A nanogel of on-site tunable pH-response for efficient anticancer drug delivery

A smart, soft and small nanoparticulate drug carrier that can efficiently transport therapeutics into tumor cells to control the intracellular drug concentration will enable major advancements in cancer therapy. To facilitate a remote modulation of the intracellular pH-regulated drug release, we have designed a new class of pH-responsive chitosan-based nanogels (<200 nm) by the physical interpenetration of chitosan chains into a nonlinear poly(ethylene glycol) (nonlinear PEG) chain network. The resultant PEG-chitosan nanogels not only respond to the changes in environmental pH over the physiologically important range of 5.0–7.4, but – more importantly – also enable us to remotely modulate the pH response by external cooling/heating. The nanogel, as well as the nanogel loaded with a model anticancer drug 5-fluorouracil (5-FU), is capable of varying its surface charge from nearly neutral to positive around tumor extracellular pH (∼6.0–6.2) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments (∼5.0) can trigger 5-FU release from the endocytosed drug carriers. While this nanogel serving as a drug carrier exhibits a reduced toxicity in combined chemo-thermo treatments, it has shown significantly enhanced therapeutic efficacy in combined chemo-cryo treatments of the model B16F10 melanoma cells, indicating its great potential for cancer therapy.