Design of dual stimuli responsive polymer modified magnetic nanoparticles for targeted anti-cancer drug delivery and enhanced MR imaging

Herein, we report a strategic design of dual temperature and pH responsive polymer integrated magnetic nanohybrids comprising of smart block copolymers and mixed ferrite nanoparticles (MFNPs) for efficient anti-cancer drug delivery and magnetic resonance imaging (MRI). Citrate stabilized mixed ferrite nanoparticles (CA-MFNPs) were intelligently modified with the dual responsive polyethyleneimine (PEI) cross-linked Pluronic F127 copolymer via the EDC/NHS method. In order to accomplish cancer targeting and imaging capability, both the folic acid (FA) and rhodamine isothiocyanate (RITC) were tethered to the nanoparticles via intricate chemical approaches. These FA targeted nanohybrids were further entrapped with doxorubicin (DOX) and their release pattern was investigated. These DOX loaded FA targeted nanoparticles (DOX-FA-Poly-MFNPs) demonstrated high drug payload and encapsulation efficiency i.e. 4.6% and 92.0%, respectively. It is shown that at the lower pH/higher temperature i.e. acidic pH (5.0) and at body temperature (37 °C), the DOX-FA-Poly-MFNPs exhibited enhanced release of DOX (drug release value ∼53%) while retaining their stealthy structure under physiological conditions (drug release value ∼12%), exhibiting an apparent thermo/pH controlled drug release pattern. The folic acid receptor (FAR) specific endocytosis to cancer cells (human cervix adenocarcinoma i.e. HeLa) in comparison to normal immortalized keratinocytes (HaCaT) cells were demonstrated via fluorescence microscopy and magnetic resonance imaging (MRI). Furthermore, these DOX-FA-Poly-MFNPs displayed effective therapeutic activity evaluated by a cytotoxicity assay and cell cycle analysis in HeLa cells. Therefore, these dual responsive mixed ferrite nanoparticles may serve as promising theranostic agents for in vivo cancer therapy. Stimuli triggered release of DOX from dual responsive theranostic nanocarriers mimicking lysosomal conditions i.e. physiological temperature (37 °C) and acidic pH (5.5).