7 results on '"D. Christopher Radford"'
Search Results
2. Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine
- Author
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Ken M. Kosak, Martha Glenn, D. Christopher Radford, Jindřich Kopeček, Phillip M. Clair, Paul J. Shami, Michael W. Deininger, Jiyuan Yang, Lian Li, Jiawei Wang, and Deborah M. Stephens
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Adult ,Male ,Lymphoma, B-Cell ,Morpholino ,Cell ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Apoptosis ,Bioengineering ,02 engineering and technology ,Deoxycytidine ,Article ,Young Adult ,03 medical and health sciences ,medicine ,Humans ,General Materials Science ,Receptor ,B cell ,Aged ,030304 developmental biology ,Aged, 80 and over ,Membrane Potential, Mitochondrial ,CD20 ,0303 health sciences ,Microscopy, Confocal ,biology ,Chemistry ,Oligonucleotide ,Cell Cycle ,Middle Aged ,Antigens, CD20 ,021001 nanoscience & nanotechnology ,Gemcitabine ,Nanomedicine ,medicine.anatomical_structure ,Cancer research ,biology.protein ,Molecular Medicine ,Female ,0210 nano-technology ,medicine.drug - Abstract
Drug-free macromolecular therapeutics (DFMT) is a new paradigm for the treatment of B cell malignancies. Apoptosis is initiated by the biorecognition of complementary oligonucleotide motifs at the cell surface resulting in crosslinking of CD20 receptors. DMFT is composed from two nanoconjugates: 1) bispecific engager, Fab’-MORF1 (anti-CD20 Fab’ fragment conjugated with morpholino oligonucleotide), and 2) a crosslinking (effector) component P-(MORF2)(X) (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple copies of complementary morpholino oligonucleotide). We evaluated this concept in 44 samples isolated from patients diagnosed with various subtypes of B cell malignancies. Apoptosis was observed in 65.9% of the samples tested. Pretreatment of cells with gemcitabine (GEM) or polymer-gemcitabine conjugate (2P-GEM) enhanced CD20 expression levels thus increasing apoptosis induced by DFMT. These positive results demonstrated that DFMT has remarkable therapeutic potential in various subtypes of B cell malignancies.
- Published
- 2019
3. Combination treatment with immunogenic and anti-PD-L1 polymer-drug conjugates of advanced tumors in a transgenic MMTV-PyMT mouse model of breast cancer
- Author
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Lian Li, D. Christopher Radford, Jindřich Kopeček, Jiyuan Yang, and Jiawei Wang
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Polymers ,medicine.medical_treatment ,Pharmaceutical Science ,Breast Neoplasms ,Mice, Transgenic ,02 engineering and technology ,B7-H1 Antigen ,03 medical and health sciences ,Mice ,Immune system ,Cancer immunotherapy ,PD-L1 ,medicine ,Tumor Microenvironment ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Cancer ,Immunotherapy ,021001 nanoscience & nanotechnology ,medicine.disease ,Immune checkpoint ,Pharmaceutical Preparations ,Cancer cell ,biology.protein ,Cancer research ,Immunogenic cell death ,Female ,0210 nano-technology ,business - Abstract
Immune checkpoint blockade has revolutionized the treatment of tumors with immunogenic microenvironments. However, low response rate and acquired resistance are still major challenges. Herein we used a more clinically relevant model of transgenic MMTV-PyMT tumor that more closely mimics the development of human breast cancer in an immunocompetent background to investigate a polymer-based chemo-immunotherapy. We have found that tumors acquired an increased degree of immune suppression during progression, rendering them unresponsive to anti-PD-L1 therapy. To treat large tumors at their advanced stage, we applied a combination strategy consisting of two polymer-drug conjugates that could induce immunogenic cell death (ICD) and disrupt the PD-L1/PD-1 interaction, respectively. Although ICD-inducing conjugate remodeled tumor immune microenvironment by facilitating significant CD8+ T cell infiltration, advanced tumor adapted the immune suppressive mechanism of elevating PD-L1 expression on both cancer cells and myeloid cells thereafter to enable continued tumor growth. Concurrent treatment of PD-L1 blocking conjugate not only abrogated the PD-L1 expression from the two disparate cellular sources, but also considerably reduced the number of immunosuppressive myeloid cells, thereby leading to a significant shrinkage of advanced tumors. Our data provide evidence that combinatory strategy of ICD-inducing and PD-L-blocking modalities could reverse immune suppression and establish a basis for the rational design of cancer immunotherapy.
- Published
- 2020
4. Broadening and Enhancing Functions of Antibodies by Self-Assembling Multimerization at Cell Surface
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Jindřich Kopeček, D. Christopher Radford, Jiyuan Yang, Lian Li, Yachao Li, and Jiawei Wang
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Morpholino ,Cell ,General Physics and Astronomy ,02 engineering and technology ,010402 general chemistry ,Antibodies, Monoclonal, Humanized ,01 natural sciences ,Morpholinos ,medicine ,Humans ,General Materials Science ,Receptor ,Monoclonal antibody therapy ,Serum Albumin ,CD20 ,biology ,Oligonucleotide ,Chemistry ,General Engineering ,Antibodies, Monoclonal ,021001 nanoscience & nanotechnology ,Actins ,0104 chemical sciences ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Receptor clustering ,Antibody ,0210 nano-technology - Abstract
[Image: see text] Monoclonal antibody therapy has offered treatment benefits. Nonetheless, a lack of efficacy still exists, partially because monovalent binding of antibodies to specific receptors fails to translate into an active response. Here, we report a pretargeting–postassembly approach that exploits the selective Watson–Crick base pairing properties of oligonucleotides and multivalently tethers receptor-prebound antibodies to albumin at the cell surface. We demonstrate that this two-step self-assembling strategy allows sequential actions of receptor binding and clustering that broadens and strengthens the functions of antibodies. We show that anti-CD20 obinutuzumab (OBN) modified with one morpholino oligonucleotide (OBN-MORF1) maintains the feature of naked OBN antibody upon CD20 binding, and results in actin redistribution, homotypic adhesion, and lysosome-mediated cell death. Consecutive treatment with albumin grafted with multiple copies of a complementary morpholino oligonucleotide (HSA-(MORF2)(x)) hybridizes with surface-attached OBN-MORF1, manipulates CD20 clustering, and engages additional signals to induce calcium influx and caspase-related apoptosis. With the two types of different mechanisms collaborating in one system, the simple design exerted a notable survival extension of mice bearing disseminated B-cell lymphomas.
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- 2019
5. Human Serum Albumin-Based Drug-Free Macromolecular Therapeutics: Apoptosis Induction by Coiled-Coil-Mediated Cross-Linking of CD20 Antigens on Lymphoma B Cell Surface
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Jindřich Kopeček, Lian Li, Libin Zhang, Jiyuan Yang, Yixin Fang, and D. Christopher Radford
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0301 basic medicine ,Lymphoma, B-Cell ,Polymers and Plastics ,medicine.drug_class ,Bioengineering ,Apoptosis ,Serum Albumin, Human ,02 engineering and technology ,Monoclonal antibody ,Article ,Biomaterials ,03 medical and health sciences ,Immunoglobulin Fab Fragments ,Antigen ,Annexin ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,Materials Chemistry ,medicine ,Humans ,Immunologic Capping ,B cell ,Chemistry ,Colocalization ,021001 nanoscience & nanotechnology ,Molecular biology ,Raji cell ,030104 developmental biology ,medicine.anatomical_structure ,Terminal deoxynucleotidyl transferase ,0210 nano-technology ,Peptides ,Rituximab ,Biotechnology - Abstract
A therapeutic platform-drug-free macromolecular therapeutics (DFMT)-that induces apoptosis in B cells by cross-linking of CD20 receptors, without the need for low molecular weight cytotoxic drug, is developed. In this report, a DFMT system is synthesized and evaluated based on human serum albumin (HSA) and two complementary coiled-coil forming peptides, CCE and CCK. Fab' fragment of anti-CD20 monoclonal antibody rituximab is attached to CCE (Fab'-CCE); multiple grafts of CCK are conjugated to HSA (HSA-(CCK)7 ). The colocalization of both nanoconjugates at the surface of non-Hodgkin's lymphoma (NHL) Raji cells is demonstrated by confocal fluorescence microscopy. The colocalization leads to coiled-coil formation, CD20 cross-linking, and apoptosis induction. The apoptotic levels are evaluated by Annexin V, Caspase 3, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Selective surface binding of DFMT to CD20+ cells is validated in experiments on a coculture of CD20+ (Raji) and CD20-(DG-75) cells. It is found that DFMT can trigger calcium influx only in Raji cells, but not in DG-75 cells. A highly specific treatment for NHL and other B cell malignancies with considerable translational potential is presented by HSA-based DFMT system.
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- 2018
6. FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy
- Author
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Jindřich Kopeček, Rui Zhang, D. Christopher Radford, and Jiyuan Yang
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Stereochemistry ,Cell Survival ,Pharmaceutical Science ,Mice, Nude ,Article ,chemistry.chemical_compound ,Mice ,In vivo ,Cell Line, Tumor ,Side chain ,Fluorescence Resonance Energy Transfer ,Methacrylamide ,Animals ,Humans ,Epirubicin ,Fluorescent Dyes ,Ovarian Neoplasms ,Antibiotics, Antineoplastic ,Chemistry ,Chain transfer ,Carbocyanines ,Tumor Burden ,Förster resonance energy transfer ,Drug delivery ,Biophysics ,Methacrylates ,Female ,Linker ,Conjugate - Abstract
To develop a biodegradable polymeric drug delivery system for the treatment of ovarian cancer with the capacity for non-invasive fate monitoring, we designed and synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates. The polymer backbone was labeled with acceptor fluorophore Cy5, while donor fluorophores (Cy3 or EPI) were attached to HPMA copolymer side chains via an enzyme-cleavable GFLG linker. This design allows elucidating separately the fate of the drug and of the polymer backbone using fluorescence resonance energy transfer (FRET). The degradable diblock conjugate (2P-EPI) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization using a bifunctional chain transfer agent (Peptide2CTA). The pharmacokinetics (PK) and therapeutic effect of 2P-EPI (Mw ~100 kDa) were determined in mice bearing human ovarian carcinoma A2780 xenografts. Compared to 1st generation conjugate (P-EPI, Mw
- Published
- 2015
7. Rational design of 'heat seeking' drug loaded polypeptide nanoparticles that thermally target solid tumors
- Author
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Ashutosh Chilkoti, Sarah R. MacEwan, Mark W. Dewhirst, D. Christopher Radford, Jonathan R. McDaniel, Xinghai Li, and Chelsea D. Landon
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Hyperthermia ,Biodistribution ,Materials science ,Letter ,Nanoparticle ,Bioengineering ,Nanotechnology ,Antineoplastic Agents ,02 engineering and technology ,Conjugated system ,010402 general chemistry ,01 natural sciences ,Mice ,Drug Delivery Systems ,In vivo ,Cell Line, Tumor ,medicine ,Fluorescence microscope ,Animals ,Humans ,General Materials Science ,thermal targeting ,Mechanical Engineering ,Rational design ,Temperature ,General Chemistry ,Hyperthermia, Induced ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,hyperthermia ,0104 chemical sciences ,Elastin ,Elastin-like polypeptides ,thermosensitive ,Drug delivery ,Colonic Neoplasms ,drug delivery ,Biophysics ,Nanoparticles ,0210 nano-technology ,Peptides - Abstract
This paper demonstrates the first example of targeting a solid tumor that is externally heated to 42 °C by "heat seeking" drug-loaded polypeptide nanoparticles. These nanoparticles consist of a thermally responsive elastin-like polypeptide (ELP) conjugated to multiple copies of a hydrophobic cancer drug. To rationally design drug-loaded nanoparticles that exhibit thermal responsiveness in the narrow temperature range between 37 and 42 °C, an analytical model was developed that relates ELP composition and chain length to the nanoparticle phase transition temperature. Suitable candidates were designed based on the predictions of the model and tested in vivo by intravital confocal fluorescence microscopy of solid tumors, which revealed that the nanoparticles aggregate in the vasculature of tumors heated to 42 °C and that the aggregation is reversible as the temperature reverts to 37 °C. Biodistribution studies showed that the most effective strategy to target the nanoparticles to tumors is to thermally cycle the tumors between 37 and 42 °C. These nanoparticles set the stage for the targeted delivery of a range of cancer chemotherapeutics by externally applied mild hyperthermia of solid tumors.
- Published
- 2014
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