Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Drug-Free Macromolecular Therapeutics--A New Paradigm in Polymeric Nanomedicines.

ABSTRACT: 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.

SUBMITTER: Chu TW

PROVIDER: S-EPMC4505834 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Drug-Free Macromolecular Therapeutics--A New Paradigm in Polymeric Nanomedicines.

Chu Te-Wei TW Kopeček Jindřich J

Biomaterials science 20150701 7

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 receptor ...[more]

PMID: 26191406

Similar Datasets

Immunogenicity of coiled-coil based drug-free macromolecular therapeutics.

Project description:A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (L- and D-CCE and L- and D-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of D-peptides and conjugates of L-peptides to induce Ab response.

| S-EPMC4019077 | biostudies-literature

Exploration and Evaluation of Therapeutic Efficacy of Drug-Free Macromolecular Therapeutics in Collagen-Induced Rheumatoid Arthritis Mouse Model.

Project description:Monoclonal antibodies (mAbs) against B cell antigens are extensively used in the treatment of rheumatoid arthritis (RA). The B cell depletion therapy prevents RA symptoms and/or alleviates existing inflammation. The previously established two-step drug-free macromolecular therapeutics (DFMT) is applied in the treatment of collagen-induced rheumatoid arthritis in a collagen-induced rheumatoid arthritis mouse model. DFMT is a B cell depletion strategy utilizing Fab' fragment of anti-CD20 mAb for biorecognition and receptor crosslinking to induce B cell apoptosis. DFMT is composed from two nanoconjugates: 1) bispecific engager, Fab'-MORF1 (anti-CD20 Fab' fragment conjugated with morpholino oligonucleotide MORF1), and 2) a crosslinking (effector) component P-(MORF2)X (N-(2-hydroxypropyl)methacrylamide copolymer grafted with multiple copies of complementary morpholino oligonucleotide MORF2). The absence of Fc fragment has the potential to avoid development of resistance and infusion-related reactions. DFMT produces B cell depletion, keeps the RA score low for more than 100 days, and shows minimal cartilage and bone erosion and inflammatory cell infiltration. Further improvements will be explored to optimize DFMT strategy in autoimmune disease treatment.

| S-EPMC7549750 | biostudies-literature

Allogeneic cell therapy: a new paradigm in therapeutics.

Project description: Not available

| S-EPMC4411634 | biostudies-literature

Amplification of CD20 Cross-Linking in Rituximab-Resistant B-Lymphoma Cells Enhances Apoptosis Induction by Drug-Free Macromolecular Therapeutics.

Project description:Although the CD20-targeted monoclonal antibody rituximab (RTX) has revolutionized the therapeutic landscape for B-cell malignancy, relapsed and refractory disease due to RTX resistance continue to constitute major challenges, illustrating the need for better therapies. Here, we apply drug-free macromolecular therapeutics (DFMT) that amplifies CD20 cross-linking to enhance apoptosis in RTX-resistant cells. Bispecific engager (anti-CD20 Fab' conjugated with oligonucleotide1) pretargets CD20 and the deletion of Fc-region minimizes its premature endocytosis in resistant cells that rapidly internalize and consume CD20/RTX complexes. Second-step delivery of multivalent polymeric effector (linear copolymer conjugated with multiple copies of complementary oligonucleotide 2) simultaneously hybridizes multiple CD20-bound engagers and strengthens CD20 ligation. Moreover, the restoration of CD20 expression by the pretreatment of cells with a polymer-gemcitabine conjugate, a CD20 expression enhancer, unleashes the full potential of DFMT in the CD20-deficient resistant cells. Hence, amplification of CD20 cross-linking is achieved by (1) the enhancement of surface CD20 accessibility, (2) the increase in CD20 expression, and (3) multimeric CD20 binding, which ultimately translates into the amplified activation of a wide range of innate apoptotic responses. We demonstrated that the altered molecular signaling pathway that originally results in RTX resistance could be circumvented and compensated by other DFMT-augmented pathways. Of note, our preliminary data provide proof-of-concept that CD20 cross-linking amplification emerges as an important strategy for overcoming RTX resistance.

| S-EPMC5916500 | biostudies-literature

Polymeric nanomedicines for the treatment of hepatic diseases.

Project description:The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.

| S-EPMC9675156 | biostudies-literature

Accelerating Therapeutics for Opportunities in Medicine: A Paradigm Shift in Drug Discovery.

Project description:Conventional drug discovery is long and costly, and suffers from high attrition rates, often leaving patients with limited or expensive treatment options. Recognizing the overwhelming need to accelerate this process and increase success, the ATOM consortium was formed by government, industry, and academic partners in October 2017. ATOM applies a team science and open-source approach to foster a paradigm shift in drug discovery. ATOM is developing and validating a precompetitive, preclinical, small molecule drug discovery platform that simultaneously optimizes pharmacokinetics, toxicity, protein-ligand interactions, systems-level models, molecular design, and novel compound generation. To achieve this, the ATOM Modeling Pipeline (AMPL) has been developed to enable advanced and emerging machine learning (ML) approaches to build models from diverse historical drug discovery data. This modular pipeline has been designed to couple with a generative algorithm that optimizes multiple parameters necessary for drug discovery. ATOM's approach is to consider the full pharmacology and therapeutic window of the drug concurrently, through computationally-driven design, thereby reducing the number of molecules that are selected for experimental validation. Here, we discuss the role of collaborative efforts such as consortia and public-private partnerships in accelerating cross disciplinary innovation and the development of open-source tools for drug discovery.

| S-EPMC7339658 | biostudies-literature

A new paradigm for macromolecular crystallography beamlines derived from high-pressure methodology and results.

Project description:Biological structures can now be investigated at high resolution by high-pressure X-ray macromolecular crystallography (HPMX). The number of HPMX studies is growing, with applications to polynucleotides, monomeric and multimeric proteins, complex assemblies and even a virus capsid. Investigations of the effects of pressure perturbation have encompassed elastic compression of the native state, study of proteins from extremophiles and trapping of higher-energy conformers that are often of biological interest; measurements of the compressibility of crystals and macromolecules were also performed. HPMX results were an incentive to investigate short and ultra-short wavelengths for standard biocrystallography. On cryocooled lysozyme crystals it was found that the data collection efficiency using 33 keV photons is increased with respect to 18 keV photons. This conclusion was extended from 33 keV down to 6.5 keV by exploiting previously published data. To be fully exploited, the potential of higher-energy photons requires detectors with a good efficiency. Accordingly, a new paradigm for MX beamlines was suggested, using conventional short and ultra-short wavelengths, aiming at the collection of very high accuracy data on crystals under standard conditions or under high pressure. The main elements of such beamlines are outlined.

| S-EPMC3004250 | biostudies-literature

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy.

Project description:Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio- and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and gamma-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.

| S-EPMC2538765 | biostudies-literature

Human Serum Albumin-Based Drug-Free Macromolecular Therapeutics: Apoptosis Induction by Coiled-Coil-Mediated Cross-Linking of CD20 Antigens on Lymphoma B Cell Surface.

Project description: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.

| S-EPMC6392022 | biostudies-literature

Microbial therapeutics: New opportunities for drug delivery.

Project description:With >40 clinical trials underway, we are nearing the first FDA-approved live microbial therapeutic. Here, Giovanni Traverso, MIT and Harvard Medical School Assistant Professor, and colleagues Miguel Jimenez and Institute Professor Robert Langer from MIT discuss the significant challenges of administering live microorganisms to patients and the opportunities for drug delivery of these new complex therapeutics.

| S-EPMC6504217 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data