Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Efficient bifunctional decadentate ligand 3p-C-DEPA for targeted ?-radioimmunotherapy applications.

ABSTRACT: A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted ?-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding (205/6)Bi, and the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of (205/6)Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. (205/6)Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of (212)Bi and (213)Bi.

SUBMITTER: Song HA

PROVIDER: S-EPMC3133935 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Efficient bifunctional decadentate ligand 3p-C-DEPA for targeted α-radioimmunotherapy applications.

Song Hyun A HA Kang Chi Soo CS Baidoo Kwamena E KE Milenic Diane E DE Chen Yunwei Y Dai Anzhi A Brechbiel M W MW Chong Hyun-Soon HS

Bioconjugate chemistry 20110523 6

A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted α-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding (205/6)Bi, and the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of (205/6)Bi-3p ...[more]

PMID: 21604692

Similar Datasets

Convenient Synthesis and Evaluation of Heptadentate Bifunctional Ligand for Radioimmunotherapy Applications.

Project description:An efficient synthetic route to a bifunctional chelating agent C-NE3TA-NCS for antibody-targeted radioimmunotherapy (RIT) applications was developed. Various synthetic methods centered on the key reaction steps including bimolecular cyclization, ring opening reactions of aziridine and aziridinium cations, and reductive aminiation were explored to optimize the preparation of a tetraaza-based chelate TANPA and C-NE3TA analogues. Heptadentate C-NE3TA-NCS was conjugated to a tumor targeting antibody and compared to hexadentate C-NOTA-NCS for radiolabeling reaction kinetics with lanthanides for RIT. C-NE3TA-antibody conjugate displayed significantly enhanced complexation kinetics with 90Y as compared to C-NOTA-antibody conjugate. The synthetic methods for TANPA and C-NE3TA-NCS reported herein have broad applications for preparation of bifunctioanl macrocyclic chelating agents.

| S-EPMC3686137 | biostudies-literature

Preclinical evaluation of NETA-based bifunctional ligand for radioimmunotherapy applications using 212Bi and 213Bi: radiolabeling, serum stability, and biodistribution and tumor uptake studies.

Project description:Despite the great potential of targeted ?-radioimmunotherapy (RIT) as demonstrated by pre-clinical and clinical trials, limited progress has been made on the improvement of chelation chemistry for (212)Bi and (213)Bi. A new bifunctional ligand 3p-C-NETA was evaluated for targeted ? RIT using (212)Bi and (213)Bi.Radiolabeling of 3p-C-NETA with (205/6)Bi, a surrogate of (212)Bi and (213)Bi, was evaluated at pH5.5 and room temperature. In vitro stability of the (205/6)Bi-3p-C-NETA-trastuzumab conjugate was evaluated using human serum (pH7, 37 °C). Immunoreactivity and specific activity of the (205/6)Bi-3p-C-NETA-trastuzumab conjugate were measured. An in vivo biodistribution study was performed to evaluate the in vivo stability and tumor targeting properties of the (205/6)Bi-3p-C-NETA-trastuzumab conjugate in athymic mice bearing subcutaneous LS174T tumor xenografts.The 3p-C-NETA-trastuzumab conjugate was extremely rapid in complexing with (205/6)Bi, and the corresponding (205/6)Bi-3p-C-NETA-trastuzumab was stable in human serum. (205/6)Bi-3p-C-NETA-trastuzumab was prepared with a high specific activity and retained immunoreactivity. (205/6)Bi-3p-C-NETA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low normal organ and high tumor uptake.The results of the in vitro and in vivo studies indicate that 3p-C-NETA is a promising chelator for RIT applications using (212)Bi and (213)Bi. Further detailed in vivo evaluations of 3p-C-NETA for targeted ? RIT are warranted.

| S-EPMC3665654 | biostudies-literature

Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer.

Project description:Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (177Lu)-labeled DLL3-targeting antibody SC16 (177Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177Lu to produce 177Lu-DTPA-SC16. Specificity and selectivity of 177Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of 177Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, 177Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that 177Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.

| S-EPMC9271187 | biostudies-literature

Preparation of a versatile bifunctional zeolite for targeted imaging applications.

Project description:Bifunctional zeolite Y was prepared for use in targeted in vivo molecular imaging applications. The strategy involved functionalization of the external surface of zeolite Y with chloropropyltriethoxysilane followed by reaction with sodium azide to form azide-functionalized NaY, which is amenable to copper(1)-catalyzed click chemistry. In this study, a model alkyne (4-pentyn-1-ol) was attached to the azide-terminated surface via click chemistry to demonstrate feasibility for attachment of molecular targeting vectors (e.g., peptides, aptamers) to the zeolite surface. The modified particle efficiently incorporates the imaging radioisotope gallium-68 ((68)Ga) into the pores of the azide-functionalized NaY zeolite to form a stable bifunctional molecular targeting vector. The result is a versatile "clickable" zeolite platform that can be tailored for future in vivo molecular targeting and imaging modalities.

| S-EPMC3112301 | biostudies-literature

Bifunctional Ligand Enables Efficient Gold-Catalyzed Hydroalkenylation of Propargylic Alcohol.

Project description:Using the previously designed biphenyl-2-ylphosphine ligand, featuring a remote tertiary amino group, the first gold-catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general-base catalyst for promoting this novel gold catalysis with good efficiency.

| S-EPMC6592274 | biostudies-literature

Synthesis and preclinical evaluation of bifunctional ligands for improved chelation chemistry of 90Y and 177Lu for targeted radioimmunotherapy.

Project description:We report a practical and high-yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, and 3p-C-DEPA for radiolabeling kinetics with (90)Y and (177)Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with (90)Y and (177)Lu. (90)Y-3p-C-NETA-trastuzumab and (177)Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of (177)Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. (177)Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using (90)Y and (177)Lu and has the potential to replace DOTA and DTPA analogues in current clinical use.

| S-EPMC3447103 | biostudies-literature

GD2-targeted immunotherapy and radioimmunotherapy.

Project description:Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions.

| S-EPMC4254523 | biostudies-literature

Mitochondria Targeted Protein-Ruthenium Photosensitizer for Efficient Photodynamic Applications.

Project description:Organelle-targeted photosensitization represents a promising approach in photodynamic therapy where the design of the active photosensitizer (PS) is very crucial. In this work, we developed a macromolecular PS with multiple copies of mitochondria-targeting groups and ruthenium complexes that displays highest phototoxicity toward several cancerous cell lines. In particular, enhanced anticancer activity was demonstrated in acute myeloid leukemia cell lines, where significant impairment of proliferation and clonogenicity occurs. Finally, attractive two-photon absorbing properties further underlined the great significance of this PS for mitochondria targeted PDT applications in deep tissue cancer therapy.

| S-EPMC5588099 | biostudies-literature

B7-H3-targeted Radioimmunotherapy of Human Cancer.

Project description:BackgroundTargeted Radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tissues is limited, presenting B7-H3 as a candidate target for RIT. This review provides an overview of the general principles of targeted RIT and discusses publications that have used radiolabeled B7-H3-targeted antibodies for RIT of cancer in preclinical or clinical studies.MethodsDatabases including PubMed, Scopus, and Google Scholar were searched for publications through June 2018 using a combination of terms including "B7-H3", "radioimmunotherapy", "targeted", "radiotherapy", and "cancer". After screening search results for relevancy, ten publications were included for discussion.ResultsB7-H3-targeted RIT studies to date range from antibody development and assessment of novel Radioimmunoconjugates (RICs) in animal models of human cancer to phase II/III trials in humans. The majority of clinical studies have used B7-H3-targeted RICs for intra- compartment RIT of central nervous system malignancies. The results of these studies have indicated high tolerability and favorable efficacy outcomes, supporting further assessment of B7-H3-targeted RIT in larger trials. Preclinical B7-H3-targeted RIT studies have also shown encouraging therapeutic outcomes in a variety of solid malignancies.ConclusionB7-H3-targeted RIT studies over the last 15 years have demonstrated feasibility for clinical development and support future assessment in a broader array of human malignancies. Future directions worthy of exploration include strategies that combine B7-H3- targeted RIT with chemotherapy or immunotherapy.

| S-EPMC8668195 | biostudies-literature

Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria.

Project description:Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P1-9R) including a TFR1-targeting peptide coupled to a nine-arginine cell-penetrating peptide (CPP) that facilitates the release of the AON from TFR1 in endosomal vesicles. We demonstrated that the P1-9R/V1 nanocomplex promotes the efficient and prolonged redirection of splicing towards the physiological splice site and subsequent normalization of WT FECH mRNA and protein levels. Finally, the P1-9R/V1 nanocomplex increases WT FECH mRNA production and significantly decreases PPIX accumulation in primary cultures of differentiating erythroid progenitors from an overt EPP-affected individual. P1-9R is a method designed to target erythroid progenitors and represents a potentially powerful tool for the in vivo delivery of therapeutic DNA in many erythroid disorders.

| S-EPMC6369449 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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