Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine

• Published in: Nanomedicine 2019-02, Vol.16, p.217-225
• Main Authors: Wang, Jiawei, Li, Lian, Yang, Jiyuan, Clair, Phillip M., Glenn, Martha J., Stephens, Deborah M., Radford, D. Christopher, Kosak, Ken M., Deininger, Michael W., Shami, Paul J., Kopeček, Jindřich
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antigens, CD20; Apoptosis; Apoptosis - drug effects; B cell lymphoma; CD20; Cell Cycle - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug-free macromolecular therapeutics; Female; Humans; Lymphoma, B-Cell - drug therapy; Male; Membrane Potential, Mitochondrial - drug effects; Microscopy, Confocal; Middle Aged; Nanomedicine; Nanomedicine - methods; Young Adult
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2018.12.011

Drug-free macromolecular therapeutics (DFMT) is a new paradigm for the treatment of B cell malignancies. Apoptosis is initiated by the biorecognition of complementary oligonucleotide motifs at the cell surface resulting in crosslinking of CD20 receptors. DMFT is composed from two nanoconjugates: 1) bispecific engager, Fab’-MORF1 (anti-CD20 Fab’ fragment conjugated with morpholino oligonucleotide), and 2) a crosslinking (effector) component P-(MORF2)X (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple copies of complementary morpholino oligonucleotide). We evaluated this concept in 44 samples isolated from patients diagnosed with various subtypes of B cell malignancies. Apoptosis was observed in 65.9% of the samples tested. Pretreatment of cells with gemcitabine (GEM) or polymer-gemcitabine conjugate (2P-GEM) enhanced CD20 expression levels thus increasing apoptosis induced by DFMT. These positive results demonstrated that DFMT has remarkable therapeutic potential in various subtypes of B cell malignancies. Drug-free macromolecular therapeutics (DFMT) is a new paradigm for the treatment of B cell malignancies. Apoptosis is initiated by crosslinking of CD20 receptors triggered by the biorecognition of complementary oligonucleotide motifs at the cell surface. The therapeutic efficacy of DFMT on 44 primary patient samples with various B-cell malignancies has been evaluated. Pretreatment of cells with gemcitabine or polymer-gemcitabine conjugate enhanced CD20 expression and increased levels of apoptosis. The results indicate that DFMT has significant translational potential. [Display omitted]