Drug-free macromolecular therapeutics for treatment of B-Cell malignancies

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Chu, Te-Wei
Title Drug-free macromolecular therapeutics for treatment of B-Cell malignancies
Date 2015-08
Description Hybrid nanomaterials composed of synthetic and biological building blocks possess high potential for the design of nanomedicines. We propose a new therapeutic approach that mimics the mechanism of immune effector cells to crosslink surface receptors of target cells and induce apoptosis. The receptor crosslinking is mediated by biorecognition of high-fidelity natural binding motifs (antibody fragments or oligonucleotides) that are grafted to the side chains of synthetic polymers. This approach features the absence of low-molecular-weight cytotoxic compounds. Thus, we name it "drug-free macromolecular therapeutics." This dissertation describes the development and preclinical evaluation of two drug-free macromolecular therapeutic platforms. The designed therapeutics were tested against B-cell malignancies that highly express the surface antigen CD20. In the first design, a multivalent conjugate comprising high-molecular-weight, linear copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple Fab' fragments of an anti-CD20 antibody was synthesized. Exposure of human non- Hodgkin lymphoma (NHL) Raji B-cells to the multivalent construct resulted in crosslinking of CD20 receptors and commencement of apoptosis. In the second design, two hybrid conjugates were produced: (1) an anti-CD20 Fab' attached to an oligonucleotide1, and (2) a linear HPMA copolymer grafted with multiple complementary oligonucleotide2. We showed that the two conjugates selfiv assembled via oligonucleotide hybridization at the surface of CD20+ B-cells, which crosslinked CD20 antigens and initiated apoptosis. When tested in a mouse xenograft model, the two conjugates, either administered consecutively or as a premixture, eradicated Raji cells and produced long-term survivors. The consecutive administration approach was chosen for further studies where a two-step pretargeting strategy was employed. We showed that the time lag between administering the two conjugates can be optimized based on pharmacokinetics and biodistribution of the Fab'-oligonucleotide1 conjugate. Using the optimized treatment regimen, the designed nanomedicine achieved superior anti-lymphoma efficacy to rituximab, a clinically used drug for NHL. We also evaluated the nanomedicine in patient mantle cell lymphoma and chronic lymphocytic leukemia cells. The treatment demonstrated potent apoptosis-inducing activity. In summary, we have developed novel nanotherapeutics that may constitute potent treatments for NHL and other B-cell malignancies. The verified concept can be applied to crosslink receptors other than CD20 and potentially treat different diseases.
Type Text
Publisher University of Utah
Subject Biomedical engineering; Pharmacy sciences; Nanotechnology
Subject MESH Biocompatible Materials; Nanostructures; Apoptosis; Nanomedicine; Nanostructures; Macromolecular Substances; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Oligonucleotides; Therapeutics; Molecular Weight; Cytotoxicity Tests, Immunologic; Acrylamides; Methacrylates; Tumor Necrosis Factor-alpha; Antibodies, Antigens, Surface; Monoclonal; Antigens, CD20; Nanoconjugates; B-Lymphocytes; Therapeutics
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Drug-Free Macromolecular Therapeutics for Treatment of B-Cell Malignancies
Rights Management Copyright © Te-Wei Chu 2015
Format Medium application/pdf
Format Extent 24,171,734 bytes
Source Original in Marriott Library Special Collections.
ARK ark:/87278/s6962rvf
Setname ir_etd
ID 197364
Reference URL https://collections.lib.utah.edu/ark:/87278/s6962rvf
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