Synthesis of Docetaxel Loaded Beta Amino Ester Based Nanoparticles Decorated with Anti-CD44 Aptamer and MMP-Acylated Heptapeptide for Enhanced Accumulation in the Breast Tumor Microenvironment

Abstract

The rapid elimination and/or off-targeting of nanoparticles by physiological or pathological barriers, with a major role for protein corona (PC) formation, are the main obstacles in nano-drug delivery systems (NDDS). Therefore, engineering advanced strategies to overcome the mentioned barriers is an urgent need for designing more effective targeting. To tackle this issue, we created transformable stealth NPs that, after exposure to the tumor microenvironment (TME), altered into two ligand-capped NPs (SRL-2 and TA1) for synergistic targeting of the 4T1 breast cancer model. A chimeric peptide and TA1 aptamer in a ratio of 9:1 were attached to the surface of a developed redox/pH-responsive docetaxel (DTX)-loaded poly (β- amino ester) micelle. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the MMP-9 in the TME of the 4T1 breast cancer model, it suddenly changed into dual-targeting NPs (containing two ligands, SRL-2 and TA1 aptamer). Interestingly, a significantly higher TME accumulation of NPs was corroborated in in vivo biodistribution and fluorescent TUNEL assay experiments. Using 4T1 tumor- bearing Balb/c mice as a pharmacological model, NPs-treated groups demonstrated impressive tumor growth suppression by just 1/10th of the DTX therapeutic dose (TD). In conclusion, cleverly designed nanostructures here will reduce the therapeutic dosage, off-targeting, and side effects of anticancer drugs.