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

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

doi:10.1007/s13346-014-0209-8

Drug Delivery and Translational Research

December 2014, Volume 4, Issue 5–6, pp 389–394

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

Authors
Authors and affiliations

Te-Wei Chu
Ken M. Kosak
Paul J. Shami
Jindřich KopečekEmail author

Clinical Research

First Online:: 07 November 2014

8 Citations
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Abstract

A new drug-free nanotherapeutic approach for B-cell malignancies was developed. Exposure of B-cells to an anti-CD20 Fab’-morpholino oligonucleotide1 (MORF1) conjugate decorated the cell surface with MORF1; further exposure of the decorated cells to multivalent polymer-oligonucleotide2 conjugates (P-MORF2) resulted in CD20 clustering at the cell surface with induction of apoptosis. We evaluated this concept in chronic lymphocytic leukemia (CLL) cells isolated from ten patients. Apoptosis and cytotoxicity were observed in eight samples, including two samples with the 17p13 deletion, which suggested a p53-independent mechanism of apoptosis induction. When compared to an anti-CD20 monoclonal antibody (mAb), the nanotherapeutic showed significantly more potent apoptosis-inducing activity and cytotoxicity. This was due to the multivalency effect (eight binding sites per polymer chain) of our design in comparison to the divalent mAb. In conclusion, we have developed a novel and potent therapeutic system against CLL and other B-cell malignancies with significant advantages over conventional chemoimmunotherapy.

Keywords

CLL B-cell CD20 Apoptosis HPMA copolymer Nanomedicine

References

1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics 2014. CA Cancer J Clin. 2014;64:9–29.PubMedCrossRefGoogle Scholar
2.
Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells Mol Dis. 2000;26:133–43.PubMedCrossRefGoogle Scholar
3.
Zhang N, Khawli LA, Hu P, Epstein AL. Generation of rituximab polymer may cause hyper-cross-linking-induced apoptosis in non-Hodgkin’s lymphomas. Clin Cancer Res. 2005;11:5971–80.PubMedCrossRefGoogle Scholar
4.
Chu T-W, Yang J, Kopeček J. Anti-CD20 multivalent HPMA copolymer-Fab’ conjugates for the direct induction of apoptosis. Biomaterials. 2012;33:7174–81.PubMedCentralPubMedCrossRefGoogle Scholar
5.
Chu T-W, Yang J, Zhang R, Sima M, Kopeček J. Cell surface self-assembly of hybrid nanoconjugates via oligonucleotide hybridization induces apoptosis. ACS Nano. 2014;8:719–30.PubMedCrossRefGoogle Scholar
6.
Press OW, Appelbaum F, Ledbetter JA, et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood. 1987;69:584–91.Google Scholar
7.
Byrd JC, Jones JJ, Woyach JA, Johnson AJ, Flynn JM. Entering the era of targeted therapy for chronic lymphocytic leukemia: Impact on the practicing clinician. J Clin Oncol. 2014;32:3039–47.CrossRefGoogle Scholar
8.
van der Kolk LE, Evers LM, Omene C, et al. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia. 2002;16:1735–44.PubMedCrossRefGoogle Scholar
9.
Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood. 1998;91:1644–52.PubMedGoogle Scholar
10.
Johnson RN, Kopečková P, Kopeček J. Synthesis and evaluation of multivalent branched HPMA copolymer − Fab′ conjugates targeted to the B-cell antigen CD20. Bioconjug Chem. 2009;20:129–37.PubMedCentralPubMedCrossRefGoogle Scholar
11.
Johnson RN, Kopečková P, Kopeček J. Biological activity of anti-CD20 multivalent HPMA copolymer − Fab’ conjugates. Biomacromolecules. 2012;13:727–35.PubMedCentralPubMedCrossRefGoogle Scholar
12.
Aluri SR, Shi P, Gustafson JA, et al. A hybrid protein-polymer nanoworm potentiates apoptosis better than a monoclonal antibody. ACS Nano. 2014;8:2064–76.PubMedCrossRefGoogle Scholar
13.
Zhang Z, Eckert MA, Ali MM, et al. DNA-scaffolded multivalent ligands to modulate cell function. ChemBioChem. 2014;15:1268–73.PubMedCrossRefGoogle Scholar
14.
Pan H, Yang J, Kopečková P, Kopeček J. Backbone degradable multiblock N-(2-hydroxypropyl)methacrylamide copolymer conjugates via reversible addition-fragmentation chain transfer polymerization and thiol-ene coupling reaction. Biomacromolecules. 2011;12:247–52.PubMedCentralPubMedCrossRefGoogle Scholar
15.
Yang J, Luo K, Pan H, Kopečková P, Kopeček J. Synthesis of biodegradable multiblock copolymers by click coupling of RAFT-generated heterotelechelic polyHPMA conjugates. React Funct Polym. 2011;71:294–302.PubMedCentralPubMedCrossRefGoogle Scholar
16.
Zhang R, Yang J, Sima M, Zhou Y, Kopeček J. Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proc Natl Acad Sci U S A. 2014;111:12181–6.PubMedCrossRefGoogle Scholar
17.
Danilov AV. Targeted therapy in chronic lymphocytic leukemia: Past, present, and future. Clin Ther. 2013;35:1258–70.PubMedCrossRefGoogle Scholar
18.
Goodwin DA, Meares CF. Advances in pretargeting biotechnology. Biotechnol Adv. 2001;19:435–50.PubMedCrossRefGoogle Scholar
19.
Gunn J, Park SI, Veiseh O, Press OW, Zhang M. A pretargeted nanoparticle system for tumor cell labeling. Mol Biosyst. 2011;7:742–8.PubMedCentralPubMedCrossRefGoogle Scholar

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Authors and Affiliations

Te-Wei Chu
- 1
Ken M. Kosak
- 2
Paul J. Shami
- 1
- 2
Jindřich Kopeček
- 1
- 3
- 4
Email author

1.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA
2.Division of Hematology and Hematologic Malignancies and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
3.Department of BioengineeringUniversity of UtahSalt Lake CityUSA
4.University of UtahSalt Lake CityUSA

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Cite this article as:: Chu, TW., Kosak, K.M., Shami, P.J. et al. Drug Deliv. and Transl. Res. (2014) 4: 389. doi:10.1007/s13346-014-0209-8

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

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