DEAE-Dextran coated paclitaxel nanoparticles act as multifunctional nano system for intranuclear delivery to triple negative breast cancer through VEGF and NOTCH1 inhibition.

Triple negative breast cancer revolution has identified a plethora of therapeutic targets making it apparent that a single target for its treatment could be rare hence creating an urge to develop robust technologies for combination drug therapy. Paclitaxel, hailed as the most significant advancement in chemotherapy faces several underpinnings due to its low solubility and permeability. Advancing research has demonstrated the role of interferons in cancer. DEAE-Dextran, an emerging molecule with evidence of interferon induction was utilized in the present study to develop a nanoformulation in conjugation with paclitaxel to target multiple therapeutic pathways, with diminution of paclitaxel adverse effects and develop a specific targeted nano system. Evidently, it was demonstrated that DEAE-Dextran coated nanoformulation portrays significant synergistic cytotoxicity in the various cell lines. Moreover, overcoming the activation of ROS by paclitaxel, the combination drug therapy more effectively inhibited ROS through ß-interferon induction. The nanoformulation was further conjugated to FITC for internalization studies which subsequently indicated maximum cellular uptake at 60min post treatment demonstrated by green fluorescence from FITC lighting up the nuclear membrane. Precisely, the mechanistic approach of nuclear-targeted nanoformulation was evaluated by in vivo xenograft studies which showed a synergistic release of ß-interferon at the target organ. Moreover, the combination nanoformulation inculcated multiple mechanistic approaches through VEGF and NOTCH1 inhibition along with dual ß and γ-interferon overexpression. Overall, the combination therapy may be a promising multifunctional nanomaterial for intranuclear drug delivery in TNBC.

A novel nanoparticles impregnated ocular insert for enhanced bioavailability to posterior segment of eye: In vitro, in vivo and stability studies.

The present investigation was carried out to demonstrate with the help of in vitro and in vivo studies that nanoparticles impregnated ocular inserts effectively delivers significant concentration of drug to the posterior segment of eye after topical administration for treatment of glaucoma. Drug loaded Nanoparticles and their ocular insert have been reported to reduce side effects of orally administered Acetazolamide. Eudragit NPs were prepared by the solvent diffusion nanoprecipitation technique. The prepared NPs were evaluated for various parameters such as particle size, zeta potential, % entrapment efficiency, % drug loading, DSC, FTIR, TEM and stability studies. Ocular inserts of NPs were prepared by solvent casting method. The prepared ocular inserts were evaluated for thickness, content uniformity, folding endurance, disintegration time, morphology and stability study. The NPs and ocular inserts were evaluated for in-vitro drug diffusion study, ex-vivo trans-corneal permeability study, in-vivo ocular tolerability and intra ocular pressure (IOP) reduction study. The optimized batch was stable for a period of 3months in lyophilized form. The optimized formulations had size range of 367nm±8nm, zeta potential around +7mV±1.3mV and 51.61%±3.84% entrapment efficiency with 19%±1.40% drug loading. The ex-vivo trans-corneal study showed higher cumulative corneal permeation, flux across corneal tissue (2.460±0.028µg/ml) and apparent corneal permeability (3.926×10-6cm2/s & 3.863×10-6cm2/s) from drug loaded Eudragit NPs and Ocular inserts as compared to drug solution (0.671±0.020µg/ml & 3.166×10-6cm2/s). In-vivo study showed the Eudragit NPs and ocular insert produced significant (P<0.001) lowering in intra ocular pressure compared with the solution of free drug after 3h of topical ocular administration. Plain Eudragit NPs caused no inflammation and/or discomfort in rabbit eyes and neither affected the intra ocular pressure establishing their safety and non irritancy.