Preclinical evaluation of investigational radiopharmaceutical RISAD-pintended for use as a diagnostic and molecular radiotherapy agent for prostate cancer

Zbigniew P. Kortylewicz, Elizabeth Mack, Charles Arthur Enke, Katherine A. Estes, R Lee Mosley, Janina Baranowska-Kortylewicz

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-30′-O- (17b-succinyl-5a-androstan-3-one)-20-deoxyuridin-50-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.

METHODS. Effects of nonradioactive ISAD-P and RISAD-P labeled with 123I, 124I, and 125I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.

RESULTS. RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for 18F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after 125IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1, 240 Gy × MBq-1 × g-1 for 125I-, 123I-, and 124I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.

CONCLUSIONS. Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)8-22
Number of pages15
JournalProstate
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2015

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Radiopharmaceuticals
Molecular Pathology
Androgen Receptors
Prostatic Neoplasms
Radiotherapy
Neoplasms
Radiometry
Potassium Iodide
Dihydrotestosterone
Poisons
Tissue Distribution
Radioisotopes
Radioactivity
Transgenic Mice
Prostate
Stomach
Thyroid Gland
Pharmacokinetics
Phosphates
Electrons

Keywords

  • Androgen receptor
  • Auger electrons
  • Molecular radiotherapy
  • Prostate cancer
  • Theranostic

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Preclinical evaluation of investigational radiopharmaceutical RISAD-pintended for use as a diagnostic and molecular radiotherapy agent for prostate cancer. / Kortylewicz, Zbigniew P.; Mack, Elizabeth; Enke, Charles Arthur; Estes, Katherine A.; Mosley, R Lee; Baranowska-Kortylewicz, Janina.

In: Prostate, Vol. 75, No. 1, 01.01.2015, p. 8-22.

Research output: Contribution to journalArticle

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title = "Preclinical evaluation of investigational radiopharmaceutical RISAD-pintended for use as a diagnostic and molecular radiotherapy agent for prostate cancer",
abstract = "BACKGROUND. The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-30′-O- (17b-succinyl-5a-androstan-3-one)-20-deoxyuridin-50-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.METHODS. Effects of nonradioactive ISAD-P and RISAD-P labeled with 123I, 124I, and 125I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.RESULTS. RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for 18F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after 125IRISAD-P administration, nearly 10{\%} of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1, 240 Gy × MBq-1 × g-1 for 125I-, 123I-, and 124I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.CONCLUSIONS. Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.",
keywords = "Androgen receptor, Auger electrons, Molecular radiotherapy, Prostate cancer, Theranostic",
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T1 - Preclinical evaluation of investigational radiopharmaceutical RISAD-pintended for use as a diagnostic and molecular radiotherapy agent for prostate cancer

AU - Kortylewicz, Zbigniew P.

AU - Mack, Elizabeth

AU - Enke, Charles Arthur

AU - Estes, Katherine A.

AU - Mosley, R Lee

AU - Baranowska-Kortylewicz, Janina

PY - 2015/1/1

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N2 - BACKGROUND. The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-30′-O- (17b-succinyl-5a-androstan-3-one)-20-deoxyuridin-50-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.METHODS. Effects of nonradioactive ISAD-P and RISAD-P labeled with 123I, 124I, and 125I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.RESULTS. RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for 18F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after 125IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1, 240 Gy × MBq-1 × g-1 for 125I-, 123I-, and 124I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.CONCLUSIONS. Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.

AB - BACKGROUND. The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-30′-O- (17b-succinyl-5a-androstan-3-one)-20-deoxyuridin-50-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.METHODS. Effects of nonradioactive ISAD-P and RISAD-P labeled with 123I, 124I, and 125I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.RESULTS. RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for 18F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after 125IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1, 240 Gy × MBq-1 × g-1 for 125I-, 123I-, and 124I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.CONCLUSIONS. Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.

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KW - Auger electrons

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KW - Prostate cancer

KW - Theranostic

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