Nanoencapsulation of natural triterpenoid celastrol for prostate cancer treatment

Abstract

Celastrol (CL), a triterpenoid extracted from the Chinese herb Tripterygium wilfordii , has recently attracted interest for its potential antitumor effects. However, unfavorable physicochemical and pharmacokinetics properties such as low solubility, poor bioavailability, and systemic toxicity, are limiting its therapeutic application. In this context, the development of innovative nanocarriers can be useful to overcome these issues, and nanoencapsulation would represent a powerful strategy. In this study, we developed novel CL-loaded poly( ε -caprolactone) nanoparticles (NPs), and investigated their antiproliferative efficacy on prostate cancer cells. CL-NPs were prepared using a nanoprecipitation method and fully characterized by physicochemical techniques. The antiproliferative effects on LNCaP, DU-145, and PC3 cell lines of CL-NPs, compared to those of free CL at different concentrations (0.5, 1.0, and 2.0 µM), were investigated. Moreover, fluorescence microscopy was utilized to examine the cellular uptake of the nanosystems. Furthermore, to elucidate impact of nanoencapsulation on the mechanism of action, Western analyses were conducted to explore apoptosis, migration, proliferation, and angiogenesis alteration of prostate cancer cells. The results confirmed that CL-NPs inhibit proliferation dose dependently in all prostate cancer cells, with inhibitory concentration 50 less than 2 µM. In particular, the NPs significantly increased cytotoxicity at lower/medium dose (0.5 and 1.0 µM) on DU145 and PC3 cell lines with respect to free CL, with modulation of apoptotic and cell cycle machinery proteins. To date, this represents the first report on the development of biocompatible polymeric NPs encapsulating CL. Our findings offer new perspectives for the exploitation of developed CL-NPs as suitable prototypes for prostate cancer treatment.

A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F

“…This formula prolongs the blood circulation time of celastrol, increasing bioavailability and reducing the frequency of dosing ( Wolfram et al, 2014 ). Celastrol nanoparticles significantly inhibits suture-induced corneal neovascularization by reducing macrophage infiltration and decreasing the expression of vascular endothelial growth factor and matrix metalloproteinase 9 in rat cornea ( Li et al, 2012c ; Sanna et al, 2015 ). Mesoporous silica nanoparticle and axitinib in PEGylate lipid bilayers increases the inhibitory activity of celastrol on angiogenesis and mitochondrial function, and enhances its anticancer activity in SCC-7, BT-474, and SH-SY5Y cells ( Choi et al, 2016 ).…”

Optimization on biodistribution and antitumor activity of tripterine using polymeric nanoparticles through RES saturation

“…It is indicative that the tumor cells have become apoptotic, and the tumor shows signs of necrosis. To circumvent the unfavorable properties of TPR, Sanna et al (2015) formulated into polymeric NPs by nanoencapsulation used for cancer treatment, finding TPR-NPs more suitable for prostatic cancer treatment. TPR-loaded polymeric micelles have also been reported able to inhibit the growth of retinoblastoma in a xenograft model by inducing apoptosis of SO-Rb 50 cells (Li et al, 2012).…”

Characterization and in vitro antitumor activity of polymeric nanoparticles loaded with Uncaria tomentosa extract

“…LNCaP cells also displayed sensitivity to unloaded Np PCL, which caused some cell inhibition and could have contributed to the higher activity of Np UT-PCL. This was unexpected based on the results reported by Sanna et al (2015) where unloaded PCL nanoparticles did not show any effect on LNCaP cells. This difference can be explained by their use of a lower PCL concentration (47.5 mg/20 mL), which is nearly 8-fold lower than the Np PCL suspension in the present work (150 mg/8.5 mL).…”

“…Previous studies with nanoparticles loaded with natural compounds, such as epigallocatechin-3-gallate (EGCG), resveratrol and curcumim, demonstrated a promising potential through their activity against PC cell lines (Sanna et al 2013). A more recent study with PCL-based nanoparticles loaded with celastrol, a triterpenoid extracted from the Tripterygium wilfordii, also showed anti-proliferative activity on LNCaP, DU145 and PC-3 cell lines (Sanna et al 2015).…”