Resveratrol (RES) is a naturally existing polyphenol which exhibits anti-oxidant, anti-inflammatory, and anti-cancer properties. In recent years, RES has attracted attention for its synergistic effect with other anti-cancer drugs for the treatment of drug resistant cancers. However, RES faces the issues of poor pharmacokinetics, stability and low solubility which limits its clinical application. In present study, RES has been loaded onto uniformly sized (~60 nm) mesoporous silica nanoparticles (MSNs) to improve its in vitro anti-proliferative activity and sensitization of Docatexal in hypoxia induced drug resistance in prostate cancer. RES was efficiently encapsulated within phosphonate (negatively charged) and amine (positively charged) modified MSNs. The effect of surface functionalization was studied on the loading, in vitro release, anti-proliferative and cytotoxic potential of RES using prostate cancer cell line. At pH 7.4 both free and NH2-MSNs loaded RES showed burst release which was plateaued with almost 90% of drug released in first 12 h. On the other hand, PO3-MSNs showed significantly slower release kinetics with only 50% drug release in first 12 h at pH 7.4. At pH 5.5, however, both the PO3-MSNs and NH2-MSNs showed significant control over release (around 40% less release compared with free RES in 24 h). Phosphonate modified MSNs significantly enhanced the anti-proliferative potential of RES with an IC50 of 7.15 μM as compared to 14.86 μM of free RES whereas amine modified MSNs didn't affect proliferation with an IC50 value higher than free RES (20.45 μM). Furthermore, RES loaded onto PO3-MSNs showed robust and dose dependent sensitization of Docatexal in hypoxic cell environment which was comparable to pure RES solution. This study provides an example of applicability of MSNs loaded with polyphenols such as RES as next generation anticancer formulations for treating drug resistant cancers such as prostate cancer.
Coenzyme-Q10 (CoQ10) is a hydrophobic benzoquinone with antioxidant and anti-inflammatory properties. It is known to reduce oxidative stress in various health conditions. However, due to the low solubility, permeability, stability, and poor oral bioavailability, the oral dose of CoQ10 required for the desired therapeutic effect is very high. In the present study, CoQ10 is encapsulated into two milk derived proteins β-lactoglobulin and lactoferrin (BLG and LF) to produce self-assembled nanostructures of around 100−300 nm with high encapsulation efficiency (5−10% w/w). Both CoQ10-BLG and CoQ10-LF nanoparticles (NPs) significantly improved the aqueous solubility of CoQ10 60-fold and 300-fold, compared to CoQ10 alone, which hardly dissolves in water. Insight into the difference in solubility enhancement between BLG and LF was obtained using in silico modeling, which predicted that LF possesses multiple prospective CoQ10 binding sites, potentially enabling greater loading of CoQ10 on LF compared to BLG, which was predicted to be less capable of binding CoQ10. At pH 7.4, CoQ10-LF NPs showed a burst release between 30 min and 2 h then plateaued at 12 h with 30% of the total drug released over 48 h. However, pure CoQ10-BLG and pure CoQ10 had a significantly lower release rate with less than 15% and 8% cumulative release in 48 h, respectively. Most importantly, both BLG and LF NPs significantly improved CoQ10 permeability compared to the pre-dissolved drug across the Caco-2 monolayer with up to 2.5-fold apparent permeability enhancement for CoQ10-LFfurther confirming the utility of this nanoencapsulation approach. Finally, in murine macrophage cells (J774A.1), CoQ10-LF NPs displayed significantly higher anti-ROS properties compared to CoQ10 (predissolved in DMSO) without affecting the cell viability. This study paves the way in improving oral bioavailability of poorly soluble drugs and nutraceuticals using milk-based self-assembled nanoparticles.
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