Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies.

Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [177Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.

A Culturally and Linguistically Appropriate Telephone Support Intervention for Diverse Family Caregivers of Persons With Dementia During the COVID-19 Pandemic.

Caregivers of persons with dementia (PWDs) were socially isolated with little support during the COVID-19 pandemic "Stay-At-Home" order in the United States. To enhance social and emotional connection for diverse caregivers, a culturally/linguistically appropriate telephone intervention provided compassionate listening, mindful breathing, and COVID-19 safety education. The study purpose was to understand caregiving challenges and to evaluate the intervention for caregivers during the early pandemic using a qualitative approach. Twenty-three caregivers participated in the intervention provided by bilingual research assistants for 3 months. Call logs were used to describe the caregivers' dialogue. Thematic analysis identified (a) the challenges, including fear of coronavirus disease, providing around-the-clock care, and forced isolation and negative emotions; and (b) caregivers' experience with the intervention, including connecting with the outside, relief from emotional stress, reliable COVID-19 information, and reinformed caregiving skills. Results suggest that the telephone support was of benefit to diverse caregivers of PWDs during the pandemic by promoting social connection and reducing emotional distress.

225Ac-H4py4pa for Targeted Alpha Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

Evaluation of Met-Val-Lys as a Renal Brush Border Enzyme-Cleavable Linker to Reduce Kidney Uptake of 68Ga-Labeled DOTA-Conjugated Peptides and Peptidomimetics.

High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of 68Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [68Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [68Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [68Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [68Ga]Ga-HTK01166. Our data demonstrated that derivatives of [68Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

Relationships within MOMS Orange County care coordinated home visitation perinatal program.

PURPOSE: The study aimed to examine how registered nurses (RNs) and paraprofessional home visitors (PHVs) work together as a team to care for underserved perinatal women in a coordinated home visitation program. DESIGN AND METHODS: Qualitative methods were used to understand the perspectives of three RNs and twenty PHVs who worked at MOMS Orange County, a community-based perinatal health program. Individual one-on-one interviews were administered with the RNs and focus groups with the PHVs. Qualitative content analysis was conducted to synthesize themes. RESULTS: RNs perceived themselves as educators, mentors, and supervisors. PHVs thought of themselves as supporters, coaches, and advocates. Interdependence and proactive communication were favorable characteristics of the relationship in which RNs trained PHVs to provide health education. The positive interactions between RNs and PHVs appeared to enhance the client-healthcare provider connection. CONCLUSIONS: Our study is one of the first to describe relationships and communication patterns among the healthcare team in a coordinated home visitation program in the United States. Future studies should examine how additional members of the team, including clients and healthcare providers, view their experiences with a home visitation program.

Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular 89Zr-THPN-Conjugates.

Zirconium-89 (89Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used 89Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative 89Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising 89Zr-chelator. In this study, we aimed to further explore this octadentate chelate in vitro and in vivo. The [ZrIV(THPN)] thermodynamic stability was quantified in solution titration studies, which revealed one of the highest formation constants reported for a zirconium chelate (log ßML 50.3(1), pM = 42.8). Solution stabilities with iron(III) were also exceptionally high and can compete with some of the strongest FeIII-chelates. A first bifunctional derivative of the octadentate ligand, p-SCN-Bn-THPN, was then produced in a multistep synthesis. To assess and compare the long-term 89Zr complex stability, bifunctional THPN, as well as the literature chelators p-SCN-Phe-DFO and p-SCN-Phe-DFO*, were conjugated to the high-molecular weight (800 kDa) polymeric carrier hyperbranched polyglycerol (HPG). The functionalized HPGs were radiolabeled with 89ZrIV, and the integrity of the radioconjugates was assessed over several days in vitro and in vivo. While all three radioconjugates remained >95% intact over 5 days in human plasma, the in vivo study in healthy mice revealed higher physiologic stability of the DFO and DFO* radiochelates over bifunctional THPN conjugates. This was evidenced by increased bone uptake of osteophilic 89ZrIV for THPN. This finding contrasts with the exceptionally high thermodynamic stability of the chelate and suggests either a kinetic or metabolic lability, or may stem from coordinative changes due to the covalent conjugation of the 89Zr-THPN radiochelate as suggested by density functional theory (DFT) calculations. These important findings inform the design of next generation 3,4-HOPO chelates with the aim of improving the physiologic stability. This study furthermore demonstrates how HPG can be used as a robust carrier tool to assess and compare the long-term in vivo stability of radiochelates.

Hispanic Mothers' Experiences with School-Based Emotional Health Curriculum and Perspectives of Their Own Mental Health Needs.

An Emotional Health Curriculum (EHC) was developed to promote positive mental health in primarily Hispanic elementary school-aged children. In order to further expand the EHC, the mothers' experiences with the curriculum were examined. Eighteen mothers participated in two focus groups. Mothers reported that they valued this curriculum as a preventive program. Importantly, all mothers wished to extend their involvement to not only assisting their child in completing the curriculum homework but also attending a proposed parenting program. This study provides preliminary evidence that mothers embraced the EHC as an accessible community mental health service for their children and sought greater involvement.

Emotional and Behavioral Health Needs in Elementary School Students in an Underserved Hispanic Community.

High rates of mental health problems in adolescents have been well documented; less is known about elementary school children in disadvantaged communities. We examined emotional and behavioral health needs in 202 third and fourth graders enrolled in a charter school in a largely Hispanic community. The child-reported Revised Child Anxiety and Depression Scale-25 and Teacher's Report Form were used to evaluate mental health needs as perceived by these children and their teachers. The prevalence of teacher-reported depression and child self-reported anxiety was 7.0% and 6.67%, respectively. Living in a single parent household was found to be a specific risk factor in that those children had higher rates of emotional and behavioral problems than children living with both parents. Evidence of higher depression and anxiety identified in this sample compared to national representative data suggests the need for development of culturally sensitive early prevention and intervention in this underserved community.

Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography.

Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with 89Zr for positron emission tomography imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, respectively. Trastuzumab conjugates of 3 and 4 were efficiently labeled with 89Zr (>95% radiochemical yield). The in vitro plasma stability of 89Zr-4-Trastuzumab and especially 89Zr-3-Trastuzumab was greatly improved over previously reported 89Zr-1-Trastuzumab and 89Zr-2-Trastuzumab, but their demetalation remained higher and faster than 89Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for 89Zr-4-Trastuzumab, followed by 89Zr-3-Trastuzumab, and to a lesser extent for 89Zr-DFO-Trastuzumab. Molecular modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.

Synthesis and evaluation of an 18 F-labeled trifluoroborate derivative of 2-nitroimidazole for imaging tumor hypoxia with positron emission tomography.

2-Nitroimidazole-based hypoxia imaging tracers such as 18 F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, 18 F-AmBF3 -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3 -Bu-2NI was prepared in 4 steps. 18 F labeling was conducted via 18 F-19 F isotope exchange reaction, and 18 F-AmBF3 -Bu-2NI was obtained in 14.8 ± 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 ± 5.2 GBq/µmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that 18 F-AmBF3 -Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post-injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of 18 F-AmBF3 -Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic 18 F-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target.

p-NO2-Bn-H4neunpa and H4neunpa-Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging.

Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H4neunpa and its immunoconjugate H4neunpa-trastuzumab for 111In radiolabeling are synthesized. The ability of p-SCN-Bn-H4neunpa and H4neunpa-trastuzumab to quantitatively radiolabel 111InCl3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111In complexes to have high stability over 5 days. Mouse biodistribution of [111In][In(p-NO2-Bn-neunpa)]-, compared to that of [111In][In(p-NH2-Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))]2-, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111In-neunpa-trastuzumab and 111In-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111In-neunpa-trastuzumab compared to that of 111In-CHX-A″-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H4neunpa to be a promising chelator for 111In (and other radiometals) with high in vitro stability and also show H4neunpa-trastuzumab to be an excellent 111In chelator with promising biodistribution in mice.

Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of 89Zr-labeled antibodies.

Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with 89Zr for imaging with positron emission tomography. Using 2,2'-iminodiacetamide as the backbone, four hydroxamate-containing moieties coupled to the diacetamide nitrogen were used for 89Zr labeling, while a pendant connected to the amino group provided an isothiocyanate group for coupling to the antibody. Both 1- and 2-conjugated Trastuzumab were labeled with 89Zr efficiently (>90% radiolabeling yield), and their 89Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to 89Zr-labeled deferoxamine-conjugated Trastuzumab, 89Zr-1- and 89Zr-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of 89Zr complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient 89Zr labeling, and could be potentially modified to provide novel chelators with improved stability.

A pioneering EMR-embedded digital health literacy tool reveals healthcare disparities for diverse older adults.

BACKGROUND: The COVID-19 pandemic transformed healthcare delivery with the rapid adoption of telehealth and digital technologies to access healthcare. Interventions are needed to ensure that older people in underserved communities do not face new technology-driven healthcare disparities. This article describes pioneering electronic medical record (EMR) embedded tools to assess and support each diverse patient's digital health literacy. METHODS: We designed and validated a rapid EMR-embedded Digital Health Engagement Tool (DHET) to assess each patient's digital literacy in English and Spanish. We built a separate, EMR-generated auto-scoring function to assess patient use of telehealth and healthcare navigation as recorded within the EMR. Combined, the tools created a complete digital literacy assessment for each patient. We then deployed the tools to conduct a pilot study to elucidate disparities. RESULTS: A total of 112 ethnic/racial diverse older patients were enrolled (mean age was 78, ranging from 57 to 96) years (SD = 8.04). The female participants were 72.3%. Among the participants, non-Hispanic Whites were 47.3%; Hispanic 25.0%; non-Hispanic Asian 19.6%; non-Hispanic others (including multi-race and non-Hispanic Black/African Americans) 8.0%. Digital literacy disparities were revealed for older adults, particularly those over 70 years old, female gender, and those reporting relying on a helper. CONCLUSION: New EMR-embedded tools enable healthcare systems to assess the ability of patients to navigate and utilize EMR capabilities, such as video telehealth appointments, messaging providers, reviewing labs/radiology reports, and requesting prescriptions. The study identified significant challenges for older patients in navigating EMRs and calls for healthcare systems to better support patient learning.

ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia.

Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P ≤ .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P = .005; ASNS tandem-repeat and related haplotype, P ≤ .01) were subsequently analyzed in the replication cohort. The E coli-dependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P = .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P ≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P ≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli-induced asparagine depletion may explain our observed results.

Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors.

OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population. STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated. RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems. CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.

Identification of genetic counseling service delivery models in practice: a report from the NSGC Service Delivery Model Task Force.

Increasing demand for genetic services has resulted in the need to evaluate current service delivery models (SDMs) and consider approaches that improve access to and efficiency of genetic counseling (GC). This study aimed to describe SDMs currently used by the GC community. The NSGC membership was surveyed regarding the use of four SDMs: in-person GC, telephone GC, group GC, and telegenetics GC. Variables related to access and components of use were also surveyed, including: appointment availability, time-per-patient, number of patients seen, billing, and geographic accessiblity. Seven hundred one usable responses were received. Of these, 54.7 % reported using an in-person SDM exclusively. The remainder (45.3 %) reported using multiple SDMs. Telephone, group and telegenetics GC were used often or always by 8.0 %, 3.2 % and 2.2 % of respondents, respectively. Those using an in-person SDM reported the ability to see the highest number of patients per week (p < 0.0001) and were the most likely to bill in some manner (p < 0.0001). Those using telegenetic and telephone GC served patients who lived the furthest away, with 48.3 % and 35.8 %% respectively providing GC to patients who live >4 h away. This study shows that genetic counselors are incorporating SDMs other than traditional in-person genetic counseling, and are utilizing more than one model. These adaptations show a trend toward shorter wait time and shorter length of appointments. Further study is indicated to analyze benefits and limitations of each individual model and factors influencing the choice to adopt particular models into practice.

The Effectiveness of Language-Specific Personal Care Education on Improving the Knowledge and Skills of Vietnamese American In-Home Supportive Service Caregivers.

BACKGROUND: In-Home Supportive-Services (IHSS) caregivers provide personal care assistance to low-income older adults. According to the California Social Service Department, 20.2% of IHSS caregivers spoke Vietnamese in one county. The purpose of this project was to improve the knowledge and skills among these Vietnamese American caregivers by providing a language-specific and culturally appropriate education on personal care. METHODS: The project used a pre- and post-test design. Under the guidance of nursing faculty, four Vietnamese-speaking nursing students provided a 2-hr educational program on personal care (e.g., bathing, oral care) to registered Vietnamese IHSS caregivers. A pre- and post-survey was conducted. RESULTS: Overall, 55 caregivers completed the surveys. The surveys showed significant increases in confidence in knowledge and skills related to personal care topics (all ps < .001). CONCLUSION: The findings demonstrated that the cultural and language-specific education was effective in increasing knowledge and confidence of Vietnamese IHSS caregivers related to personal care for older adults.

Report from the National Society of Genetic Counselors service delivery model task force: a proposal to define models, components, and modes of referral.

The Service Delivery Model Task Force (SDMTF) was appointed in 2009 by the leadership of the National Society of Genetic Counselors (NSGC) with a charge to research and assess the capacity of all existing service delivery models to improve access to genetic counseling services in the context of increasing demand for genetic testing and counseling. In approaching this charge, the SDMTF found that there were varying interpretations of what was meant by "service delivery models" and the group held extensive discussions about current practices to arrive at consensus of proposed definitions for current genetic service delivery models, modes of referral and components of service delivery. The major goal of these proposed definitions is to allow for conversations to begin to address the charge to the committee. We propose that current models of service delivery can be defined by: 1) the methods in which genetic counseling services are delivered (In-person, Telephone, Group and Telegenetics), 2) the way they are accessed by patients (Traditional referral, Tandem, Triage, Rescue and Self-referral) and 3) the variable components that depend upon multiple factors unique to each service setting. This report by the SDMTF provides a starting point whereby standardized terminology can be used in future studies that assess the effectiveness of these described models to overcome barriers to access to genetic counseling services.

Trastuzumab-conjugated oxine-based ligand for [89Zr]Zr4+ immunoPET.

A new, bifunctional chelating ligand for immuno-Positron Emission Tomography (PET) was designed, synthesized, and conjugated to Trastuzumab for a proof-of-concept study with 89Zr. H4neunox was synthesized from the tris(2-aminoethyl)amine backbone, decorated with 8-hydroxyquinoline moieties, and utilizes a primary amine for functionalization. A maleimide moiety extends the chelator to create H4neunox-mal for antibody conjugation via maleimide-thiol click chemistry. Preliminary 89Zr radiolabeling of H4neunox indicated quantitative radiolabeling at 1 × 10-5 M, but improved inertness towards human serum (96% intact at 7 d) and Fe3+ (92% intact at 24 h) compared to the previously synthesized H5decaox. The chelator was successfully conjugated to the monoclonal antibody, Trastuzumab, and used in preliminary radiolabeling reactions (37 °C, 2 h) with 89Zr. Radiochemical assessments of the new H4neunox-Trastuzumab conjugate include 89Zr radiolabeling, spin filter purification, cell-binding immunoreactivity, and in vivo PET imaging and biodistribution in SKOV-3 tumour bearing nude mice, performed in comparison with the desferrioxamine B analog, DFO-Trastuzumab. The [89Zr]Zr(neunox-Trastuzumab) showed lowered inertness towards serum (76% intact at 24 h) as well as demetallation in vivo through bone uptake (21% ID/g) in PET imaging and biodistribution studies when compared to [89Zr]Zr(DFO-Trastuzumab). Although the combination of the chelator and antibody had detrimental effects on their intended purposes, nonetheless, the primary amine platform of H4neunox developed here provides an oxine-based bifunctional ligand for further derivatizations with other targeting vectors.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs.

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a "theranostic pair" imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.