Radionuclide Therapy Of Cancer Research Articles

Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile.

The prostate-specific membrane antigen (PSMA) has emerged as an attractive prostate cancer associated target for radiotheragnostic application using PSMA-specific radioligands. The aim of this study was to design new PSMA ligands modified with an albumin-binding moiety in order to optimize their tissue distribution profile. The compounds were prepared by conjugation of a urea-based PSMA-binding entity, a DOTA chelator, and 4-( p-iodophenyl)butyric acid using multistep solid phase synthesis. The three ligands (PSMA-ALB-02, PSMA-ALB-05, and PSMA-ALB-07) were designed with varying linker entities. Radiolabeling with 177Lu was performed at a specific activity of up to 50 MBq/nmol resulting in radioligands of >98% radiochemical purity and high stability. In vitro investigations revealed high binding of all three PSMA radioligands to mouse (>64%) and human plasma proteins (>94%). Uptake and internalization into PSMA-positive PC-3 PIP tumor cells was equally high for all radioligands. Negligible accumulation was found in PSMA-negative PC-3 flu cells, indicating PSMA-specific binding of all radioligands. Biodistribution and imaging studies performed in PC-3 PIP/flu tumor-bearing mice showed enhanced blood circulation of the new radioligands when compared to the clinically employed 177Lu-PSMA-617. The PC-3 PIP tumor uptake of all three radioligands was very high (76.4 ± 2.5% IA/g, 79.4 ± 11.1% IA/g, and 84.6 ± 14.2% IA/g, respectively) at 24 h post injection (p.i.) resulting in tumor-to-blood ratios of ∼176, ∼48, and ∼107, respectively, whereas uptake into PC-3 flu tumors was negligible. Kidney uptake at 24 h p.i. was lowest for 177Lu-PSMA-ALB-02 (10.7 ± 0.92% IA/g), while 177Lu-PSMA-ALB-05 and 177Lu-PSMA-ALB-07 showed higher renal retention (23.9 ± 4.02% IA/g and 51.9 ± 6.34% IA/g, respectively). Tumor-to-background ratios calculated from values of the area under the curve (AUC) of time-dependent biodistribution data were in favor of 177Lu-PSMA-ALB-02 (tumor-to-blood, 46; tumor-to-kidney, 5.9) when compared to 177Lu-PSMA-ALB-05 (17 and 3.7, respectively) and 177Lu-PSMA-ALB-07 (39 and 2.1, respectively). The high accumulation of the radioligands in PC-3 PIP tumors was visualized on SPECT/CT images demonstrating increasing tumor-to-kidney ratios over time. Taking all of the characteristics into account, 177Lu-PSMA-ALB-02 emerged as the most promising candidate. The applied concept may be attractive for future clinical translation potentially enabling more potent and convenient prostate cancer radionuclide therapy.

Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Experimental and analytical dose assessment of patient’s family members treated with I-131

Radiation exposure to the patient’s family members is one of the major concerns during thyroid cancer radionuclide therapy. The aim of this study was to measure the total effective dose of the family members by means of thermoluminescence personal dosimeter, and compare with those calculated by analytical methods. Eighty five adult family members of fifty one patients volunteered to participate in this research study. Considering the minimum and maximum range of dose rate from 15 μsv/h to 120 μsv/h at patient s’ release time, the calculated mean and median dose values of family members were 0.45 mSv and 0.28 mSv, respectively. Moreover, almost all the family members doses were measured to be less than the dose constraint of 5 mSv recommended by Basic Safety Standards. Considering the influence parameters such as patient dose rate and administrated activity, the total effective dose of family members were calculated by TEDE and NRC formulas and compared with those of experimental results. The results indicated that, it is fruitful to use the quantitative calculations for releasing patients treated with I-131 and correct estimation of patient s’ family doses.

Experimental and Analytical Dose Assessment of Patient's Family Members Treated with I-131

Radiation exposure to the patient’s family members is one of the major concerns during thyroid cancer radionuclide therapy. The aim of this study was to measure the total effective dose of the family members by means of thermoluminescence personal dosimeter, and compare with those calculated by analytical methods. Eighty five adult family members of fifty one patients volunteered to participate in this research study. Considering the minimum and maximum range of dose rate from 15 μsv/h to 120 μsv/h at patient s’ release time, the calculated mean and median dose values of family members were 0.45 mSv and 0.28 mSv, respectively. Moreover, almost all the family members doses were measured to be less than the dose constraint of 5 mSv recommended by Basic Safety Standards. Considering the influence parameters such as patient dose rate and administrated activity, the total effective dose of family members were calculated by TEDE and NRC formulas and compared with those of experimental results. The results indicated that, it is fruitful to use the quantitative calculations for releasing patients treated with I-131 and correct estimation of patient s’ family doses.

Targeted Radionuclide Therapy: Practical Applications and Future Prospects.

In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success.

(177)Lu-Labeled Cerasomes Encapsulating Indocyanine Green for Cancer Theranostics.

This Article reported the fabrication of a robust theranostic cerasome encapsulating indocyanine green (ICG) by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DSPE-PEG2000-DOTA), followed by chelating radioisotope of (177)Lu. Its applications in optical and nuclear imaging of tumor uptake and biodistribution, as well as photothermal killing of cancer cells, were investigated. It was found that the obtained cerasome could act efficiently as fluorescence contrast agent as well as nuclear imaging tracer. Encapsulating ICG into cerasome could protect ICG from degradation, aggregation, and fast elimination from body, resulting in remarkable improvement in near-infrared fluorescence imaging, photothermal stability, and in vivo pharmacokinetic profile. Both fluorescence and nuclear imaging showed that such agent could selectively accumulate in tumor site after intravenous injection of the cerasome agent into Lewis lung carcinoma tumor bearing mice, resulting in efficient photothermal ablation of tumor through a one-time NIR laser irradiation at the best time window. The ability to track the uptake of cerasomes on a whole body basis could provide researchers with an excellent tool for developing cerasome-based drug delivery agents, especially the strategy of labeling cerasomes with theranostic radionuclide (177)Lu, enabling the ability of the (177)Lu-labeled cerasomes for radionuclide cancer therapy and even the combined therapy.

Abstract MP15: Afferent Arteriolar Endothelial-dependent Dilation is Impaired Prior to the Development of Radiation-induced Nephropathy and Hypertension

Chronic kidney disease (CKD) occurs in 15% of hematopoietic stem cell transplant (HSCT) patients, and has been clearly linked to irradiation at the time of the HSCT. CKD due to radiation also occurs after radionuclide therapy for cancer. Radiation nephropathy is expressed in rats and in humans as proteinuria, azotemia, and hypertension. There is a latent period of 6-8 weeks after irradiation to the development of proteinuria, azotemia, and hypertension in rats. This study tested the hypothesis that afferent arteriolar responses to the endothelial-dependent dilator acetylcholine are impaired prior to the development of proteinuria, azotemia, and hypertension in rats exposed to total body irradiation (TBI). Male WAG/RijCmcr rats were subjected to TBI (11 Gy) and afferent arteriolar responses to acetylcholine using the juxtamedullary nephron technique were determined at one, three, and six weeks. Systolic blood pressure (117 ± 6 vs. 119 ± 4 mmHg) and BUN (15.6 ± 1.4 vs. 15.8 ± 0.8 mg/dl) were not different between control and TBI groups at 6 weeks. Afferent arteriolar diameters averaged 22.5 ± 0.8 μm (n=30) in controls and 21.7 ± 0.7 μm (n=27) in TBI rats and were not different between control and TBI groups at 1, 3, or 6 weeks. Acetylcholine dilator responses were progressively attenuated from one to six weeks in TBI compared to control rats. During exposure to acetylcholine (0.01, 0.1, 1, and 10 μmol/L), afferent diameter increased by 8 ± 2%, 18 ± 3%, 27 ± 2% and 31 ± 3% in control rats (n=6), and 3 ± 2%, 9 ± 3%, 12 ± 3%, and 16 ± 3% in kidneys of 3 week TBI rats (n=8, p<0.05). However, TBI did not change the norepinephrine-mediated vasoconstrictor responses or the nitroprusside vasodilator responses at 1, 3, or 6 weeks. Renal microvessels were isolated from control and TBI groups at 3 and 6 weeks for protein expression assessment of endothelial enzymatic pathways Cyp2C, COX, and NOS. We found that epoxygenase Cyp2C23 and Cyp2C11 protein expressions were significantly lower 3 and 6 weeks following TBI compared to control rats. Taken together, these results indicate that the impaired afferent arteriolar endothelial-dependent acetylcholine responses and decreased epoxygenase enzymes precede the development of proteinuria, azotemia, and hypertension in irradiated rats.

Targeted radionuclide therapies for pancreatic cancer.

Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

Recent Advances in Molecular Image-Guided Cancer Radionuclide Therapy.

Cancer-targeted radionuclide therapy is a promising approach for the treatment of a wide variety of malignancies, especially those resistant to conventional therapies. However, to improve the use of targeted radionuclide therapy for the management of cancer patients, the in vivo behaviors, dosimetry, and efficacy of radiotherapeutic agents need to be well characterized and monitored. Molecular imaging, which is a powerful tool for the noninvasive characterization and quantification of biological processes in living subjects at the cellular and molecular levels, plays an important role in the guidance of cancer radionuclide therapy. In this review, we introduce the radiotherapeutics for cancer-targeted therapy and summarize the most recent evidence supporting the use of molecular imaging to guide cancer radionuclide therapy.

Synthesis and characterization of Her2-NLP peptide conjugates targeting circulating breast cancer cells: cellular uptake and localization by fluorescent microscopic imaging.

To synthesize a fluorescent Her2-NLP peptide conjugate consisting of Her2/neu targeting peptide and nuclear localization sequence peptide (NLP) and assess its cellular uptake and intracellular localization for radionuclide cancer therapy targeting Her2/neu-positive circulating breast cancer cells (CBCC). Fluorescent Cy5.5 Her2-NLP peptide conjugate was synthesized by coupling a bivalent peptide sequence, which consisted of a Her2-binding peptide (NH2-GSGKCCYSL) and an NLP peptide (CGYGPKKKRKVGG) linked by a polyethylene glycol (PEG) chain with 6 repeating units, with an activated Cy5.5 ester. The conjugate was separated and purified by HPLC and then characterized by Maldi-MS. The intracellular localization of fluorescent Cy5.5 Her2-NLP peptide conjugate was assessed by fluorescent microscopic imaging using a confocal microscope after incubation of Cy5.5-Her2-NLP with Her2/neu positive breast cancer cells and Her2/neu negative control breast cancer cells, respectively. Fluorescent signals were detected in cytoplasm of Her2/neu positive breast cancer cells (SKBR-3 and BT474 cell lines), but not or little in cytoplasm of Her2/neu negative breast cancer cells (MDA-MB-231), after incubation of the breast cancer cells with Cy5.5-Her2-NLP conjugates in vitro. No fluorescent signals were detected within the nuclei of Her2/neu positive SKBR-3 and BT474 breast cancer cells, neither Her2/neu negative MDA-MB-231 cells, incubated with the Cy5.5-Her2-NLP peptide conjugates, suggesting poor nuclear localization of the Cy5.5-Her2-NLP conjugates localized within the cytoplasm after their cellular uptake and internalization by the Her2/neu positive breast cancer cells. Her2-binding peptide (KCCYSL) is a promising agent for radionuclide therapy of Her2/neu positive breast cancer using a β(-) or α emitting radionuclide, but poor nuclear localization of the Her2-NLP peptide conjugates may limit its use for eradication of Her2/neu-positive CBCC using I-125 or other Auger electron emitting radionuclide.

Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy

Owing to its cytotoxicity, free copper is chelated by protein side chains and does not exist in vivo. Several chaperones transport copper to various cell compartments, but none have been identified that traffic copper to the nucleus. Copper-64 decays by β (+) and β (-) emission, allowing positron emission tomography and targeted radionuclide therapy for cancer. Because the delivery of (64)Cu to the cell nucleus may enhance the therapeutic effect of copper radiopharmaceuticals, elucidation of the pathway(s) involved in transporting copper to the tumor cell nucleus is important for optimizing treatment. We identified Atox1 as one of the proteins that binds copper in the nucleus. Mouse embryonic fibroblast cells, positive and negative for Atox1, were used to determine the role of Atox1 in (64)Cu transport to the nucleus. Mouse embryonic fibroblast Atox1(+/+) cells accumulated more (64)Cu in the nucleus than did Atox1(-/-) cells. HCT116 colorectal cancer cells expressing p53 (+/+) and not expressing p53 (-/-) were used to evaluate the role of this tumor suppressor protein in (64)Cu transport. In cells treated with cisplatin, the uptake of (64)Cu in the nucleus of HCT116 p53(+/+) cells was greater than that in HCT116 p53(-/-) cells. Atox1 expression increased in HCT116 p53(+/+) and p53(-/-) cells treated with cisplatin; however, Atox1 localized to the nuclei of p53(+/+) cells more than in the p53(-/-) cells. The data presented here indicate that Atox1 is involved in copper transport to the nucleus, and cisplatin affects nuclear transport of (64)Cu in HCT116 cells by upregulating the expression and the nuclear localization of Atox1.

癌のアイソトープ内用療法の現状と将来

癌のアイソトープ内用療法の現状と将来

Prospects for enhancement of targeted radionuclide therapy of cancer using ultrasound

Ultrasound-mediated drug delivery is a promising means of enhancing delivery, distribution and effectiveness of drugs within tumours. In this review, prospects for exploiting ultrasound to improve the tumour delivery and distribution of radiolabelled antibodies for radioimmunotherapy and to overcome barriers imposed by tumour microenvironment are discussed.

EPR-effect: Utilizing size-dependent Nanoparticle Delivery to Solid Tumors

EPR-effect: Utilizing size-dependent Nanoparticle Delivery to Solid Tumors

What is the Role of the Bystander Response in Radionuclide Therapies?

Radionuclide therapy for cancer is undergoing a renaissance, with a wide range of radionuclide and clinical delivery systems currently under investigation. Dosimetry at the cellular and sub-cellular level is complex with inhomogeneity and incomplete targeting of all cells such that some tumor cells will receive little or no direct radiation energy. There is now sufficient preclinical evidence of a Bystander response which can modulate the biology of these un-irradiated cells with current research demonstrating both protective and inhibitory responses. Dependence upon fraction of irradiated cells has also been found and the presence of functional gap junctions appears to be import for several Bystander responses. The selection of either high or low LET radionuclides may be critical. While low LET radionuclides appear to have a Bystander response proportional to dose, the dose-response from high LET radionuclides are more complex. In media transfer experiments a “U” shaped response curve has been demonstrated for high LET treatments. However this “U” shaped response has not been seen with co-culture experiments and its relevance remains uncertain. For high LET treatments there is a suggestion that dose rate effects may also be important with inhibitory effects noted with 125I labelling study and a stimulatory seen with 123I labelling in one study.

Outpatient therapeutic nuclear oncology

In the beginning, nuclear medicine was radionuclide therapy, which has evolved into molecular tumour-targeted control of metastatic cancer. Safe, efficacious, clinical practice of therapeutic nuclear oncology may now be based upon accurate personalised dosimetry by quantitative gamma SPECT/CT imaging to prescribe tumoricidal activities without critical organ toxicity. Preferred therapy radionuclides possess gamma emission of modest energy and abundance to enable quantitative SPECT/CT imaging for calculation of the beta therapy dosimetry, without radiation exposure risk to hospital personnel, carers, family or members of the public. The safety of outpatient radiopharmaceutical therapy of cancer with Iodine-131, Samarium-153, Holmium-166, Rhenium-186, Rhenium-188, Lutetium-177 and Indium-111 is reviewed. Measured activity release rates and radiation exposure to carers and the public are all within recommendations and guidelines of international regulatory agencies and, when permitted by local regulatory authorities allow cost-effective, safe, outpatient radionuclide therapy of cancer without isolation in hospital.

Therapeutic Use of Avidin Is Not Hampered by Antiavidin Antibodies in Humans

Hen egg white avidin is increasingly used in the clinic as part of multifactor treatments such as pretargeted radionuclide therapy of cancer or as an antidote of biotinylated drugs. Taking into account that naturally occurring human antiavidin antibodies (HAVA) are common in humans, the present work investigates avidin immunogenicity as part of risk/benefit evaluations. Sera from 139 oncology patients naive to avidin were confirmed to exhibit HAVA with lognormally distributed titers. HAVA were boosted after avidin treatment, with no correlation with the avidin dose or with the basal titer. No antibody-related clinical symptoms were observed in 21 HAVA-positive patients treated with avidin. In mouse models, high mouse antiavidin antibody titers, induced to simulate the worst human condition, neither reduced the biotin uptake of intratissue-injected avidin nor affected the capacity of intravenously injected avidin to clear a biotinylated drug from circulation. In both models the avidin treatment was well tolerated. Results indicate that avidin immunogenicity does not affect its safety and efficacy, thus encouraging its further use in clinical applications.

Production of the Auger emitter 119Sb for targeted radionuclide therapy using a small PET-cyclotron

The use of Auger electrons in radionuclide therapy of cancer is a promising tool for specific tumor cell killing of micrometastases and small tumors. The radioisotope 119Sb has recently been identified as a potent Auger-emitter for therapy. We here present a method for producing this isotope using a low-energy cyclotron. With this method, it will be possible to produce clinically relevant amounts of 119Sb radioactivity with high chemical and radionuclidic purity for cancer therapy.

Zielgerichtete Radionuklidtherapie mit α-Emittern - Grundlagen, experimentelle und erste klinische Studien

α-particle emitting nuclides are highly cytotoxic and are thus promising candidates for use in targeted radionuclide therapy of cancer. Due to their high linear energy transfer (LET) combined with a short range in tissue, α-particles cause severe DNA-damages that are repaired inaccurately and finally trigger cell death. For targeted therapy, α-emitters like actinium-225, astatine-211, bismuth-213 and thorium-227 are coupled to antibodies or receptor ligands via appropriate chelators that bind to proteins that are overexpressed or exclusively expressed on tumour cells. Application of α-emitters seems particularly promising for targeted therapy of disseminated tumour cells and small tumour cell clusters that remain in the body following resection of the primary tumour. α-emitter conjugates have been successfully applied in numerous experimental studies for therapy of ovarian, colon, gastric and breast cancer. Initial clinical trials evaluating α-emitter antibody conjugates in terms of tolerance and therapeutic efficacy also have shown positive results in patients with melanoma, ovarian cancer, acute myeloid lymphoma (AML) and glioma. Therefore the aim could be clinical establishment of targeted α-emitter radionuclide therapy as one part of a multimodal concept for therapy of cancer.

The behaviour of selected yttrium containing bioactive glass microspheres in simulated body environments

The study aims at the manufacture and investigation of biodegradable glass microspheres incorporated with yttrium potentially useful for radionuclide therapy of cancer. The glass microspheres in the SiO2-Na2O-P2O5-CaO-K2O-MgO system containing yttrium were prepared by conventional melting and flame spheroidization. The behaviour of the yttrium silicate glass microspheres was investigated under in vitro conditions using simulated body fluid (SBF) and Tris buffer solution (TBS), for different periods of time, according to half-life time of the Y-90. The local structure of the glasses and the effect of yttrium on the biodegradability process were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy and Back Scattered Electron Imaging of Scanning Electron Microscopy (BEI-SEM) equipped with Energy Dispersive X-ray (EDX) analysis. UV-VIS spectrometry and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used for analyzing the release behaviour of silica and yttrium in the two used solutions. The results indicate that the addition of yttrium to a bioactive glass increases its structural stability which therefore, induced a different behaviour of the glasses in simulated body environments.