Thermo/redox/pH-triple sensitive poly(N-isopropylacrylamide-co-acrylic acid) nanogels for anticancer drug delivery.

The clinical application of doxorubicin (DOX), like other anticancer drugs, is limited by insufficient cellular uptake and the numerous drug resistance mechanisms existing in cells. The development of smart nanomaterials capable of carrying the drugs into the cells and of releasing them under the control of the microenvironment is an interesting approach that may increase the success of the anticancer drugs currently in use. Herein, we report an easy process to prepare biocompatible nanogels (NGs) with thermo/redox/pH-triple sensitivity, which are highly effective in the intracellular delivery of DOX. Redox-sensitive/degradable NGs (PNA-BAC) and nondegradable NGs (PNA-MBA) were prepared through in situ polymerization of N-isopropylacrylamide (NIPAM) and acrylic acid (AA) in the presence of sodium dodecyl sulfate (SDS) as a surfactant, using N,N'-bis(acryloyl)cystamine (BAC) as a biodegradable crosslinker or N,N'-methylene bisacrylamide (MBA) as a nondegradable crosslinker, respectively. After that, the cationic DOX drug was loaded into the NGs through electrostatic interactions, by simply mixing them in aqueous solution. Compared to nondegradable PNA-MBA NGs, PNA-BAC NGs not only presented a higher DOX drug loading capacity, but also allowed a more sustainable drug release behavior under physiological conditions. More importantly, PNA-BAC NGs displayed thermo-induced drug release properties and an in vitro accelerated release of DOX under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments. The thermo/redox/pH multi-sensitive NGs can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in a high DOX intracellular accumulation and an improved cytotoxicity when compared with free DOX and DOX-loaded nondegradable PNA-MBA NGs. The developed NGs can be possibly used as an effective platform for the delivery of cationic therapeutic agents for biomedical applications.