Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors

Stephen Kennel, Lara L. Chappell, Kate Dadachova, Martin W. Brechbiel, Trish K. Lankford, Ila A. Davis, Michael Stabin, Saed Mirzadeh

Research output: Contribution to journalArticle

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Abstract

Several alpha particle emitting radioisotopes have been studied for use in radioimmunotherapy. Ac-225 has the potential advantages of a relatively long half life of 10 days, and a yield of 4 alpha emissions in its decay chain with a total energy release of ~28 MeV. A new, 12 coordination site chelating ligand, HEHA, has been chemically modified for coupling to targeting proteins without loss of chelating ability. HEHA was coupled with MAb 201B which binds to thrombomodulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BALB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistribution data at 1 and 4 h postinjection indicated that, as expected, 225Ac was delivered to lung efficiently (>300 % ID/g). The 225Ac was slowly released from the lung with an initial t(1/2) = 49 h, and the released 225Ac accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free 225Ac. In addition to the slow release of 225Ac from the chelate, data indicated that decay daughters of 225Ac were also released from the lung. Immediately after organ harvest, the level of 213Bi, the third alpha-decay daughter, was found to be deficient in the lungs and to be in excess in the kidney, relative to equilibrium values. Injected doses of 225Ac MAb 201B of 1.0 μCi, delivering a minimum calculated absorbed dose of about 6 Gy to the lungs, was effective in killing lung tumors, but also proved acutely radiotoxic. Animals treated with 1.0 μCi or more of the 225Ac radioconjugate died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for 225Ac as a radioimmunotherapeutic agent is compromised not only by the slow release of 225Ac from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotopes released from the target organ.

Original languageEnglish (US)
Pages (from-to)235-244
Number of pages10
JournalCancer Biotherapy and Radiopharmaceuticals
Volume15
Issue number3
DOIs
StatePublished - Jan 1 2000

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Radioimmunotherapy
Blood Vessels
Lung
Neoplasms
Radioisotopes
Alpha Particles
Wasting Syndrome
Thrombomodulin
Protein Transport
Chelating Agents
Half-Life
Breast Neoplasms
Ligands
Kidney
Injections
Liver

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology
  • Cancer Research

Cite this

Kennel, S., Chappell, L. L., Dadachova, K., Brechbiel, M. W., Lankford, T. K., Davis, I. A., ... Mirzadeh, S. (2000). Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors. Cancer Biotherapy and Radiopharmaceuticals, 15(3), 235-244. https://doi.org/10.1089/108497800414329

Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors. / Kennel, Stephen; Chappell, Lara L.; Dadachova, Kate; Brechbiel, Martin W.; Lankford, Trish K.; Davis, Ila A.; Stabin, Michael; Mirzadeh, Saed.

In: Cancer Biotherapy and Radiopharmaceuticals, Vol. 15, No. 3, 01.01.2000, p. 235-244.

Research output: Contribution to journalArticle

Kennel, S, Chappell, LL, Dadachova, K, Brechbiel, MW, Lankford, TK, Davis, IA, Stabin, M & Mirzadeh, S 2000, 'Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors', Cancer Biotherapy and Radiopharmaceuticals, vol. 15, no. 3, pp. 235-244. https://doi.org/10.1089/108497800414329
Kennel, Stephen ; Chappell, Lara L. ; Dadachova, Kate ; Brechbiel, Martin W. ; Lankford, Trish K. ; Davis, Ila A. ; Stabin, Michael ; Mirzadeh, Saed. / Evaluation of 225Ac for vascular targeted radioimmunotherapy of lung tumors. In: Cancer Biotherapy and Radiopharmaceuticals. 2000 ; Vol. 15, No. 3. pp. 235-244.
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