Preclinical evaluation of investigational radiopharmaceutical RISAD-P intended for use as a diagnostic and molecular radiotherapy agent for prostate cancer. Prostate. 2015; 75:8-22:

Our results indicate that 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 hours post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range. The transient uptake of radioactivity is observed in the genitourinary tract and in stomach. Without the potassium iodide blockade, thyroid uptake is also observed. 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.

Co-targeting androgen receptor and DNA for imaging and molecular radiotherapy of prostate cancer: in vitro studies. Prostate. 2014; 74:1634-46:

These studies describe RISAD-P, a theranostic drug, which targets androgen receptor. Its subcellular metabolite participates in DNA synthesis and co-targets DNA. RISAD-P is a promising candidate for imaging of the AR expression and tumor proliferation as well as molecular radiotherapy of prostate cancer. The uptake of RISAD-P by prostate cancer cells is proportional to the AR levels and independent of the radionuclide. The intracellular accumulation of radioactivity is directly proportional to the extracellular concentration of RISAD-P and the duration of exposure. Initially, RISAD-P is trapped in the cytoplasm. Within 24 hours, radioactivity is associated exclusively with DNA. The RISAD-P radiotoxicity is determined by the radionuclide; however, the cellular responses are directly proportional to the AR expression levels. LNCaP cells expressing high levels of AR are killed at the rate of up to 60% per day after a brief 1 hour RISAD-P treatment.

Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2′-deoxyuridine, 5-iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-fluorothymidine for molecular radiotherapy of cancer: synthesis and biological evaluation. J Med Chem. 2012; 55:2649-71:

These studies confirm that targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Radioactive cyclosaligenyl monophosphates were designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC50 values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma, and ovarian and colorectal cancers.

Radiolabeled 5-iodo-3′-O-(17beta-succinyl-5alpha-androstan-3-one)-2′-deoxyuridine and its 5′-monophosphate for imaging and therapy of androgen receptor-positive cancers: synthesis and biological evaluation. J Med Chem. 2009; 52:5124-43:

Two radioactive drugs that target androgen receptor and co-target DNA were studied. Both were found to have properties desired in androgen receptor-imaging radiopharmaceuticals. The uptake in cancer cells depends on the presence of androgen receptor. During the intracellular degradation, metabolites 5-125I-iodo-2′-deoxyuridine and its 5′-monophosphate are liberated. These metabolites participate in the DNA synthesis, providing the opportunity for the simultaneous evaluation of the AR status and tumor cell proliferation. The intracellular trapping of these drugs and release of metabolites able to participate in the DNA synthesis allow the site-specific delivery of lethal doses of radiation to cancer cells. Biodistribution and imaging studies show preferential uptake and retention of both drugs in intraperitoneal xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress androgen receptor. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed in multidrug resistant and radioresistant tumor models.

Tumor localization and systemic absorption of intravesical instillation of radio-iodinated iododeoxyuridine in patients with bladder cancer. J Urol. 1999; 162:58-62:

In this study, the parent drug was evaluated in 11 patients with bladder cancer after 24 intravesical instillations. The imaging was positive in all patients with bladder cancer. Average tumor uptake was 0.19% of the instilled dose. Preferential uptake of IUdR in the tumor was observed in cancer samples from 6 patients that underent microautoradiographic tissue analysis. The tumor-to-normal bladder ratio ranged from 3.2 to 74,000 (median 202). Intravesical instillation of radio-iodinated IUdR achieved selective localization in bladder tumors with minimal uptake by the normal bladder and minimal systemic absorption. Intravesical IUdR therapy has the potential to be safe and useful in select patients with superficial bladder cancer.

Prodrugs in site-selective delivery of radiopharmaceuticals. Q J Nucl Med. 1997; 41:127-39:

In this study, we review basic rules for the design of site-selective prodrugs and various modes of their activation with particular emphasis on our drugs designed for targeted delivery. Site-specific diagnostic radiopharmaceuticals are routine in the nuclear medicine applications, but the instances of targeting of radiotherapeutic prodrugs are surprisingly rare. We have concentrated on our own efforts on design and synthesis of site-selective prodrugs of 5-125I-iodo-2′-deoxyuridine for cancer radiotherapy. The prodrugs of for targeted delivery include several derivatives with altered permeability, polymeric and macromolecular prodrugs for a carrier-mediated or local delivery; metabolically trapped prodrugs; and glycoconjugates for oral colon-specific delivery. We also describe prodrugs of several diagnostic agents in the context of the metabolic trapping as the primary targeting modality. For various diagnostic agents the prodrug target-associated enzymes are discussed and examples of the site-specific release of the active agent are given.

Radiolabeled iododeoxyuridine: safety evaluation. J Nucl Med. 1996; 37:13S-16S:

No evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices in pigs or humans treated with the parent drug was detected. For this reason, we can anticipate little or no effect on normal tissues when 125I-RTDT is used as a molecular radiotherapeutic.

5-[125I]iodo-2′-deoxyuridine in the radiotherapy of brain tumors in rats. J Nucl Med. 1998; 39:1148-54:

Here we substantiate the therapeutic potential of the parent drug 125IUdR in solid tumors that are accessible to direct administration. The findings also demonstrate the ability of this Auger-electron-emitting radiopharmaceutical to diffuse within normal tissues suggesting an important role of these drugs in the eradication of microscopic tumor deposits.

Tumor targeting by intra-arterial infusion of 5-123I-iodo-2′-deoxyuridine in patients with liver metastases from colorectal cancer. J Nucl Med. 1996; 37:22S-25S:

Tumor incorporation of 123IUdR infused intra-arterially in patients with liver metastases was analyzed. No significant uptake was detected in the bone marrow or in other normal dividing tissues. These results encourage further studies to examine of the therapeutic potential of RTDT in cancer.

Strand breaks after the decay of iodine-125 in proximity to plasmid pBR322 DNA. Radiat Res. 1997; 147:401-8:

Our results indicate that 123IUdR incorporated into the DNA cells is about eight times more effective in causing clonogenic death than 280-kVp X rays per unit of energy absorbed in the nucleus. This extreme radiotoxicity is attributed to the fact that 123I is the Auger electron emitter.

Radiotoxicity of 5-[123I]iodo-2′-deoxyuridine in V79 cells: a comparison with 5-[125I]iodo-2′-deoxyuridine. Radiat Res. 1989; 118:532-44:

We also show that radiotoxicity of Auger electrons is site-of-decay specific. For example, the decay of 125I bound to a DNA-intercalating compound produces DNA double strand breaks more efficiently than 125I bound to a non-intercalating compound. Our data supports the theoretical prediction that the DNA double strand breaks yield is highly dependent on the proximity of the Auger electron emitter to DNA.

Tumor targeting potential and metabolism of 5-[125I]iodo-2′-deoxyuridine injected intratumorally in patients with breast cancer. Ann N Y Acad Sci. 1993; 698:204-11:

The aim of this work was to evaluate the metabolism and selectivity – based on differential cell proliferation kinetics – of 125IUdR, the parent drug, in patients with breast cancer. 125IUdR was injected intra-tumor by ultrasound-guided percutaneous injection in 7 patients with breast cancer 24 hours before ablative surgery. The radioactivity of tumor and the surrounding tissues was measured and microautoradiography was used to determine the site of incorporation. High tumor-to-non-tumor ratios were obtained (mean 147, range 27-397) with average tumor-to-blood ratios at the time of surgery equal to ~33. On average ~0.02% of the injected dose was present per gram of tumor. Microautoradiography confirmed the high values of tumor-to-non-tumor ratios and demonstrated the specificity of 125IUdR incorporation into the DNA of tumor cells. Our results suggest the potential of radiolabeled IUdR for tumor targeting in humans, to be used whenever a satisfactory route of locoregional administration allowing for homogeneous tracer distribution within the tumor mass is accessible and in the presence of favorable tumor cell proliferations kinetics.