Enhanced anti-tumor efficacy and tumor accumulation of Tamoxifen through cRGD functionalized cholesterol based lipopolymeric nanoparticles for targeted breast cancer therapy

Targeting ligand mediated drug delivery systems hold promise for enhancing the anti-tumor efficacy and suppressing the off-target effects of chemotherapeutic molecules. The current study aims at the development of a peptide conjugated cholesterol based lipopolymeric nanoparticles for delivery of Tamoxifen (TMX). cRGD conjugated, cholesterol containing lipopolymers were successfully synthesized by maleimide-thiol coupling and characterized by 1H NMR. Emulsion-solvent evaporation technique was employed to formulate TMX loaded cRGD conjugated lipopolymeric nanoparticles which were further analyzed to determine the particle size, encapsulation efficiency and release kinetics and compared with TMX loaded mPEG-MTC-Chol nanoparticles. The cRGD conjugated lipopolymeric nanoparticles exhibited particle size -133.61 +/- 4.70 nm with 43.86 +/- 1.85 % encapsulation efficiency. Interestingly, the presence of cRGD greatly enhanced the cellular internalization and inhibitory activity of lipopolymeric nanoparticles in 4T1 cells with an IC50 value of -19.04 mu M in comparison to TMX loaded mPEG-MTC-Chol NP (-28.07 mu M) Further, as evidenced by the rise in sub-diploid DNA content, TMX loaded cRGD-PEG-MTC Chol nanoparticles triggered apoptosis -2.34 fold greater than TMX loaded mPEGMTC-Chol nanoparticles. Additionally, cRGD-PEG-MTC-Chol nanoparticles demonstrated longer half-life (-1.84 fold) and improved bioavailibility (-2.1 fold) and a -2 fold increment in drug concentration within the isolated tumor tissues when administered as cRGD-PEG-MTC-Chol NP vs mPEG-MTC-Chol NP in tumor bearing mice. This could be majorly attributed to integrin mediated receptor endocytosis which concurrently accounted for significant anti-tumor effects in EAC breast cancer mouse model.