Co-Encapsulation of Hydrophilic and Hydrophobic Drugs into Human H Chain Ferritin Nanocarrier Enhances Antitumor Efficacy.

The biocompatible protein nanocarrier with homogeneous particle size is a promising candidate material for the delivery of targeted drugs to tumors. Doxorubicin (DOX) is a commonly prescribed anthracycline antitumor drug, although it may cause nephrotoxicity and cardiotoxicity. The Chinese herbal remedy ursolic acid (UA), a pentacyclic triterpenoid with anticancer action, has been used as a potential drug sensitizer to increase the effectiveness of chemotherapy and pharmacological therapy. Therefore, the dose of DOX can be reduced by compatibility with UA to lower its side effects. Ferritin binds to tumor cells through an interaction with the transferrin receptor 1 (TfR1), which is overexpressed in human cancer cells. In this study, the hydrophobic drug UA and the hydrophilic drug DOX were successfully encapsulated into the ferritin inner cavity using the thermal treatment method incubated at 60 °C for 4 h. The results demonstrated that loaded ferritin could specifically enter breast cancer cells MCF-7 and non-small-cell lung cancer cells A549 in comparison with free UA and DOX, enhancing their therapeutic effects. The loading ratio of two drugs was optimized in the constructed nanocarriers, and the effectiveness of the constructed nanodrugs in inhibiting tumor proliferation was verified by cell apoptosis and three-dimensional (3D) tumor spheroids studies. For the first time, the hydrophilic and hydrophobic drugs were loaded simultaneously within unmodified ferritin without other addition of additives, which would reduce the toxic side effects of DOX and enhance its therapeutic effect. This study also showed that the ferritin-based nanocarrier has potential for drug delivery to tumors.