Combined pH-responsive chemotherapy and glutathione-triggered photosensitization to overcome drug-resistant hepatocellular carcinoma - a SPP/JPP Young Investigator Award paper

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

Detail(s)

Original languageEnglish
Pages (from-to)1387-1401
Journal / PublicationJournal of Porphyrins and Phthalocyanines
Volume24
Issue number11
Publication statusPublished - Nov 2020

Abstract

Doxorubicin (DOX) resistance, which results in a reduced accumulation of DOX in the nucleus and hence decreased DNA damage, is a major challenge for chemotherapy against hepatocellular carcinoma. In this paper, we combined chemotherapy with photodynamic therapy (PDT) to combat DOX-resistant human hepatocellular carcinoma cells. We have prepared the polymeric micelles conjugating with DOX and zinc(II) phthalocyanine (ZnPc) through a pH-responsive hydrazone linker and a glutathione (GSH)-responsive disulfide linker, respectively. The polymeric micelles (DOX-ZnPc-micelles) exhibited a spherical shape with a size of about 98 nm diameter and showed excellent stability in aqueous solution. Due to the self-quenching of the ZnPc inside the micelles, DOX-ZnPc-micelles did not emit fluorescence upon red light irradiation. Drug release experiments verified that DOX and ZnPc could be released under acidic conditions and reducing environments, respectively. A higher concentration of DOX was internalized into DOX-resistant R-HepG2 cells through the delivery of polymeric micelles when compared with the free DOX, hence DOX-ZnPc-micelles exhibited a significant enhancement in anticancer activity. The IC50 value of DOX against R-HepG2 cells was found to be 21 μM when combined with PDT and it was 5-fold less than that of a single treatment of DOX (102 μM). The DOX-ZnPc-micelles could induce cell apoptosis and necrosis on R-HepG2 cells by combined therapeutic modalities, while these micelles induced only apoptosis on HepG2 cells. We have demonstrated that utilization of polymeric micelles can significantly enhance the cellular uptake and cytotoxicity of DOX against R-HepG2 cells when compared with free DOX. Moreover, PDT can act as an adjuvant therapeutic modality and combine with chemotherapy to further improve therapeutic efficacy. Overall speaking, DOX-ZnPc-micelles can overcome DOX resistance and induce a synergistic therapeutic effect against DOX-resistant R-HepG2 cells, hence improving the therapeutic efficacy when compared with monotherapy.

Research Area(s)

  • chemotherapy, doxorubicin, photodynamic therapy, phthalocyanine, polymeric micelles

Citation Format(s)

Combined pH-responsive chemotherapy and glutathione-triggered photosensitization to overcome drug-resistant hepatocellular carcinoma - a SPP/JPP Young Investigator Award paper. / Gao, Di; Lo, Pui-Chi.

In: Journal of Porphyrins and Phthalocyanines, Vol. 24, No. 11, 11.2020, p. 1387-1401 .

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review