The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696055 | PMC |
http://dx.doi.org/10.3390/pharmaceutics12111088 | DOI Listing |
Clin Cancer Res
December 2024
Université Laval, Quebec City, QC, Canada.
Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted alpha therapies. Antibody-drug conjugates (ADCs) are highly cytotoxic. Combining [225Ac]Ac with ADC to develop an antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, is expected to be more effective than its ADC (trastuzumab-PEG6-DM1) against breast cancer (BC).
View Article and Find Full Text PDFTheranostics
December 2024
Department of Nuclear Medicine, Inselspital, University of Bern, Bern, Switzerland.
Radiopharmaceutical therapy (RPT) is an emerging prostate cancer treatment that delivers radiation to specific molecules within the tumor microenvironment (TME), causing DNA damage and cell death. Given TME heterogeneity, it's crucial to explore RPT dosimetry and biological impacts at the cellular level. We integrated spatial transcriptomics (ST) with computational modeling to investigate the effects of RPT targeting prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAP), and gastrin-releasing peptide receptor (GRPR) each labelled with beta-emitting lutetium-177 (Lu) and alpha-emitting actinium-225 (Ac).
View Article and Find Full Text PDFNucl Med Biol
November 2024
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:
Background: Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach - leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) - can minimize off-target toxicity related to TAT, often associated with full-length antibodies.
View Article and Find Full Text PDFNucl Med Biol
November 2024
Joint Research Centre, European Commission, Karlsruhe, Germany.
Background: Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay via the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier.
View Article and Find Full Text PDFEur J Clin Invest
November 2024
Nuclear Medicine, Gruppo Ospedaliero Moncucco, Clinica Moncucco, Lugano, Switzerland.
Background: Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [Lu]Lu-prostate-specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium-225 (Ac), an alpha-emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!