Drug-free macromolecular therapeutics exhibit amplified apoptosis in G2/M phase arrested cells
Drug-free macromolecular therapeutics (DFMT) have been recently developed to treat non-Hodgkin lymphoma (NHL). It is a consecutive delivery of two nanoconjugates: (1) bispecific engager that pretargets surface CD20, and (2) multivalent effector polymer that hybridises with CD20-bound engagers. Witho...
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Published in | Journal of drug targeting Vol. 27; no. 5-6; pp. 566 - 572 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
England
Taylor & Francis
03.07.2019
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Subjects | |
Online Access | Get full text |
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Summary: | Drug-free macromolecular therapeutics (DFMT) have been recently developed to treat non-Hodgkin lymphoma (NHL). It is a consecutive delivery of two nanoconjugates: (1) bispecific engager that pretargets surface CD20, and (2) multivalent effector polymer that hybridises with CD20-bound engagers. Without the need of low molecular weight drug, the hybridisation of morpholino oligonucleotide containing DFMT at NHL cell surface triggers CD20 crosslinking and subsequent apoptosis. We have previously determined various factors that affect the efficacy of DFMT regarding the synthetic structures. Here, we show that DFMT-mediated apoptosis is also influenced by the state of cells. Compared with other cell cycle states, cells arrested at G2/M phase exhibit enhanced CD20 expression, and have more sustainable CD20 binding by DFMT, resulting in a higher degree of DFMT-mediated CD20 crosslinking. Moreover, the anti-apoptotic Bcl-2 protein was phosphorylated in G2/M phase, thereby increasing the cell susceptibility to DFMT. As a result, DFMT mediated augmented apoptosis in G2/M phase cells. When DFMT was combined with a polymer-docetaxel conjugate that triggered G2/M blockage, a combinatorial apoptotic effect was achieved to induce programmed cell death. Our findings suggest the co-delivery of DFMT and G2/M inhibiting drug combinations may present a therapeutic advantage in NHL treatment. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1061-186X 1029-2330 |
DOI: | 10.1080/1061186X.2018.1521414 |