The 18‐membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all ...225Ac (26 kBq) in 5 min at RT. 225Ac(macropa)+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa‐NCS, was conjugated to trastuzumab as well as to the prostate‐specific membrane antigen‐targeting compound RPS‐070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa‐Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac‐macropa‐RPS‐070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft‐tissue metastases.
Actinium in action! A macrocyclic ligand exhibits unprecedented radiolabeling efficiency for the large α‐emitting radionuclide 225Ac3+. This ligand is extremely promising for the implementation of 225Ac in targeted alpha therapy for cancer. RCY=radiochemical yield.
Purpose
Fibroblast activation protein-α (FAPα) is uniquely expressed in activated fibroblasts, including cancer-associated fibroblasts that populate tumor stroma and contribute to proliferation and ...immunosuppression. Radiolabeled FAPα inhibitors enable imaging of multiple human cancers, but time-dependent clearance from tumors currently limits their utility as FAPα-targeted radiotherapeutics. We sought to increase the area under the curve (AUC) by constructing a trifunctional ligand that binds FAPα with high affinity and also binds albumin and theranostic radiometals.
Procedures
RPS-309 comprised a FAPα-targeting moiety, an albumin-binding group, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Inhibition of recombinant human FAPα (rhFAPα) was determined by colorimetric assay. Affinity for human serum albumin (HSA) was determined by high-performance affinity chromatography. The tissue distribution of
68
GaGa-RPS-309 in SW872 tumor xenograft-bearing mice was imaged by microPET/CT and quantified by biodistribution studies performed from 30 min to 3 h post injection (p.i.). The biodistribution of
177
LuLu-RPS-309 was determined at 4, 24, and 96 h p.i.
Results
RPS-309 inhibits rhFAPα with IC
50
= 7.3 ± 1.4 nM.
68
GaGa-RPS-309 is taken up specifically by FAPα-expressing cells and binds HSA with
K
d
= 4.6 ± 0.1 μM. Uptake of the radiolabeled ligand in tumors was evident from 30 min p.i. (> 5 %ID/g) and was significantly reduced by co-injection of RPS-309. Specific skeletal uptake was also observed. Activity in tumors was constant through 4 h p.i., but cleared significantly by 24 h. The AUC in this period was 127 (%ID/g) × h.
Conclusions
RPS-309 is a high-affinity FAPα inhibitor with prolonged plasma residence. Introduction of the albumin-binding group did not compromise FAPα binding. Although initial tumor uptake was high and FAPα-specific, RPS-309 also progressively cleared from tumors. Nevertheless, RPS-309 incorporates multiple sites in which structural diversity can be introduced, and therefore serves as a platform for future structure-activity relationship studies.
In 2007 the Department of Education introduced the standards-based Advanced Certificate in Education: School Management and Leadership. The standardisation of leadership and management development in ...South African schools has been uncritically accepted by most academics and professionals. The purpose of this article is to problematise the standardisation of leadership and management development, using the critiques of the Interstate School Leadership Licensure Consortium standards of the United States as the basis of analysis. This article indicates the following areas of concern: the lack of clarity regarding the empirical basis of the unit standards; the incorporation of certain non-empirical ideals into the programme; the generic instead of contextualised approaches to leadership and management development; the use of a generic programme for school principals, deputy principals, and heads of department in spite of their differentiated roles; and the lack of a single, generally accepted policy document containing an exposition of the role of school principals that could form the basis of leadership and management development. This emphasises the need for the unit standards to be subjected to regular scrutiny and revision to address areas of concern and to ensure relevance thereof in the face of current developments and empirical research findings.
Purpose
Treatment of late-stage prostate cancer by targeted radiotherapeutics such as
131
I-MIP-1095 and
177
Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical ...settings, but targeted radioligand therapy (RLT) with
177
Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as
68
Ga
3+
,
177
Lu
3+
and
225
Ac
3+
.
Methods
Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an
N
ε
-(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator
p
-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to
177
Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using
66
Ga
3+
and biodistribution studies at 4 h, 24 h and 96 h p.i. with
177
Lu
3+
.
Results
PSMA affinity was high (IC
50
= 1–10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for
177
Lu-PSMA-617 over 96 h. The highest uptake was achieved with
177
Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand
177
Lu-RPS-067. Each of the compounds showed slower blood clearance than
177
Lu-PSMA-617, with clearance proportional to linker length.
Conclusions
The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with
177
Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis.
GaPentixafor is a promising ligand ...for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of
Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of
FRPS-534 (7.2 ± 0.3 %ID/g) and
FRPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background,
FRPS-547, and especially
FRPS-534, are promising
F-labeled candidates for imaging CXCR4 expression.
Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to ...therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity.
Four structurally related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin-binding group or inserting a polyethylene glycol 8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity and were radiolabeled with
Ga and
Lu. Tissue kinetics were determined in male BALB/C
mice bearing LNCaP xenograft tumors.
Each of the compounds binds PSMA with a half-maximal inhibitory concentration of no more than 10 nM. The albumin-binding group had a minimal effect on PSMA affinity but changed albumin affinity by an order of magnitude. However, the addition of a polyethylene glycol 8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of
Lu-RPS-072 (34.9 ± 2.4 %ID/g) and
Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h after injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the following order:
Lu-RPS-072 >
Lu-RPS-077 >
Lu-RPS-063 >
Lu-RPS-071. Increased linker length corresponded to more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for
Lu-RPS-072.
The tumor AUC and tumor-to-kidney ratio of
Lu-RPS-072 are significantly enhanced compared with any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are considered. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors, and is a highly promising candidate for targeted radioligand therapy.
Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among ...candidate positron-emitting radionuclides, 66Ga (t1/2 = 9.5 h, β+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of 66Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules. 66Ga was produced by irradiation of a natZn target. 66Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 ± 2.8% recovery of 66Ga3+. Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the 68GaGa-labeled ligands did. Although there are multiple challenges to the use of 66Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h.
Prostate-specific membrane antigen (PSMA)-targeted radiotherapy of prostate cancer (PCa) has emerged recently as a promising approach to the treatment of disseminated disease. A small number of ...ligands have been evaluated in patients, and although early tumor response is encouraging, relapse rate is high and these compounds localize to the parotid, salivary, and lacrimal glands as well as to the kidney, leading to dose-limiting toxicities and adverse events affecting quality of life. We envision that dual-target binding ligands displaying high affinity for PSMA and appropriate affinity for human serum albumin (HSA) may demonstrate a higher therapeutic index and be suitable for treatment of PCa by targeted α-therapy.
Six novel urea-based ligands with varying affinities for PSMA and HSA were synthesized, labeled with
I, and evaluated by in vitro binding and uptake assays in LNCaP cells. Four compounds were advanced for further evaluation in a preclinical model of PCa. The compounds were compared with MIP-1095, a PSMA ligand currently in clinical evaluation.
The compounds demonstrated affinity for PSMA on the order of 4-40 nM and affinity for HSA in the range of 1-53 μM. Compounds with relatively high affinity for HSA (≤2 μM) showed high and sustained blood-pool activity and reduced uptake in the kidneys.
I-RPS-027, with a 50% inhibitory concentration (PSMA) of 15 nM and a dissociation constant (HSA) of 11.2 μM, cleared from the blood over the course of 48 h and showed good tumor uptake (10 percentage injected dose per gram) and retention and a greater than 5-fold decrease in kidney uptake relative to MIP-1095. The tumor-to-kidney ratio of
I-RPS-027 was greater than 3:1 at 24 h after injection, increasing to 7:1 by 72 h.
RPS-027 shows dual targeting to PSMA and albumin, resulting in a high tumor uptake, highly favorable tissue distribution, and promising therapeutic profile in a preclinical model of prostate cancer. In comparison to existing ligands proposed for targeted therapy of prostate cancer, RPS-027 has tumor-to-tissue ratios that predict a significant reduction in side effects during therapy. Using iodine/radioiodine as a surrogate for the radiohalogen
At, we therefore propose dual-target binding ligands such as RPS-027 as next-generation radiopharmaceuticals for targeted α-therapy using
At.
The current study describes how a community-partnered participatory research (CPPR) model was used to enhance hair cortisol research engagement among low-income adults of diverse ethnicities and ...sexual and gender identities. Participants' reported motivations and concerns surrounding providing a hair sample are also described. Participants from a larger longitudinal study were invited to provide a hair sample and/or complete acceptability interviews. Results indicated that 71% of all persons (N=133) contacted participated in the current study, of whom 82% provided hair samples. Several themes emerged from the interviews indicating that participants were motivated to provide a hair sample due to internal and external factors; however, concerns about mistrust of research remained. Thus, collecting biospecimens in research with underserved groups requires careful consideration of benefits and risks to the individual and their communities. Our results provide guidelines for engaging low-income racially/ethnically and sexually diverse community members in biospecimen research to understand stress-health relationships.
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