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.

The DOX-loaded PNA nanogels have different hydrophilic/hydrophobic states in the vicinity of normal and cancer cells under hyperthermia treatments due to its pH-dependent LCST, leading to a different cellular internalization of DOX–PNA nanogels.Figure optionsDownload as PowerPoint slideResearch highlights▶ Prepared PNA nanogels with appropriate pH-dependent LCST for drug delivery. ▶ Multi-response mechanisms of the DOX–PNA conjugates. ▶ Acid/heating condition is favorable for nanogels to distinguish tumor cells.