title: Cell surface self-assembly of hybrid nanoconjugates via oligonucleotide hybridization induces apoptosis.
abstract: 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.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/Center for Controlled Chemical Delivery, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Te-Wei
authors.initials: TW
authors.lastname: Chu
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Monika
authors.initials: M
authors.lastname: Sima
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D016513:Mice, SCID; D060172:Morpholinos / Q000737:chemistry*; D058726:Nanoconjugates; D009693:Nucleic Acid Hybridization
chemical_list: D018951:Antigens, CD20; D007128:Immunoglobulin Fragments; D008689:Methacrylates; D060172:Morpholinos; D058726:Nanoconjugates; C032802:hydroxypropyl methacrylate