Drug-free macromolecular therapeutics induce apoptosis of patient chronic lymphocytic leukemia cells

Chu, Te Wei; Kosak, Ken M.; Shami, Paul J.; Kopeček, Jindřich

doi:10.1007/s13346-014-0209-8

Cited by 25 publications

(24 citation statements)

References 21 publications

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“…17,113,114,116 In our drug-free approach, P-(CCK) y or P-(MORF2) x with valences up to 9 or 10 have been synthesized (using ~100 kDa polymer backbones). These conjugates would have multimeric interactions with targets, which possibly accounted for their significantly better therapeutic performance than the divalent mAbs as observed by Chu et al 106,107 . Previously we have shown that, in addition to the valence, the MW of the polymer backbone also had a positive influence on the efficiency of CD20 crosslinking and apoptosis in vitro .…”

Section: Advantages Of Drug-free Macromolecular Therapeuticsmentioning

confidence: 90%

Drug-free macromolecular therapeutics – a new paradigm in polymeric nanomedicines

Chu

Kopeček

2015

Biomater. Sci.

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This review highlights a unique research area in polymer-based nanomedicine designs. Drug-free macromolecular therapeutics induce apoptosis of malignant cells by the crosslinking of surface non-internalizing receptors. The receptor crosslinking is mediated by the biorecognition of high-fidelity natural binding motifs (such as antiparallel coiled-coil peptides or complementary oligonucleotides) that are grafted to the side chains of polymers or attached to targeting moieties against cell receptors. This approach features the absence of low-molecular-weight cytotoxic compounds. Here, we summarize the rationales, different designs, and advantages of drug-free macromolecular therapeutics. Recent developments of novel therapeutic systems for B-cell lymphomas are discussed, as well as relevant approaches for other diseases. We conclude by pointing out various potential future directions in this exciting new field.

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Section: Advantages Of Drug-free Macromolecular Therapeuticsmentioning

confidence: 90%

Drug-free macromolecular therapeutics – a new paradigm in polymeric nanomedicines

Chu

Kopeček

2015

Biomater. Sci.

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“…Our previous studies have shown the efficacy of the MORF-based drug-free macromolecular therapeutics in an animal model of NHL [12,14] and on patient cells [15]. The aim of this study was to determine the relationship between the detailed structure of the nanoconjugates and apoptosis induction in Raji cells to allow system optimization.…”

Section: Discussionmentioning

confidence: 99%

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

Zhang

Fang

Yang

et al. 2017

Journal of Controlled Release

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Recently, we developed a new paradigm in macromolecular therapeutics that avoids the use of low molecular weight drugs. The activity of the “drug-free macromolecular therapeutics” is based on the biorecognition of complementary motifs at cell surface resulting in receptor crosslinking and apoptosis induction. The system is composed of two nanoconjugates: (1) a single-stranded morpholino oligonucleotide (MORF1) attached to an anti-CD20 Fab′ fragment (Fab′-MORF1); (2) multiple copies of complementary oligonucleotide MORF2 grafted to a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) – P-(MORF2)x. The two conjugates crosslink CD20 antigens via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells and induce apoptosis. Preclinical studies in a murine model of human non-Hodgkin’s lymphoma showed cancer cells eradication and long-term survivors. The aim of this study was to determine the relationship between the detailed structure of the nanoconjugates and apoptosis induction in Raji cells to allow system optimization. The factors studied include the length of the MORF sequence, the valence of P-(MORF2)x (varying x), molecular weight of P-(MORF2)x, incorporation of a miniPEG spacer between Fab′ and MORF1 and between polymer backbone and pendant MORF2, and comparison of two Fab′ fragments, one from 1F5 antibody (Fab′1F5), the other from Rituximab (Fab′RTX). The results of apoptosis induction in human Burkitt’s B-cell non-Hodgkin’s lymphoma (NHL) Raji cells as determined using three apoptotic assays (Annexin V, Caspase 3, and TUNEL) indicated that: a) An improvement of apoptotic activity was observed for a 28 base pair MORF sequence when compared to MORFs composed of 20 and 25 base pairs. The differences depended on type of assay, concentration and exposure schedule (consecutive vs. premixed). b) The higher the valence of P-(MORF2)x the higher the levels of apoptosis. c) Higher molecular weight of P-(MORF2)x induced higher levels of apoptosis. d) A miniPEG8 spacer was effective in enhancing apoptotic levels in contrast to a miniPEG2 spacer. e) There was not a statistically significant difference when comparing Fab′1F5-MORF1 with Fab′RTX-MORF1.

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“…We further evaluated the nanomedicines using cells from 10 patients with chronic lymphocytic leukemia (CLL) [242]. Apoptosis and cytotoxicity were observed in 8 patients including two with the 17p13 deletion, a high-risk prognostic factor.…”

Section: New Paradigm: Drug-free Macromolecular Therapeuticsmentioning

confidence: 99%

Design of smart HPMA copolymer-based nanomedicines

Yang

Kopeček

2016

Journal of Controlled Release

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The state-of-the art in water-soluble macromolecular therapeutics has been reviewed. First the design principles for polymer-drug conjugates are discussed followed by two recent developments in the field: a) The design, synthesis and properties of backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. The enhanced intravascular half-life of such conjugates creates a concentration gradient (blood vs. tumor) for an extended time interval resulting in increased solid tumor accumulation by enhanced permeability and retention (EPR) effect with concomitant increase in efficacy. b) Drug-free macromolecular therapeutics is a new paradigm in macromolecular therapeutics. Apoptosis in malignant cell is induced by crosslinking of cell surface non-internalizing receptors. Crosslinking of receptors is mediated by the biorecognition of two nanoconjugates containing high-fidelity complementary motifs (peptides or oligonucleotides). Results for the treatment of B cell lymphomas in animal models and patient cells demonstrate the high translational potential of this aproach.

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Drug-free macromolecular therapeutics induce apoptosis of patient chronic lymphocytic leukemia cells

Cited by 25 publications

References 21 publications

Drug-free macromolecular therapeutics – a new paradigm in polymeric nanomedicines

Drug-free macromolecular therapeutics – a new paradigm in polymeric nanomedicines

Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells

Design of smart HPMA copolymer-based nanomedicines

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