Thermoresponsive nanoparticles for targeted and controlled delivery of doxorubicin in triple negative breast cancer: a 2D and 3D in vitro evaluation.

Controlled release of chemotherapeutic drugs is a key factor in cancer therapy. In this regard, temperature triggered release of drugs offers a precise control over the release within the tumour region, thus avoiding premature drug release and unspecific toxicity. In this work a novel polymeric N-isopropylacrylamide-based nanocarrier was developed to carry and release doxorubicin in response to the natural higher temperature of solid triple negative breast cancer tumours. The nanocarrier was further functionalized with folic acid moieties to improve the targeting of these cells. The obtained results show that the produced nanoparticles presented a thermoresponsive behaviour with a transition temperature of 42 °C. Moreover, a high drug loading was achieved (9.7%) followed by a sustained and temperature dependent drug release (55% at 37 °C and 86% at 40 °C). Regarding biosafety, the nanoparticles were cytocompatible up to a concentration of 5,000 µg mL− 1, non-haemolytic, non-thrombogenic and anti-fouling, showing good properties to be intravenously administered. When tested against triple negative breast cancer cells in 2D models, a concentration and time dependent cytotoxic effect was observed, where folic acid-functionalized nanoparticles resulted in a lowering of the IC50 value in 77%, when compared with non-functionalized nanoparticles. Finally, a 3D in vitro model of the tumour was optimized, with the objective of better mimicking an in vivo scenario, where the NPs presented an effective tumour cell reduction in a temperature dependent manner. In conclusion, this work was able to optimize a novel nanoparticle to improve doxorubicin delivery in a controlled fashion, with specific targeting capabilities towards cancer cells, even in 3D systems where drug penetration is usually limited.