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...

Full description

Saved in:
Bibliographic Details
Published inJournal of drug targeting Vol. 27; no. 5-6; pp. 566 - 572
Main Authors Li, Lian, Yang, Jiyuan, Wang, Jiawei, Kopeček, Jindřich
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 03.07.2019
Subjects
Online AccessGet full text

Cover

Loading…
More Information
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.
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