The development of nanotechnology combined with the progress of cell and molecular biology has permitted to investigate the interaction between nanoconstructs and cell surface receptors at molecular level. Herein we present an example of rational nanomedicine design based on structure and function of CD20, one of the most reliable biomarkers for B-cell malignancies. CD20 is a transmembrane glycoprotein; its crosslinking results in activation of tyrosine kinases, release of intracellular stores of calcium ions, and initiation of apoptosis. We designed a new therapeutic system comprising two nanoconjugates: a pretargeting component (anti-CD20 Fab' attached to a morpholino oligonucleotide, MORF1) and a crosslinking component (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (P) grafted with multiple copies of the complementary oligonucleotide, MORF2). Consecutive treatment with the two nanoconjugates resulted in CD20 clustering on the cell surface and effective eradication of malignant B-cells in vitro and in vivo. There is no need for toxins or immune effector functions [1]. Cortical actin and cholesterol in the plasma membrane promoted the aggregation of lipid raft associated molecules to form clusters after treatment with nanoconjugates [2]. In addition, the time lag between administration of the pretargeting conjugate (Fab'-MORF1) and the crosslinking conjugate (P-(MORF2)x) can be optimized based on pharmacokinetics and biodistribution of the first conjugate, in order to achieve maximum tumor/tissue accumulation ratio in individual subjects [3]. This approach enabled more efficient treatment and achieved superior therapeutic outcomes in mice when compared to the immunotherapy using rituximab. The research was supported by NIH grants GM095606 and CA156933. 1. T.-W. Chu, J. Yang, R. Zhang, M. Sima, J. Kopeček, ACS Nano 8, 719 (2014). 2. J.M. Hartley, T.-W. Chu, E.M. Peterson, R. Zhang, J. Yang, J. Harris, J. Kopeček, ChemBioChem 16, 1725 (2015). 3. T.-W. Chu, R. Zhang, J. Yang, M.P. Chao, P.J. Shami, J. Kopeček, Theranostics 5, 834 (2015).

Self-assembly of nanoconjugates on the cell surface triggers apoptosis

251st National Meeting (2016)

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