New strategy of diagnostic imaging probes prior to administrating molecular target drugs
| Project/Area Number |
20K16722
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 52040:Radiological sciences-related
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
Effendi Nurmaya 金沢大学, 新学術創成研究機構, 研究協力員 (60842911)
|
|---|
| Project Period (FY) |
2021-11-01 – 2023-03-31
|
| Project Status |
Completed (Fiscal Year 2022)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
|---|
| Keywords | Imaging / Osimertinib / Peptide / EGFR / PDGFRb / TKI / NSCLC / peptide-drug-conjugates / cathepsin B / imaging / Nuclear Medicine / Antibody |
|---|
| Outline of Research at the Start |
Here, radioiodinated and radiobrominated Osimertinib-antibody conjugates will be prepared. After conjugation, radiolabeled Osimertinib-antibody be purified and evaluated their binding affinity toward molecular target and their activity as EGFR imaging agent in vitro and in vivo.
|
| Outline of Final Research Achievements |
Tyrosine kinase receptors (TKRs) are transmembrane proteins consisting of the extracellular domain for ligand binding and the intracellular part for signaling. PDGFRβ and EGFR are the subfamilies of RTKs. Seven radiotracers, 67Ga-DOTA-linker-IPLPPPRRPFFK peptides, were synthesized. Their feasibility as PDGFRb imaging agents were evaluated in vitro and in vivo. [67Ga]Ga-DOTA-EG2-IPLPPPRRPFFK and [67Ga]Ga-DOTA-EG4-IPLPPPRRPFFK showed promising result than others. Two radiohalogenated Osimertinib, 125I-Osimertinib & 77Br-Osimertinib, were synthesized. Their feasibilities as imaging agents of NSCLC with L858R/T790M mutation were evaluated in vitro and in vivo. Their accumulation in tumor was higher than in blood and muscle. Due to high lung uptake than tumor, the probe's structure needs to be modified. To visualize EFGR with mutation, a novel probe peptide-osimertinib-conjugated compound containing an enzyme-cleavable linker is currently being synthesized and evaluated.
|
| Academic Significance and Societal Importance of the Research Achievements |
Overexpression of PDGFRβ and EGFR as the subfamilies of TKRs associated with various human cancer. Imaging agents targeting PDGFRβ and mutated-EGFR can help determine their expression level via imaging to optimize and evaluate the effectiveness of treatment outcomes.
|
Report
(3 results)
Research Products
(2 results)
-
[Journal Article] Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib2022
Author(s)
Mishiro K, Nishii R, Sawazaki I, Sofuku T, Fuchigami T, Sudo H, Effendi N, Makino A, Kiyono Y, Shiba K, Taki J, Kinuya S, Ogawa K.
-
Journal Title
J Med Chem
Volume: 65
Issue: 3
Pages: 1835-1847
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
