Abstract:Introduction-Peripheral mu (μ) opioid receptors are implicated in pain, bowel dysfunction and the progression of certain cancers. In an effort to identify radioligands well suited for imaging these peripheral sites, we have prepared and evaluated four hydrophilic [ 111 In]-labeled, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated μ tetrapeptides. Methods-Peptides were prepared by solid-phase techniques, using orthogonal strategies to achieve branching to DOTA, and then characterized b… Show more
“…The p-isothiocyanate group forms a thiourea linkage with ε-amino groups on lysines on the mAbs. Peptides may be assembled by solid-phase peptide synthesis which allows a chelator to be positioned at a specific location in the sequence to complex radiometals (Lever et al 2019). Fig.…”
Background: Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results: AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125 I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125 I and 123 I) or radiometal chelation (111 In, 67 Ga, 99m Tc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111 In-DTPAoctreotide and 125 I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125 I-mAb 425, with minimal normal tissue toxicity. Conclusions: Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.
“…The p-isothiocyanate group forms a thiourea linkage with ε-amino groups on lysines on the mAbs. Peptides may be assembled by solid-phase peptide synthesis which allows a chelator to be positioned at a specific location in the sequence to complex radiometals (Lever et al 2019). Fig.…”
Background: Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results: AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125 I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125 I and 123 I) or radiometal chelation (111 In, 67 Ga, 99m Tc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111 In-DTPAoctreotide and 125 I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125 I-mAb 425, with minimal normal tissue toxicity. Conclusions: Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.
“…In‐111 with interesting physical properties (half‐life of 2.8 days, decaying by electron capture [EC] with subsequent emission of gamma photons of 173 and 247 keV [89% and 94% intensity, respectively]) is an ideal radionuclide for the detection and diagnosis of infections and inflammatory lesions using single photon emission computed tomography (SPECT) 21 . It is widely used for the labeling of mAbs 22–24 . This remarkable position in targeted diagnosis is achieved due to the suitable physical half‐life of In‐111 (for compatibility with relatively slow pharmacokinetics of intact mAbs and for subsequent production steps), well‐established In‐111 chemistry as well as easily production and availability 25…”
In this study, [111In]In‐DOTA‐PR81 was developed, and its preliminary preclinical qualifications were assessed for single photon emission computed tomography (SPECT) imaging of breast cancer. DOTA‐NHS‐ester was practiced and successively purified by molecular filtration. The chelate:mAb ratio was determined by spectrophotometry. DOTA‐PR81 was radiolabeled with In‐111 and its radiochemical yield, in vitro stability, in vitro internalization, and immunoreactivity tests were performed. SPECT imaging and tissue counting were applied to evaluate the tissue distribution of [111In]In‐DOTA‐hIgG and [111In]In‐DOTA‐PR81 in BALB/c mice bearing breast tumors. The radiochemical yield of [111In]In‐DOTA‐PR81 complex was >95.0 ± 0.5% (ITLC), and the specific activity was 170 ± 44 MBq/mg. Conjugation reaction resulted in the average number of chelators attached to a mAb (c/a) of 3.4 ± 0.3:1. The radioimmunoconjugate showed immunoreactivity towards MCF7 cell line and MUC1 antigen while its significant in vitro and in vivo stability were investigated over 48 h, respectively (93.0 ± 1.2% in phosphate‐buffered saline (PBS) and 84.0 ± 1.3% in human serum). The peak concentration of internalized activity of [111In]In‐DOTA‐PR81 was between 4 to 6 h. In comparison with control probes, the complex was accumulated with high specificity and sensitivity at the tumor site. Achieved results indicated that [111In]In‐DOTA‐PR81 could be contemplated as an appropriate radiotracer for prognostic imaging of antigens in oncology.
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