Multidrug resistance (MDR) contributes to failure of chemotherapy. We here show that biodegradable polymeric nanogels are able to overcome MDR via folic acid targeting. The nanogels are based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) (p(HEMAm-co-AzEMAm)-Gly-HEMAm), covalently loaded with the chemotherapeutic drug doxorubicin (DOX) and subsequently decorated with a folic acid-PEG conjugate via copper-free click chemistry. pH-Responsive drug release is achieved via the acid-labile hydrazone bond between DOX and the methacrylamide polymeric network. Cellular uptake and cytotoxicity analyses in folate receptor-positive B16F10 melanoma versus folate receptor-negative A549 lung carcinoma cells confirmed specific uptake of the targeted nanogels. Confocal microscopy demonstrated efficient internalization, lysosomal trafficking, drug release and nuclear localization of DOX. We also show that DOX resistance in 4T1 breast cancer cells results in upregulation of the folate receptor, and that folic acid targeted nanogels can be employed to bypass drug efflux pumps, resulting in highly efficient killing of resistant cancer cells. In conclusion, folic acid functionalized nanogels with pH-controlled drug release seem to hold significant potential for treating multidrug resistant malignancies.

Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic 52074 Aachen Germany

Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic 52074 Aachen Germany and Department of Targeted Therapeutics MIRA Institute for Biomedical Engineering and Technical Medicine University of Twente Enschede 7522 NB The Netherlands

Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht 3584 CG The Netherlands

Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht 3584 CG The Netherlands and Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic 52074 Aachen Germany and Department of Targeted Therapeutics MIRA Institute for Biomedical Engineering and Technical Medicine University of Twente Enschede 7522 NB The Netherlands

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovsky Square 2 162 06 Prague 6 Czech Republic

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