Dual temperature/pH-sensitive drug delivery of poly(N-isopropylacrylamide-co-acrylic acid) nanogels conjugated with doxorubicin for potential application in tumor hyperthermia therapy.

In this paper, a dual temperature/pH-sensitive poly(N-isopropylacrylamide-co-acrylic acid) nanogel (PNA) was prepared and utilized as a drug carrier. The anti-cancer drug doxorubicin (DOX) was covalent bound to PNA via an acid-labile hydrazone linkage. DOX-PNA conjugates had a pH-dependent LCST, which was 41°C and 43°C at pH 5.3 and 6.8 respectively, but higher than 50°C at pH 7.4. The nanogels which were hydrophilic below LCST and changed to hydrophobic state above LCST possessed dual pH/temperature dependent cellular uptake and cytotoxicity. With increasing temperature, the cellular uptake of DOX-PNA was almost no difference at pH 7.4, but enhanced about 43% at pH 6.8. So the cytotoxicity of DOX-PNA also increased in higher temperature and lower pH value. It was able to distinguish tumor extracellular pH from physiological pH under hyperthermia of 43°C, suggesting a great potential for anti-cancer therapy.