DNA‐Scaffolded Multivalent Ligands to Modulate Cell Function

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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“…, polypeptides, 116 poly-DNA 17 ). Mobility and biodistribution of carriers should be characterized.…”

Section: Conclusion and Beyondmentioning

confidence: 99%

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

Chu

Kopeček

2015

Biomater. Sci.

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“…This was likely due to multivalency of the P-MORF2 conjugate (8 binding sites per chain) in comparison to the divalent mAb. Our lab [10, 11] and others [12, 13] have previously shown that the multivalency of anti-CD20 constructs can increase binding affinity and apoptosis-inducing efficiency by several fold, when compared to their monovalent or divalent counterparts. We have also reported that, in addition to valence, the polymer length ( i.e.…”

Section: Resultsmentioning

confidence: 99%

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

Chu

Kosak

Shami

et al. 2014

Drug Deliv. and Transl. Res.

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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 10 patients. Apoptosis and cytotoxicity were observed in eight samples, including 2 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 (8 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 chemo-immunotherapy.

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“…Lately, a variety of self-assembled and biofunctionalized polymer domains have now been used to successfully regulate signaling networks [13]. In future, the design of potent multivalent conjugates that can organize cell receptors into nanoscale clusters and control cell fate will further impact this research field [1,14,15].…”

Section: Molecular Nanopatterns For Controlling Transmembrane Clusteringmentioning

confidence: 99%

Receptor Clustering Control and Associated Force Sensing by Surface Patterning: When Force Matters

Cavalcanti‐Adam

Spatz

2015

Nanomedicine (Lond.)

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Nanostructured and chemically functionalized materials which mimic architectural and mechanical features of natural cell microenvironments hold promise for a better understanding and control of cell physiological processes through molecular and nanoscale interactions. Ultimately, the design of defined scaffolds for tissue engineering based on these material properties will advance regenerative medicine. The clustering of transmembrane receptors into defined nanoscale structures triggers and regulates specific signaling networks with unprecedented precision and is involved in transducing forces between the cell and the matrix. Only few material-based technologies exist today that enable the local control of receptor clustering and are able to measure mechanotransduction-based cellular reactions. Receptor clustering and regulatory ligand–receptor interactions stimulate a variety of biological processes. Herein lies an opportunity for interdisciplinary efforts between the fields of engineering, chemistry and biology to design new materials with the aim of controlling and quantifying nanoscale and molecular interactions at cellular boundaries. These efforts, inspired by the cell microenvironment, have recently led to the creation of nanostructured surfaces for controlling and guiding cell adhesion and function in a predictable manner [1,2]. The cell microenvironment contains chemical and physical cues that arise from a complex, albeit defined, architecture of extracellular matrix networks. Achieving a defined spatial patterning of extracellular matrix cues at the nanoscale, while independently tuning the chemical and physical properties of surfaces, has been a challenge. Although the achievements made thus far have created a more detailed picture of how cells interact with their microenvironment, it has also raised new questions. Current techniques used to investigate the effects of extracellular matrix ligand presentation on cell functions work by independently manipulating variables like ligand density, clustering and spacing [3–5]. The application of surfaces that present a specific spatial pattern of molecules and peptides at the nanoscale have elucidated the minimal requirements needed for activating signaling networks. In particular, strong interest has been devoted to understanding the spatial aspects of focal adhesion maturation, the assembly of discrete structures upon integrin binding to the extracellular matrix and large-scale clustering of hundreds of receptors. Focal adhesions transmit tensile stresses from the extracellular space to the cytoskeleton, thereby converting force cues into biochemical signals that regulate cell functions [6]

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DNA‐Scaffolded Multivalent Ligands to Modulate Cell Function

Cited by 44 publications

References 43 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 induce apoptosis of patient chronic lymphocytic leukemia cells

Receptor Clustering Control and Associated Force Sensing by Surface Patterning: When Force Matters

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