Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.

Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited. Recently identified C. elegans proteins TEBP-1 (also called DTN-1) and TEBP-2 (also called DTN-2) are functional homologs of TRF proteins, but how they bind DNA and whether or how they dimerize is not known. TEBP-1 and TEBP-2 harbor three Myb-containing domains (MCDs) and no obvious dimerization domain. We demonstrate biochemically that only the third MCD binds DNA. We solve the X-ray crystal structure of TEBP-2 MCD3 with telomeric dsDNA to reveal the structural mechanism of telomeric dsDNA protection in C. elegans. Mutagenesis of the DNA-binding site of TEBP-1 and TEBP-2 compromises DNA binding in vitro, and increases DNA damage signaling, lengthens telomeres, and decreases brood size in vivo. Via an X-ray crystal structure, biochemical validation of the dimerization interface, and SEC-MALS analysis, we demonstrate that MCD1 and MCD2 form a composite dimerization module that facilitates not only TEBP-1 and TEBP-2 homodimerization but also heterodimerization. These findings provide fundamental insights into C. elegans telomeric dsDNA protection and highlight how different eukaryotes have evolved distinct strategies to solve the chromosome end protection problem.

PLEIOTROPIC REGULATORY LOCUS1 maintains actin microfilament integrity to regulate pavement cell morphogenesis.

Actin dynamics are critical for plant cell morphogenesis, but the underlying signaling mechanisms regulating these dynamics are not well understood. Here, we established that PLEIOTROPIC REGULATORY LOCUS1 (PRL1) modulates leaf pavement cell (PC) morphogenesis in Arabidopsis (Arabidopsis thaliana) by maintaining the dynamic homeostasis of actin microfilaments (MF). Our previous studies indicated that PC shape was determined by antagonistic RHO-RELATED GTPase FROM PLANTS 2 (ROP2) and RHO-RELATED GTPase FROM PLANTS 6 (ROP6) signaling pathways that promote cortical MF and microtubule organization, respectively. Our genetic screen for additional components in ROP6-mediated signaling identified prl1 alleles. Genetic analysis confirmed that PRL1 plays a key role in PC morphogenesis. Mutations in PRL1 caused cortical MF depolymerization, resulting in defective PC morphogenesis. Further genetic analysis revealed that PRL1 is epistatic to ROP2 and ROP6 in PC morphogenesis. Mutations in PRL1 enhanced the effects of ROP2 and ROP6 in PC morphogenesis, leading to a synergistic phenotype in the PCs of ROP2 prl1 and ROP6 prl1. Furthermore, the activities of ROP2 and ROP6 were differentially altered in prl1 mutants, suggesting that ROP2 and ROP6 function downstream of PRL1. Additionally, cortical MF depolymerization in prl1 mutants occurred independently of ROP2 and ROP6, implying that these proteins impact PC morphogenesis in the prl1 mutant through other cellular processes. Our research indicates that PRL1 preserves the structural integrity of actin and facilitates pavement cell morphogenesis in Arabidopsis.

Breakthrough infection and reinfection in patients with mpox.

Recently, patients with Mpox breakthrough infection or reinfection were constantly reported. However, the induction, risk factors, and important clinical symptoms of breakthrough infection and reinfection of Mpox virus (MPXV), as well as the factors affecting the effectiveness of Mpox vaccine are not characterized. Herein, a literature review was preformed to summarize the risk factors and important clinical symptoms of patients with Mpox breakthrough infection or reinfection, as well as the factors affecting the effectiveness of smallpox vaccine against Mpox. Results showed that MSM sexual behavior, condomless sexual behavior, multiple sexual partners, close contact, HIV infection, and the presence of comorbidity are important risk factors for Mpox breakthrough infection and reinfection. Genital ulcers, proctitis, and lymphadenopathy are the important clinical symptoms of Mpox breakthrough infection and reinfection. The effectiveness of emergent vaccination of smallpox vaccine for post-exposure of MPXV is associated with smallpox vaccination history, interval between exposure and vaccination, and history of HIV infection. This review provides a better understanding for the risk factors and important clinical symptoms of Mpox breakthrough infection and reinfection, as well as the formulation of Mpox vaccine vaccination strategies.

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders.

Recycling of spent lithium-ion batteries for a sustainable future: recent advancements.

Lithium-ion batteries (LIBs) are widely used as power storage systems in electronic devices and electric vehicles (EVs). Recycling of spent LIBs is of utmost importance from various perspectives including recovery of valuable metals (mostly Co and Li) and mitigation of environmental pollution. Recycling methods such as direct recycling, pyrometallurgy, hydrometallurgy, bio-hydrometallurgy (bioleaching) and electrometallurgy are generally used to resynthesise LIBs. These methods have their own benefits and drawbacks. This manuscript provides a critical review of recent advances in the recycling of spent LIBs, including the development of recycling processes, identification of the products obtained from recycling, and the effects of recycling methods on environmental burdens. Insights into chemical reactions, thermodynamics, kinetics, and the influence of operating parameters of each recycling technology are provided. The sustainability of recycling technologies (e.g., life cycle assessment and life cycle cost analysis) is critically evaluated. Finally, the existing challenges and future prospects are presented for further development of sustainable, highly efficient, and environmentally benign recycling of spent LIBs to contribute to the circular economy.

Recent advances in Rh(I)-catalyzed enantioselective C-H functionalization.

Chiral carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds are pervasive and very essential in natural products, bioactive molecules, and functional materials, and their catalytic construction has emerged as one of the hottest research fields in synthetic organic chemistry. The last decade has witnessed vigorous progress in Rh(I)-catalyzed asymmetric C-H functionalization as a complement to Rh(II) and Rh(III) catalysis. This review aims to provide the most comprehensive and up-to-date summary covering the recent advances in Rh(I)-catalyzed C-H activation for asymmetric functionalization. In addition to the development of diverse reactions, chiral ligand design and mechanistic investigation (inner-sphere mechanism, outer-sphere mechanism, and 1,4-Rh migration) will also be highlighted.

Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

Locational and functional characterization of PI4KB in the mouse embryo.

Phosphatidylinositol 4-kinase beta (PI4KB) is a member of the PI4K family, which is mainly enriched and functions in the Golgi apparatus. The kinase domain of PI4KB catalyzes the phosphorylation of phosphatidylinositol to form phosphatidylinositol 4-phosphate, a process that regulates various sub-cellular events, such as non-vesicular cholesterol and ceramide transport, protein glycosylation, and vesicle transport, as well as cytoplasmic division. In this study, a strain of PI4KB knockout mouse, immunofluorescence, reverse transcription polymerase chain reaction and microinjection were used to characterize the cytological location and biological function of PI4KB in the mouse embryos. we found that knocking down Pi4kb in mouse embryos resulted in embryonic lethality at around embryonic day (E) 7.5. Additionally, we observed dramatic fluctuations in PI4KB expression during the development of preimplantation embryos, with high expression in the 4-cell and morula stages. PI4KB colocalized with the Golgi marker protein TGN46 in the perinuclear and cytoplasmic regions in early blastomeres. Postimplantation, PI4KB was highly expressed in the epiblast of E7.5 embryos. Treatment of embryos with PI4KB inhibitors was found to inhibit the development of the morula into a blastocyst and the normal progression of cytoplasmic division during the formation of a 4-cell embryo. These findings suggest that PI4KB plays an important role in mouse embryogenesis by regulating various intracellular vital functions of embryonic cells.

Leveraging Isoreticular Principle to Elucidate the Key Role of Inherent Hydrogen-Bonding Anchoring Sites in Enhancing Water Sorption Cyclability of Zr(IV) Metal-Organic Frameworks.

Water adsorption/desorption cyclability of porous materials is a prerequisite for diverse applications, including atmospheric water harvesting (AWH), humidity autocontrol (HAC), heat pumps and chillers, and hydrolytic catalysis. However, unambiguous molecular insights into the correlation between underlying building blocks and the cyclability are still highly elusive. In this work, by taking advantage of the well-established isoreticular synthetic principle in Zr(IV) metal-organic frameworks (Zr-MOFs), we show that the inherent density of hydrogen atoms in the organic skeleton can play a key role in regulating the water sorption cyclability of MOFs. The ease of isoreticular practice of Zr-MOFs enables the successful syntheses of two pairs of isostructural Zr-MOFs (NU-901 and NU-903, NU-950 and SJTU-9) from pyrene- or benzene-cored carboxylate linkers, which feature scu and sqc topological nets, respectively. NU-901 and NU-950 comprised of pyrene skeletons carrying more hydrogen-bonding anchoring sites show distinctly inferior cyclability as compared with NU-903 and SJTU-9 built of benzene units. Single-crystal X-ray crystallography analysis of the hydrated structure clearly unveils the water molecule-involved interactions with the hydrogen-bonding donors of benzene moieties. Remarkably, NU-903 and SJTU-9 isomers exhibit outstanding water vapor sorption capacities as well as working capacities at the desired humidity range with potential implementations covering indoor humidity control and water harvesting. Our findings uncover the importance of hydrogen-bonding anchoring site engineering of organic scaffold in manipulating the framework durability toward water sorption cycle and will also likely facilitate the rational design and development of highly robust porous materials.

A GSH-Responsive Prodrug with Simultaneous Triple-Activation Capacity for Photodynamic/Sonodynamic Combination Therapy with Inhibited Skin Phototoxicity.

Herein, a dual-sensitizer prodrug, named pro-THPC, has been designed to function as both a photosensitizer and a sonosensitizer prodrug for precise antitumor combination therapy with minimized skin phototoxicity. Pro-THPC could be activated by glutathione (GSH) to release the dual-sensitizer, THPC, which simultaneously switches on fluorescence emission and combined capabilities of photodynamic therapy (PDT) and sonodynamic therapy (SDT). Pro-THPC is further formulated into nanoparticles (NPs) for water dispersity to enable in vivo applications. In vivo fluorescence imaging shows that the pro-THPC NPs group exhibits a significantly higher tumor-to-normal tissue ratio (T/N) (T/N = 5.2 ± 0.55) compared to the "always on" THPC NPs group (T/N = 2.9 ± 0.47) and the pro-THPC NPs group co-administrated with GSH synthesis inhibitor (buthionine sulfoximine, BSO) (T/N = 3.2 ± 0.63). In addition, the generation of the designed dual-sensitizer's reactive oxygen species (ROS) is effectively confined within the tumor tissues due to the relatively strong correlation between ROS generation and fluorescence emission. In vivo studies further demonstrate the remarkable efficacy of the designed pro-THPC NPs to eradicate tumors through the combination of PDT and SDT while significantly reducing skin phototoxicity.

Deformable Smart DNA Nanomachine for Synergistic Intracellular Cancer-Related miRNAs Imaging and Chemo-Gene Therapy of Drug-Resistant Tumors.

Diagnosis and treatment of tumor especially drug-resistant tumor remains a huge challenge, which requires intelligent nanomedicines with low toxic side effects and high efficacy. Herein, deformable smart DNA nanomachines are developed for synergistic intracellular cancer-related miRNAs imaging and chemo-gene therapy of drug-resistant tumors. The tetrahedral DNA framework (MA-TDNA) with fluorescence quenched component and five antennas is self-assembled first, and then DOX molecules are loaded on the MA-TDNAs followed by linking MUC1-aptamer and Mcl-1 siRNA to the antennas of MA-TDNA, so that the apt-MA-TDNA@DOX-siRNA (DNA nanomachines) is constructed. The DNA nanomachine can respond to two tumor-related miRNAs in vitro and in vivo, which can undergo intelligent miRNA-triggered opening of the framework, resulting in the "turn on" of the fluorescence for sensitively and specifically sensing intracellular miRNAs. Meanwhile, both miRNA-responded rapid release and pH-responded release of DOX are achieved for chemotherapy of tumor. In addition, the gene therapy of the DNA nanomachines is achieved due to the miRNA-specific capture and the RNase H triggered release of Mcl-1 siRNA. The DNA nanomachines intergrading both tumor imaging and chemo-gene therapy in single nanostructures realized efficient tumor-targeted, image-guided, and microenvironment-responsive tumor diagnosis and treatment, which provides a synergetic antitumor effect on drug-resistant tumor.

Harnessing Natural Evaporation for Electricity Generation using MOF-Based Nanochannels.

Functionalized nanochannels can convert environmental thermal energy into electrical energy by driving water evaporation. This process involves the interaction between the solid-liquid interface and the natural water evaporation. The evaporation-driven water potential effect is a novel green environmental energy capture technology that has a wide range of applications and does not depend on geographical location or environmental conditions, it can generate power as long as there is water, light, and heat. However, suitable materials and structures are needed to harness this natural process for power generation. MOF materials are an emerging field for water evaporation power generation, but there are still many challenges to overcome. This work uses MOF-801, which has high porosity, charged surface, and hydrophilicity, to enhance the output performance of evaporation-driven power generation. It can produce an open circuit voltage of ≈2.2 V and a short circuit current of ≈1.9 µA. This work has a simple structure, easy preparation, low-cost and readily available materials, and good stability. It can operate stably in natural environments with high practical value.

Correlating Young's Modulus with High Thermal Conductivity in Organic Conjugated Small Molecules.

Attaining elevated thermal conductivity in organic materials stands as a coveted objective, particularly within electronic packaging, thermal interface materials, and organic matrix heat exchangers. These applications have reignited interest in researching thermally conductive organic materials. The understanding of thermal transport mechanisms in these organic materials is currently constrained. This study concentrates on N, N'-dioctyl-3,4,9,10-perylenedicarboximide (PTCDI-C8), an organic conjugated crystal. A correlation between elevated thermal conductivity and augmented Young's modulus is substantiated through meticulous experimentation. Achievement via employing the physical vapor transport method, capitalizing on the robust C═C covalent linkages running through the organic matrix chain, bolstered by π-π stacking and noncovalent affiliations that intertwine the chains. The coexistence of these dynamic interactions, alongside the perpendicular alignment of PTCDI-C8 molecules, is confirmed through structural analysis. PTCDI-C8 thin film exhibits an out-of-plane thermal conductivity of 3.1 ± 0.1 W m-1 K-1, as determined by time-domain thermoreflectance. This outpaces conventional organic materials by an order of magnitude. Nanoindentation tests and molecular dynamics simulations elucidate how molecular orientation and intermolecular forces within PTCDI-C8 molecules drive the film's high Young's modulus, contributing to its elevated thermal conductivity. This study's progress offers theoretical guidance for designing high thermal conductivity organic materials, expanding their applications and performance potential.

Tailoring nondiffracting fields with a non-Markovian phase imprint.

We experimentally generate nondiffracting speckles that carry non-Markovian properties by encoding the wavefront of a monochromatic laser beam with ring-shaped non-Markovian phases. The resulting non-Markovian nondiffracting fields present a ring-shaped pattern and central dark notches, which are analyzed with an expression of the orbital angular momentum spectra of the wavefront possessing ring-shaped non-Markovian phases. Furthermore, we demonstrate that the intensity profiles of these non-Markovian nondiffracting fields exhibit stability over multiple Rayleigh ranges, and their statistical properties could be controlled with the non-Markovianity of the input phase masks. This work presents an approach for simultaneously tailoring the diffracting property and non-Markovianity of optical fields and provides a deeper understanding of non-Markovian processes.

Compact mode converters in thin-film lithium niobate integrated platforms.

Mode converters, crucial elements within photonic integrated circuits (PICs) designed for multimode optical transmission and switching systems, present a challenge due to their bulky structures in thin-film lithium niobate (TFLN) integrated platforms, which are incompatible with the compact and efficient nature desired for dense PICs. In this work, we propose TE1-TE0, TE2-TE0, and TE3-TE0 mode converters in shallowly etched TFLN, within small footprints. The experimental results show that the insertion loss is 0.4 dB, 0.6 dB, and 0.5 dB for the compact TE1-TE0, TE2-TE0, and TE3-TE0 mode converters, respectively, and these devices can be operated within a wide 1 dB bandwidth (BW) over 100 nm. This work facilitates the development of low-loss, broadband, and compact monolithically integrated photonic devices for future multimode communication networks in TFLN integrated platforms.

A comparison of [18F]AlF- and 68Ga-labeled dual targeting heterodimer FAPI-RGD in malignant tumor: preclinical evaluation and pilot clinical PET/CT imaging.

Due to the heterogeneity of tumors, strategies to improve the effectiveness of dual-targeting tracers in tumor diagnostics have been intensively practiced. In this study, the radiolabeled [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both fibroblast activation protein (FAP) and integrin αvß3 to enhance specific tumor uptake and retention, was synthesized and evaluated. The tracer was compared with [68Ga]Ga-LNC1007 in preclinical and clinical settings. METHODS: The preparation of [18F]AlF- and 68Ga-labeled FAPI-RGD was carried out with an optimized protocol. The stability was tested in PBS and fetal bovine serum (FBS). Cellular uptake and in vivo distribution of the two products were compared and carried out on the U87MG cell line and its xenograft model. The safety and dosimetry of [18F]AlF-LNC1007 PET/CT scan were evaluated in six patients with malignant tumors. RESULTS: Two radiolabeling protocols of [18F]AlF-/[68Ga]Ga-LNC1007 were developed and optimized to give a high yield of tracers with good stability. In vivo microPET images showed that the two tracers exhibited comparable pharmacokinetic characteristics, with high tumor uptake and prolonged tumor retention. In vivo distribution data showed that the target-to-non-target ratios of [18F]AlF-LNC1007 were similar to[68Ga]Ga-LNC1007. A total of six patients underwent [18F]AlF-LNC1007 PET/CT evaluation while two had head-to-head [18F]FDG PET/CT scans. The total body effective dose was 9.94E-03 mSv/MBq. The biodistribution curve showed optimal normal organ uptake with high tumor uptake and long retention of up to 3h p.i., and notably, the tumor-to-background ratio increased over time. CONCLUSION: We successfully prepared an [18F]AlF-LNC1007 dual-targeting PET probe with comparable performances as [68Ga]Ga-LNC1007. With prolonged tumor retention and tumor specificity, it produced good imaging quality in preclinical and clinical translational studies, indicating that [18F]AlF-LNC1007 is a promising non-invasive tracer for detecting tumors expressing FAP and/or integrin avß3, with the prospect of clinical implementation.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. METHODS: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. RESULTS: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. CONCLUSION: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

Synthesis, preclinical, and initial clinical evaluation of integrin αVß3 and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [68Ga]Ga-RGD-RM26-03.

Integrin receptor αvß3 and gastrin-releasing peptide receptor (GRPR) expression of tumors could be detected using PET imaging with radiolabeled Arg-Gly-Asp (RGD) and the antagonistic bombesin analog RM26, respectively. The purpose of this study was to investigate the dual receptor-targeting property of the heterodimer RGD-RM26-03 (denoted as LNC1015), demonstrate the tumor diagnostic value of [68Ga]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. METHODS: LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [68Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of 18F-fluorodeoxyglucose (FDG). RESULTS: [68Ga]Ga-LNC1015 had good stability in saline for at least 2 h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [68Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [68Ga]Ga-RGD and [68Ga]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [68Ga]Ga-LNC1015 PET/CT were significantly higher than those in [18F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. CONCLUSION: The dual targeting radiotracer [68Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [68Ga]Ga-RGD and [68Ga]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.