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Open AccessArticle

Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy

1
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
2
Section for Pharmaceutics and Social Pharmacy, Department of Pharmacy, University of Oslo, 0371 Oslo, Norway
3
Department of Core Facilities and Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
4
Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 417; https://doi.org/10.3390/cancers12020417
Received: 7 January 2020 / Revised: 6 February 2020 / Accepted: 7 February 2020 / Published: 11 February 2020
(This article belongs to the Special Issue Photodynamic Therapy (PDT) in Oncology)
Lysosomal accumulation of sunitinib has been suggested as an underlying mechanism of resistance. Here, we investigated if photochemical internalization (PCI), a technology for cytosolic release of drugs entrapped in endosomes and lysosomes, would activate lysosomal sequestered sunitinib. By super-resolution fluorescence microscopy, sunitinib was found to accumulate in the membrane of endo/lysosomal compartments together with the photosensitizer disulfonated tetraphenylchlorin (TPCS2a). Furthermore, the treatment effect was potentiated by PCI in the human HT-29 and the mouse CT26.WT colon cancer cell lines. The cytotoxic outcome of sunitinib-PCI was, however, highly dependent on the treatment protocol. Thus, neoadjuvant PCI inhibited lysosomal accumulation of sunitinib. PCI also inhibited lysosomal sequestering of sunitinib in HT29/SR cells with acquired sunitinib resistance, but did not reverse the resistance. The mechanism of acquired sunitinib resistance in HT29/SR cells was therefore not related to lysosomal sequestering. Sunitinib-PCI was further evaluated on HT-29 xenografts in athymic mice, but was found to induce only a minor effect on tumor growth delay. In immunocompetent mice sunitinib-PCI enhanced areas of treatment-induced necrosis compared to the monotherapy groups. However, the tumor growth was not delayed, and decreased infiltration of CD3-positive T cells was indicated as a possible mechanism behind the failed overall response. View Full-Text
Keywords: sunitinib; photochemical internalization; photodynamic therapy; lysosomal sequestration; cytosolic release; photochemical release; sunitinib resistance sunitinib; photochemical internalization; photodynamic therapy; lysosomal sequestration; cytosolic release; photochemical release; sunitinib resistance
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MDPI and ACS Style

Wong, J.J.W.; Berstad, M.B.; Fremstedal, A.S.V.; Berg, K.; Patzke, S.; Sørensen, V.; Peng, Q.; Selbo, P.K.; Weyergang, A. Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy. Cancers 2020, 12, 417. https://doi.org/10.3390/cancers12020417

AMA Style

Wong JJW, Berstad MB, Fremstedal ASV, Berg K, Patzke S, Sørensen V, Peng Q, Selbo PK, Weyergang A. Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy. Cancers. 2020; 12(2):417. https://doi.org/10.3390/cancers12020417

Chicago/Turabian Style

Wong, Judith Jing Wen; Berstad, Maria Brandal; Fremstedal, Ane Sofie Viset; Berg, Kristian; Patzke, Sebastian; Sørensen, Vigdis; Peng, Qian; Selbo, Pål Kristian; Weyergang, Anette. 2020. "Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy" Cancers 12, no. 2: 417. https://doi.org/10.3390/cancers12020417

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