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.