(177)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model.
ABSTRACT: BACKGROUND:(177)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of (177)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. RESULTS:(177)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/?g. Prior to administration, the radiochemical purity was measured as s?>?99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq (177)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of (177)Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. CONCLUSIONS:The (177)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.
Project description:Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [<sup>68</sup>Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi, and [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> in patients with various cancers. The FAPi agents, [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi and [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub>, were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq) [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub>. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi (<i>p</i> < 0.011). [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> had significantly longer median whole-body Te compared to that of [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5); <i>p</i>-0.0167]. The Te of tumor lesions was significantly higher for [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> compared to [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5); <i>p</i>-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi, and [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> compared to [<sup>177</sup>Lu]Lu-DOTA.SA.FAPi. [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub> is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.
Project description:BACKGROUND:(?177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168 h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of (177)Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period. RESULTS:The mean absorbed dose to the bone marrow was estimated to 0.20 Gy (0.11-0.37 Gy) per 7.4 GBq of (177)Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb (p?=?0.01), WBC (p?<?0.01) and PLT (p?<?0.01) counts. The total mean absorbed dose to the bone marrow was 0.64 Gy (0.30-1.5 Gy) per 24 GBq (8.2-37 GBq) of (177)Lu-DOTATATE and also correlated with a decrease in Hb (p?<?0.01), WBC (p?=?0.01) and PLT (p?<?0.01) counts. CONCLUSIONS:The planar image-based method developed in this study resulted in similar absorbed doses to the bone marrow as reported in earlier studies with blood-based bone marrow dosimetry. The results correlated with haematological toxicity, making it a promising method for estimating bone marrow doses in (177)Lu-DOTATATE treatment without the need for blood and urine sampling.
Project description:<h4>Introduction</h4>PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [<sup>177</sup>Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties.<h4>Methods</h4>Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120-160 μg) [<sup>177</sup>Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers.<h4>Results</h4>[<sup>177</sup>Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [<sup>177</sup>Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [<sup>177</sup>Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased.<h4>Conclusion</h4>Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.
Project description:The use of an albumin binder has been shown to improve tumor uptake of prostate-specific membrane antigen (PSMA)-targeting radiotherapeutic agents. The aim of this study was to develop improved radiotherapeutic agents that combine an optimized affinity-modifying group and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. <b>Methods:</b> <sup>68</sup>Ga-labeled DOTA-conjugated lysine-ureido-glutamate-based PSMA-targeting agents bearing various affinity-modifying groups or albumin binders were synthesized and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. The optimized affinity-modifying group and albumin binders were combined, and the resulting derivatives were radiolabeled with <sup>177</sup>Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. <b>Results:</b> Affinity-modifying group optimization revealed that <sup>68</sup>Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine affinity-modifying group had the highest tumor uptake (23.1 ± 6.11 percentage injected dose [%ID]/g at 1 h after injection). Albumin binder optimization showed that <sup>68</sup>Ga-HTK03055 and <sup>68</sup>Ga-HTK03086 bearing the <i>N</i>-(4-(<i>p</i>-chlorophenyl)butanoyl)-Gly and <i>N</i>-(4-(<i>p</i>-methoxyphenyl)butanoyl)-Gly motifs, respectively, had relatively faster tumor accumulation (∼30 %ID/g at 3 h after injection) and lower average kidney uptake (<55 %ID/g at both 1 and 3 h after injection). Combining the tranexamic acid-9-anthrylalanine affinity-modifying group with <i>N</i>-(4-(<i>p</i>-chlorophenyl)butanoyl)-Gly and <i>N</i>-(4-(<i>p</i>-methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. <sup>177</sup>Lu-HTK03121 and <sup>177</sup>Lu-HTK03123 had extremely high peak uptake (104 ± 20.3 and 70.8 ± 23.7 %ID/g, respectively) in LNCaP tumor xenografts, and this peak was sustained up to 120 h after injection. Dosimetry calculation showed that compared with <sup>177</sup>Lu-PSMA-617, <sup>177</sup>Lu-HTK03121 and <sup>177</sup>Lu-HTK03123 delivered 18.7- and 12.7-fold higher absorbed dose to tumor but only 6.4- and 6.3-fold higher absorbed dose to kidneys, leading to 2.9- and 2.0-fold improvement in the tumor-to-kidney absorbed dose ratios. <b>Conclusion:</b> With greatly enhanced tumor uptake and tumor-to-kidney absorbed dose ratio, <sup>177</sup>Lu-HTK03121 and <sup>177</sup>Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of <sup>177</sup>Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer.
Project description:This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with <sup>177</sup>Lu-DOTATATE in patients with and without skeletal metastases. <b>Methods:</b> This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of <sup>177</sup>Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time-activity concentration curve for the low-uptake compartment. This time-activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of <sup>177</sup>Lu-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. <b>Results:</b> Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12-0.33, 0.15-1.44, 0.19-1.71, 0.21-1.60, and 0.18-2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (<i>r</i> <sub>s</sub>) were -0.49 for the planar method, -0.61 for L4-SPECT, -0.63 for V-SPECT, -0.63 for L-SPECT, and -0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (<i>r</i> <sub>s</sub> = -0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (<i>r</i> <sub>s</sub> = -0.61 to -0.74). The mean bone marrow absorbed doses were 3%-69% higher for patients with skeletal metastases than for patients without. <b>Conclusion:</b> The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.
Project description:<h4>Introduction</h4>While [<sup>177</sup>Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [<sup>177</sup>Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter.<h4>Methods</h4>Ten mHSPC patients underwent two cycles of [<sup>177</sup>Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values.<h4>Results</h4>Kinetics of [<sup>177</sup>Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047).<h4>Conclusions</h4>We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.
Project description:Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger ?<sub>1</sub>-microglobulin (A1M) together with 177-Lutetium (<sup>177</sup>Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [<sup>177</sup>Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [<sup>177</sup>Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([<sup>99m</sup>Tc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [<sup>177</sup>Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [<sup>99m</sup>Tc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [<sup>177</sup>Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [<sup>99m</sup>Tc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [<sup>177</sup>Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.
Project description:1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with <sup>64</sup>Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [<sup>177</sup>Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to <sup>177</sup>Lu based on the [<sup>64</sup>Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [<sup>64</sup>Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [<sup>64</sup>Cu]Cu-1C1m-Fc could be of interest to give an indication of <sup>177</sup>Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the <sup>177</sup>Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with <sup>64</sup>Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [<sup>177</sup>Lu]Lu-1C1m-Fc.
Project description:<b><i>Rationale</i></b> : Pretargeted radioimmunotherapy (PRIT) based upon bioorthogonal click chemistry has been investigated for the first time in the context of peritoneal carcinomatosis using a CEA-targeting 35A7 mAb bearing <i>trans</i>-cyclooctene (TCO) moieties and several <sup>177</sup>Lu-labeled tetrazine (Tz) radioligands. Starting from three Tz probes containing PEG linkers of varying lengths between the DOTA and Tz groups (<i>i.e</i>. PEG<sub>n</sub> = 3, 7, or 11, respectively, for Tz-<b>1</b>, Tz-<b>2</b>, and Tz-<b>3</b>), we selected [<sup>177</sup>Lu]Lu-Tz<b>-2</b> as the most appropriate for pretargeted SPECT imaging and demonstrated its efficacy in tumor growth control. <b><i>Methods:</i></b> An orthotopic model of peritoneal carcinomatosis (PC) was obtained following the intraperitoneal (i.p.) injection of A431-CEA-Luc cells in nude mice. Tumor growth was assessed using bioluminescence imaging. Anti-CEA 35A7 mAb was grafted with 2-3 TCO <i>per</i> immunoglobulin. Pretargeted SPECT imaging and biodistribution experiments were performed to quantify the activity concentrations of [<sup>177</sup>Lu]Lu-Tz-<b>1-3</b> in tumors and non-target organs to determine the optimal Tz probe for the PRIT of PC. <b><i>Results:</i></b> The pharmacokinetic profiles of [<sup>177</sup>Lu]Lu-Tz-<b>1-3</b> alone were determined using both SPECT imaging and biodistribution experiments. These data revealed that [<sup>177</sup>Lu]Lu-Tz-<b>1</b> was cleared <i>via</i> both the renal and hepatic systems<b>,</b> while [<sup>177</sup>Lu]Lu-Tz-<b>2</b> and [<sup>177</sup>Lu]Lu-Tz-<b>3</b> were predominantly excreted <i>via</i> the renal system. In addition, these results illuminated that the longer the PEG linker, the more rapidly the Tz radioligand was cleared from the peritoneal cavity. The absorbed radiation dose corresponding to pretargeting with 35A7-TCO followed 24 h later by [<sup>177</sup>Lu]Lu-Tz-<b>1-4</b> was higher for tumors following the administration of [<sup>177</sup>Lu]Lu-Tz-<b>2</b> (<i>i.e</i>. 0.59 Gy/MBq) compared to either [<sup>177</sup>Lu]Lu-Tz-<b>1</b> (<i>i.e</i>. 0.25 Gy/MBq) and [<sup>177</sup>Lu]Lu-Tz-<b>3</b> (<i>i.e</i>. 0.18 Gy/MBq). In a longitudinal PRIT study, we showed that the i.p. injection of 40 MBq of [<sup>177</sup>Lu]Lu-Tz-<b>2</b> 24 hours after the systemic administration of 35A7-TCO significantly slowed tumor growth compared to control mice receiving only saline or 40 MBq of [<sup>177</sup>Lu]Lu-Tz-<b>2</b> alone. <i>Ex vivo</i> measurement of the peritoneal carcinomatosis index (PCI) confirmed that PRIT significantly reduced tumor growth (PCI = 15.5 ± 2.3 after PRIT <i>vs</i> 30.0 ± 2.3 and 30.8 ± 1.4 for the NaCl and [<sup>177</sup>Lu]Lu-Tz-<b>2</b> alone groups, respectively). <b><i>Conclusion</i></b> : Our results clearly demonstrate the impact of the length of PEG linkers upon the biodistribution profiles of <sup>177</sup>Lu-labeled Tz radioligands. Furthermore, we demonstrated for the first time the possibility of using bioorthogonal chemistry for both the pretargeted SPECT and PRIT of peritoneal carcinomatosis.
Project description:Brachytherapy can provide sufficient doses to head and neck squamous cell carcinoma (HNSCC) with minimal damage to nearby normal tissues. In this study, the β<sup>-</sup>-emitter <sup>177</sup>Lu was conjugated to DTPA-polyethylene glycol (PEG) decorated gold nanostars (<sup>177</sup>Lu-DTPA-pAuNS) used in surface-enhanced Raman scattering and photothermal therapy (PTT). The accumulation and therapeutic efficacy of <sup>177</sup>Lu-DTPA-pAuNS were compared with those of <sup>177</sup>Lu-DTPA on an orthotopic HNSCC tumor model. The SPECT/CT imaging and biodistribution studies showed that <sup>177</sup>Lu-DTPA-pAuNS can be accumulated in the tumor up to 15 days, but <sup>177</sup>Lu-DTPA could not be detected at 24 h after injection. The tumor viability and growth were suppressed by injected <sup>177</sup>Lu-DTPA-pAuNS but not nonconjugated <sup>177</sup>Lu-DTPA, as evaluated by bioluminescent imaging. The radiation-absorbed dose of the normal organ was the highest in the liver (0.33 mSv/MBq) estimated in a 73 kg adult, but that of tumorsphere (0.5 g) was 3.55 mGy/MBq, while intravenous injection of <sup>177</sup>Lu-DTPA-pAuNS resulted in 1.97 mSv/MBq and 0.13 mGy/MBq for liver and tumorsphere, respectively. We also observed further enhancement of tumor-suppressive effects by a combination of <sup>177</sup>Lu-DTPA-pAuNS and PTT compared to <sup>177</sup>Lu-DTPA-pAuNS alone. In conclusion, <sup>1</sup><sup>77</sup>Lu-DTPA-pAuNS may be considered as a potential radiopharmaceutical agent for HNSCC brachytherapy.