Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin

Y. Chen, O. Tezcan, D. Li, N. Beztsinna, B. Lou, T. Etrych, K. Ulbrich, J. M. Metselaar, T. Lammers, Wim E. Hennink

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)10404-10419
Number of pages16
JournalNanoscale
Volume9
Issue number29
DOIs
Publication statusPublished - 7 Aug 2017

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Folic Acid
Doxorubicin
Acids
Cells
Pharmaceutical Preparations
Chemotherapy
Confocal microscopy
Cytotoxicity
Polyethylene glycols
Hydrazones
NanoGel
Pumps
Copper
methacrylamide

Cite this

Chen, Y. ; Tezcan, O. ; Li, D. ; Beztsinna, N. ; Lou, B. ; Etrych, T. ; Ulbrich, K. ; Metselaar, J. M. ; Lammers, T. ; Hennink, Wim E. / Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin. In: Nanoscale. 2017 ; Vol. 9, No. 29. pp. 10404-10419.
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abstract = "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.",
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Chen, Y, Tezcan, O, Li, D, Beztsinna, N, Lou, B, Etrych, T, Ulbrich, K, Metselaar, JM, Lammers, T & Hennink, WE 2017, 'Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin' Nanoscale, vol. 9, no. 29, pp. 10404-10419. https://doi.org/10.1039/c7nr03592f

Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin. / Chen, Y.; Tezcan, O.; Li, D.; Beztsinna, N.; Lou, B.; Etrych, T.; Ulbrich, K.; Metselaar, J. M.; Lammers, T.; Hennink, Wim E.

In: Nanoscale, Vol. 9, No. 29, 07.08.2017, p. 10404-10419.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Li, D.

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AU - Lou, B.

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