Etoposide encased folic acid adorned mesoporous silica nanoparticles as potent nanovehicles for enhanced prostate cancer therapy: synthesis, characterization, cellular uptake and biodistribution

Abstract

The present research was motivated by the dire need to design a targeted and safe Nano-vehicle for delivery of Etoposide (ETE), which would be tolerant of normal cells and exclusively toxic to prostate cancer cells. The folic acid functionalized mesoporous silica nanoparticles (MSNs) constructed by using a facile method acting as a unique selective platform for ETE delivery for effective prostate cancer treatment. FA@MSNs possessed good payload and encouraging in vitro release was obtained for ETE caged inside FA-MSNs compared with ETE-MSNs alone. Further, FA@MSNs exhibited an improved blood compatibility compared with pristine silica. The cellular analysis on PC-3 and LNCaP cell lines unveiled an excellent performance of cytotoxicity. Apoptosis assay confirmed a programmed cell death ruling out necrosis. Most importantly enhanced cellular uptake was obtained for FITC#FA@MSNs. In addition, pharmacokinetic and biodistribution studies in healthy mice indicated a favourable longer circulation time and reduced plasma elimination rate for ETE/FA@MSNs than free ETE. Further, histological and cell cytotoxicity results proved that nanocarriers themselves were safe without any noticeable toxicity. The results showed that FA@MSNs were ideal candidates for safe and effective delivery of ETE and hold a substantial potential as drug delivery vehicles for enhanced prostate cancer therapy.

Folic acid conjugated polymeric drug delivery vehicle for targeted cancer detection in hepatocellular carcinoma

“…The synthesis of a polymeric nanosystem offers several challenges, including the inefficiency associated with chemical conjugation of the targeting folate ligand with the polymer core, as well as the potential cytotoxicity of the vehicle itself. Folate‐targeted intracellular delivery of therapeutic load to pathogenic tissues has been the subject of multiple studies (Bittleman, Dong, Roman, & Lee, ; Saroj & Rajput, ; Stella et al, ; Xia et al, ; Zhang et al, ). All of these studies show conjugation of folic acid into a PEG polymer (Stella et al, ; Zhang et al, ), Silica/Selenium nanoparticle (Saroj & Rajput, ; Xia et al, ), or cellulose nanocrystals (Bittleman et al, ) for selective delivery.…”

“…However, chemical characterization of folic acid in the nano molecule, and/or biological evaluation of the synthesized nanocarriers in non‐folate expressing (negative) cell types are often limited. While these carriers show great promise in cell culture‐based assays, their efficacy and targetability need to be evaluated in an in vivo HCC model (Bittleman et al, ; Saroj & Rajput, ; Stella et al, ; Zhang et al, ). A folate targeting selenium nanoparticle delivering therapeutic siRNA has shown promise in restricting tumors in a xenograft mouse model (Xia et al, ).…”

Mesoporous Silica Nanoparticles: Properties and Strategies for Enhancing Clinical Effect

“…Proteins mAbs Specific binding with surface antigens on target cells [190][191][192][193][194] Fabs Specific binding with surface antigens on target cells [195,196] Transferrin Binds to overexpressed transferrin receptor 1 [167,[197][198][199] Affibodies Engineered proteins designed to selectively bind to specific receptor on target cell [61,200] Heparin Anti-angiogenesis agent and ligand-receptor targeting with overexpressed surface heparanase [201] Peptides RGD Overexpressed integrin α V β 3 are selectively bound [128,166,202] pHLIPs Transmembrane insertion resulting from acidic tumor microenvironment [38,62] CPPs Specific or nonspecific interaction with the cell membrane or proteins on its surface [189,[203][204][205][206][207][208][209] Nucleic Acids Aptamers Overexpressed surface receptor proteins (e.g., GLUT1) are targeted by designed nucleic acid chains [60,[210][211][212][213][214] Small Molecules Folate/Folic Acid Ligand-receptor targeting between folate and folate receptor α [202,[215][216][217][218][219][220] Hyaluronic Acid Overexpressed CD44 on tumor cell surfaces binds with HA…”

“…It should be noted that short HA chain lengths should be used when using HA for targeting, as they increase the engulfment efficiency [264]. Tumor cell overexpression of folate receptor α encourage the use of folate as another small molecule active targeting option for MSNs [202,[215][216][217][218][219][220].…”

Silica‐Based Nanoparticles as Drug Delivery Vehicles for Prostate Cancer Treatment

“…In this work, the carboxylate group on FA was used to control the delivery of the ETS using the same principle of protonation of carboxylic acid groups at a pH lower than the pKa. At lower pH, the negative charge of FA reduced, thus reducing the electrostatic attraction between ETS and FA resulting in the higher release of ETS at lower pH values [174] . Instead of PAA, gelatin has also been coated on MSNs for controlling the release of topotecan (TOP) at targeted sites [160] .…”