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At least 19 recordsLinked to original sources

PubMed2002

Actinium-225 conjugates of MAb CC49 and humanized delta CH2CC49.

Radioisotopes with moderate half-lives are essential for conventional radioimmunotherapy using tumor-selective MAbs which require days for localization. Actinium-225, with a half-life of 10 days and a yield of 4 alpha particles in its decay chain, may be an ideal choice for tumor-targeted radioimmunotherapy. Release of daughter radioisotopes from the primary chelator after the first decay has been a complication with the use of 225Ac. It has been reported that the domain-deleted product of MAb CC49, Hu-delta CH2 CC49, is able to extravasate and penetrate more deeply into tumors than the parent IgG molecule. We reasoned that once the 225Ac-chelate-MAb had penetrated into the tumor, the daughter radioisotopes would remain trapped even if they had been released from the primary chelator. Actinium-225 HEHA MAb CC49 conjugates were tested for distribution, micro-distribution and therapy in immunocompromised mice which had LS174T tumors growing at subcutaneous or intramuscular sites. Both 125I and 225Ac CC49 and Hu-delta CH2 CC49 were efficient in delivery of the radioisotopes to tumor sites. Tissue micro-autoradiography for the two antibody forms did not demonstrate any differences in micro-distribution of either 125I or 225Ac in the tumor. Furthermore, there was no detectable difference for the two carriers in the tumor retention of daughter radioisotopes from 225Ac. Therapy experiments with 225Ac were complicated by radiotoxicity of the conjugates. The lethal dose was about 0.5 microCi in two strains of mice regardless of the carrier. At injected doses of 0.5 and 0.25 microCi, CC49 was slightly active in tumor stasis, whereas no consistent significant effect of 225Ac-Hu-delta CH2 CC49 on growth of tumors was observed. The potential of 225Ac in radioimmunotherapy is limited by the radiotoxicity of its daughter radioisotopes. Its potential will only be realized if stable conjugates, capable of daughter radioisotope retention, can be devised.

Actinium↗

PubMed2005

Vertical distribution, migration rates, and model comparison of actinium in a semi-arid environment.

Vertical soil characterization and migration of radionuclides were investigated at four radioactively contaminated sites on Kirtland Air Force Base (KAFB), New Mexico to determine the vertical downward migration of radionuclides in a semi-arid environment. The surface soils (0-15 cm) were intentionally contaminated with Brazilian sludge (containing (232)Thorium and other radionuclides) approximately 40 years ago, in order to simulate the conditions resulting from a nuclear weapons accident. Site grading consisted of manually raking or machine disking the sludge. The majority of the radioactivity was found in the top 15 cm of soil, with retention ranging from 69 to 88%. Two models, a compartment diffusion model and leach rate model, were evaluated to determine their capabilities and limitations in predicting radionuclide behavior. The migration rates of actinium were calculated with the diffusion compartment and the leach rate models for all sites, and ranged from 0.009 to 0.1 cm/yr increasing with depth. The migration rates calculated with the leach rate models were similar to those using the diffusion compartment model and did not increase with depth (0.045-0.076, 0.0 cm/yr). The research found that the physical and chemical properties governing transport processes of water and solutes in soil provide a valid radionuclide transport model. The evaluation also showed that the physical model has fewer limitations and may be more applicable to this environment.

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PubMed2004

Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides.

The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.

Actinium↗

PubMedDate not supplied

Influence of the linker on the biodistribution and catabolism of actinium-225 self-immolative tumor-targeted isotope generators.

Current limitations to applications of monoclonal antibody (mAb) targeted isotope generators in radioimmunotherapy include the low mAb labeling yields and the nonspecific radiation of normal tissues by nontargeted radioimmunoconjugates (RIC). Radiotoxicity occurs in normal organs that metabolize radiolabeled proteins and peptides, primarily liver and kidneys, or in radiosensitive organs with prolonged exposure to the isotope from the blood, such as the bone marrow. Actinium-225 nanogenerators also have the problem of released agar-emitting daughters. We developed two new bifunctional chelating agents (BCA) in order to address these issues. Thiol-maleimide conjugation chemistry was employed to increase the efficiency of the mAb radiolabelings by up to 8-fold. In addition, one bifunctional chelating agent incorporated a cleavable linker to alter the catabolism of the alpha-particle-emitting mAb conjugate. This linker was designed to be sensitive to cathepsins to allow release and clearance of the chelated radiometal after internalization of the radioimmunoconjugate into the cell. We compared the properties of the cleavable conjugate (mAb-DOTA-G3FC) to noncleavable constructs (mAb-DOTA-NCS and mAb-DOTA-SH). The cleavable RIC was able to release 80% of its radioactive payload when incubated with purified cathepsin B. The catabolism of the constructs mAb-DOTA-G3FC and mAb-DOTA-NCS was investigated in vitro and in vivo. RIC integrity was retained at 85% over a period of 136 h in mouse serum in vivo. Both conjugates were degraded over time inside HL-60 cells after internalization and in mouse liver in vivo. While we found that the rates of degradation of the two RICs in those conditions were similar, the amounts of the radiolabeled product residues were different. The cleavable mAb-DOTA-G3FC conjugate yielded a larger proportion of fragments below 6kDa in size in mouse liver in vivo after 12 h than the DOTA-NCS conjugate. Biodistribution studies in mice showed that the mAb-DOTA-G3FC construct yielded a higher liver dose and prolonged liver retention of radioactivity compared to the mAb-DOTA-NCS conjugate. The accumulation in the liver seemed to be in part caused by the maleimide functionalization of the antibody, since the noncleavable mAb-DOTA-SH maleimide-functionalized control conjugate displayed the same biodistribution pattern. These results provide an insight into the catabolism of RICs, by demonstrating that the release of the radioisotope from a RIC is not a sufficient condition to allow the radioactive moiety to clear from the body. The excretion mechanisms of radiolabeled fragments seem to constitute a major limiting step in the chain of events leading to their clearance.

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PubMed1999

Improved in vivo stability of actinium-225 macrocyclic complexes.

The favorable nuclear properties of actinium-225 ((225)Ac) have led to proposal of this isotope for use in radioimmunotherapy. In an effort to reduce the toxicity of free (225)Ac, a series of ligands were evaluated for stability in vivo. Loss of (225)Ac from acyclic chelating agents resulted in high liver uptake and poor whole body clearance. The macrocyclic ligands c-DOTA, PEPA, and HEHA were evaluated, and (225)Ac-HEHA showed exceptional stability in vivo. (225)Ac chelated with EDTA, DTPA, DOTA, or PEPA permitted substantial accumulation of the radionuclide to the liver, while the (225)Ac-HEHA complex was essentially excreted within minutes of administration. The preparation of the ligands and radiolabeled complexes and the biodistribution results will be discussed.

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PubMed2004

Alpha-particle emitting atomic generator (Actinium-225)-labeled trastuzumab (herceptin) targeting of breast cancer spheroids: efficacy versus HER2/neu expression.

PURPOSE: The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the alpha-particle emitting atomic generator, actinium-225 ((225)Ac), against breast cancer spheroids with different HER2/neu expression levels. (225)Ac has a 10-day half-life and a decay scheme yielding four alpha-particles. EXPERIMENTAL DESIGN: The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of (225)Ac-trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period. RESULTS: The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20-30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30-40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR(37). An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After alpha-particle irradiation a DVR(37) of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively. CONCLUSION: These studies suggest that (225)Ac-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.

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PubMed2005

Renal tubulointerstitial changes after internal irradiation with alpha-particle-emitting actinium daughters.

The effect of external gamma irradiation on the kidneys is well described. However, the mechanisms of radiation nephropathy as a consequence of targeted radionuclide therapies are poorly understood. The functional and morphologic changes were studied chronologically (from 10 to 40 wk) in mouse kidneys after injection with an actinium-225 (225Ac) nanogenerator, a molecular-sized, antibody-targeted, in vivo generator of alpha-particle-emitting elements. Renal irradiation from free, radioactive daughters of 225Ac led to time-dependent reduction in renal function manifesting as increase in blood urea nitrogen. The histopathologic changes corresponded with the decline in renal function. Glomerular, tubular, and endothelial cell nuclear pleomorphism and focal tubular cell injury, lysis, and karyorrhexis were observed as early as 10 wk. Progressive thinning of the cortex as a result of widespread tubulolysis, collapsed tubules, glomerular crowding, decrease in glomerular cellularity, interstitial inflammation, and an elevated juxtaglomerular cell count were noted at 20 to 30 wk after treatment. By 35 to 40 wk, regeneration of simplified tubules with tubular atrophy and loss with focal, mild interstitial fibrosis had occurred. A lower juxtaglomerular cell count with focal cytoplasmic vacuolization, suggesting increased degranulation, was also observed in this period. A focal increase in tubular and interstitial cell TGF-beta1 expression starting at 20 wk, peaking at 25 wk, and later declining in intensity with mild increase in the extracellular matrix deposition was noticed. These findings suggest that internally delivered alpha-particle irradiation-induced loss of tubular epithelial cells triggers a chain of adaptive changes that result in progressive renal parenchymal damage accompanied by a loss of renal function. These findings are dissimilar to those seen after gamma or beta irradiation of kidneys.

Actinium↗

PubMed2003

Targeted actinium-225 in vivo generators for therapy of ovarian cancer.

Advanced ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p. radioimmunotherapy in a mouse model of human ovarian cancer. Use of a targeted actinium-225 ((225)Ac) in vivo generator of alpha particles exploits the extreme, selective cytotoxicity of alpha particles, while providing a feasible half-life to enable delivery to tumor. (225)Ac chelated with 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid was conjugated to trastuzumab, an anti-HER-2/neu antibody. The radioimmunoconjugate was tested for immunoreactivity, internalization, and cytotoxicity using a human ovarian carcinoma cell line, SKOV3. (225)Ac-labeled trastuzumab retained immunoreactivity (50-90%), rapidly internalized into cells (50% at 2 h), and had an ED(50) of 1.3 nCi/ml after 4 days of incubation in vitro. i.p. administered (225)Ac- or (111)In-labeled trastuzumab behaved similarly with high tumor uptake [56-60% injected dose per gram (% ID/g) at 4 h, which increased to 65-70% ID/g at 24 h]. Tumor uptake was 3-5-fold higher than liver and spleen, the normal organs with the highest uptake. i.v. administration of (111)In-labeled trastuzumab produced slightly higher normal organ uptake compared with i.p.-administered (111)In-labeled trastuzumab. However, tumor uptake was low, 5%-26% ID/g. Therapy was examined with native trastuzumab and 220, 330, and 450 nCi of (225)Ac-labeled trastuzumab or (225)Ac-labeled control antibody at different dosing schedules. Therapy was initiated 9 days after tumor seeding. Groups of control mice and those administered native trastuzumab had median survivals of 33 and 37 or 44 days, respectively. Median survival was 52-126 days with (225)Ac-labeled trastuzumab at various doses and schedules, and 48-64 days for (225)Ac-labeled control the same schedules. Deaths from toxicity occurred with the highest activity levels. In conclusion, i.p. administration with a (225)Ac-labeled internalizing anti-HER-2/neu antibody can extend survival significantly in a nude mouse model of human ovarian cancer at levels that produce no apparent gross toxicity.

Actinium↗

PubMedDate not supplied

Thorium and actinium polyphosphonate compounds as bone-seeking alpha particle-emitting agents.

The present study explores the use of alpha-particle-emitting, bone-seeking agents as candidates for targeted radiotherapy. Actinium and thorium 1,4,7,10 tetraazacyclododecane N,N',N'',N''' 1,4,7,10-tetra(methylene) phosphonic acid (DOTMP) and thorium-diethylene triamine N,N',N'' penta(methylene) phosphonic acid (DTMP) were prepared and their biodistribution evaluated in conventional Balb/C mice at four hours after injection. All three bone-seeking agents showed a high uptake in bone and a low uptake in soft tissues. Among the soft tissue organs, only kidney had a relatively high uptake. The femur/kidney ratios for 227Th-DTMP, 228-Ac-DOTMP and 227Th-DOTMP were 14.2, 7.6 and 6.0, respectively. A higher liver uptake of 228Ac-DOTMP was seen than for 227Th-DTMP and 227Th-DOTMP. This suggests that some demetallation of the 228Ac-DOTMP complex had occurred. The results indicate that 225Ac-DOTMP, 227Th-DOTMP and 227Th-DTMP have promising properties as potential therapeutic bone-seeking agents.

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PubMed2005

Production of actinium-225 for alpha particle mediated radioimmunotherapy.

The initial clinical trials for treatment of acute myeloid leukemia have demonstrated the effectiveness of the alpha emitter (213)Bi in killing cancer cells. Bismuth-213 is obtained from a radionuclide generator system from decay of 10-days (225)Ac parent. Recent pre-clinical studies have also shown the potential application of both (213)Bi, and the (225)Ac parent radionuclide in a variety of cancer systems and targeted radiotherapy. This paper describes our five years of experience in production of (225)Ac in partial support of the on-going clinical trials. A four-step chemical process, consisting of both anion and cation exchange chromatography, is utilized for routine separation of carrier-free (225)Ac from a mixture of (228)Th, (229)Th and (232)Th. The separation of Ra and Ac from Th is achieved using the marcoporous anion exchange resin MP1 in 8M HNO(3) media. Two sequential MP1/NO(3) columns provide a separation factor of approximately 10(6) for Ra and Ac from Th. The separation of Ac from Ra is accomplished on a low cross-linking cation exchange resin AG50-X4 using 1.2M HNO(3) as eluant. Two sequential AG50/NO(3) columns provide a separation factor of approximately 10(2) for Ac from Ra. A 60-day processing schedule has been adopted in order to reduce the processing cost and to provide the highest levels of (225)Ac possible. Over an 8-week campaign, a total of approximately 100 mCi of (225)Ac (approximately 80% of the theoretical yield) is shipped in 5-6 batches, with the first batch typically consisting of approximately 50 mCi. After the initial separation and purification of Ac, the Ra pool is re-processed on a bi-weekly schedule or as needed to provide smaller batches of (225)Ac. The averaged radioisotopic purity of the (225)Ac was 99.6 +/- 0.7% with a (225)Ra content of < or =0.6%, and an average (229)Th content of (4(-4)(+5)) x 10(-5)%.

Actinium↗

PubMed1974