to produce ultra-long-lived products. PLA is widely used in sutures [ 21 ], bone implants [ 22 ], screws [ 22 ], and continuous drug delivery [ 23 , 24 , 25 ]. LUPRON DEPOT ® (4/6 months) [ 26 ], which uses PLA as a slow-release material, has been approved by the U.S. Food and Drug Administration for various diseases, including prostate cancer, endometriosis, myoma, and precocious puberty.…”

Enhanced anticancer efficacy of docetaxel through galbanic acid encapsulated into PLA-PEG nanoparticles in treatment of colon cancer, in vitro and in vivo study

“…The combination index (CI) concept is defined to evaluate the synergistic, antagonistic, or additive effects of drug combinations. 29…”

“…Galbanic acid (GBA), 2-cyclohexene-1-butanoic acid, is a lipophilic sesquiterpene coumarin with multiple useful biological properties including cytotoxic, 22 anti-angiogenic, anti-bacterial, 23 and apoptotic effects in cancer cells. 24,25 The mechanisms of the anti-cancer effects of GBA are through permeability glycoprotein (P-gp) inhibitory effect 26 and inhibition of farnesyl protein transferase (FTase) enzyme. 27 Despite its efficacy, the poor water-solubility of galbanic acid limits its clinical use.…”

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen

“…PVA was added as it forms a thin outer coating on the NPs, enhancing their stability. 28,32 This mixture was sonicated for 1 min and kept overnight with string to remove the organic solvent. Excess PVA and noncapsulated carborane were then removed by centrifugation.…”