Estrone decorated poly-ion complex micelles for targeted melittin delivery to hormone responsive breast cancer cells.

Tumor targeting has revolutionized cancer research, especially active cellular targeting of nanoparticles where they are specifically homed to pathological site to deliver the therapeutics. This strategy which involves the utilization of affinity ligands on the surface of the nano-carriers minimizes the non-specific uptake of the nano-carriers and the subsequent harmful side effects in healthy cells. Estrone, one of the mammalian estrogens, has affinity for estrogen receptors (ERα) which are over-expressed in hormone-responsive breast cancers. Despite holding promise, the potential of estrone in active targeting of nanoparticles has barely been explored. Herein, we developed estrone appended poly-ion complex (PIC) micelle to deliver melittin, a cytotoxic peptide, to breast cancer cells. Amino functionalization of estrone was performed to conjugate estrone to the di-block polymer synthesized by RAFT polymerization. Estrone conjugated polyethylene glycol methyl ether methacrylate-b-poly tert-butyl methacrylate (POEGMEMA-PtBuMA) could complex with melittin to form PIC micelles of size around 60 nm ensuing from the electrostatic interaction of the deprotected polymer and melittin in aqueous media. Polyethylene glycol methyl ether acrylate-b-poly acrylic acid (POEGMEA-PAA) was also later incorporated to afford PIC micelles that could exhibit similar cytotoxicity as free melittin in the cytotoxicity studies. The estrone attached PIC micelles exhibited improved cytotoxicity in 2D and 3D cellular models of MCF-7 cells. Crosslinking of the PIC micelles was also performed to improve the stability of the micelles and prevent melittin degradation from enzymatic attack. Flow cytometry demonstrated an enhanced cellular uptake greater than 6-fold with the estrone conjugated PIC micelles thereby establishing a profound difference in the targeting efficacy of the PIC micelles between MCF-7 and MDA-MB231 cells. Furthermore, the distribution of the PIC micelles in the spheroids was revealed by light sheet microscopy. The results demonstrate the potential of estrone anchored PIC micelles for targeted delivery of therapeutics to hormone responsive breast cancer cells.