Cell Surface Self-Assembly of Hybrid Nanoconjugates via Oligonucleotide Hybridization Induces Apoptosis

• Published in: ACS nano Vol. 8; no. 1; pp. 719 - 730
• Main Authors: Chu, Te-Wei, Yang, Jiyuan, Zhang, Rui, Sima, Monika, Kopeček, Jindřich
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.01.2014
• Subjects: Animals; Antigens; Antigens, CD20 - immunology; Apoptosis; Cell Membrane - metabolism; Circular Dichroism; Crosslinking; Drug Screening Assays, Antitumor; Female; Humans; Immunoglobulin Fragments - immunology; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - pathology; Methacrylates - chemistry; Mice; Mice, SCID; Morpholinos - chemistry; Nanoconjugates; Nanomaterials; Nanostructure; Nucleic Acid Hybridization; Oligonucleotides; Platforms; Receptors; Self assembly; CD20; N-(2-hydroxypropyl)methacrylamide (HPMA); morpholino oligonucleotide; biorecognition; apoptosis; receptor cross-linking; B-cell lymphoma
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn4053827

Hybrid nanomaterials composed of synthetic and biological building blocks possess high potential for the design of nanomedicines. The use of self-assembling nanomaterials as “bio-mimics” may trigger cellular events and result in new therapeutic effects. Motivated by this rationale, we designed a therapeutic platform that mimics the mechanism of immune effector cells to cross-link surface receptors of target cells and induce apoptosis. This platform was tested against B-cell lymphomas that highly express the surface antigen CD20. Here, two nanoconjugates were synthesized: (1) an anti-CD20 Fab′ fragment covalently linked to a single-stranded morpholino oligonucleotide (MORF1), and (2) a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple copies of the complementary oligonucleotide MORF2. We show that the two conjugates self-assemble via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells, which cross-links CD20 antigens and initiates apoptosis. When tested in a murine model of human non-Hodgkin’s lymphoma, the two conjugates, either administered consecutively or as a premixture, eradicated cancer cells and produced long-term survivors. The designed therapeutics contains no small-molecule cytotoxic compounds and is immune-independent, aiming to improve over chemotherapy, radiotherapy and immunotherapy. This therapeutic platform can be applied to cross-link any noninternalizing receptor and potentially treat other diseases.