Molecular Pharmaceutics最新文献

{"title":"Amphiphilic Acyclic Cucurbit[<i>n</i>]uril: Synthesis, Self-Assembly, and Chemotherapeutic Delivery to Overcome Multidrug Resistance.","authors":"Zizhen Zhao, Danying Ma, Shuyi Wang, Wei Zhou, Dan-Wei Zhang, Zhan-Ting Li, Da Ma","doi":"10.1021/acs.molpharmaceut.5c00012","DOIUrl":"10.1021/acs.molpharmaceut.5c00012","url":null,"abstract":"<p><p>A new amphiphilic acyclic cucurbit[<i>n</i>]uril (CB[<i>n</i>]) is designed and synthesized. This amphiphilic acyclic CB[<i>n</i>] could encapsulate pharmaceutical drugs via a host-guest interaction. Self-assembly of this acyclic CB[<i>n</i>] forms spherical nanoparticles with diameters of 91 nm in water. The self-assembled nanoparticles are capable of delivering doxorubicin with high efficiency. Cell experiments show that the doxorubicin-loaded nanoparticles can improve cellular uptake and cytotoxicity by using the MCF-7/ADR cell line. The A549 tumor-bearing mouse model shows that self-assembled nanoparticles help overcome multidrug resistance in vivo. Cell study and histological assays confirm the biocompatibility of self-assembled nanoparticles.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2259-2265"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles\".","authors":"Savvas Dimiou, James McCabe, Rebecca Booth, Jonathan Booth, Kalyan Nidadavole, Olof Svensson, Anders Sparén, Lennart Lindfors, Vasiliki Paraskevopoulou, Heather Mead, Lydia Coates, David Workman, Dave Martin, Kevin Treacher, Sanyogitta Puri, Lynne S Taylor, Bin Yang","doi":"10.1021/acs.molpharmaceut.5c00307","DOIUrl":"10.1021/acs.molpharmaceut.5c00307","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2316-2318"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Insight into Lipid Nanoparticle Assembly from NMR Spectroscopy and Molecular Dynamics Simulation.","authors":"Mingyue Li, Ryan Schroder, Umut Ozuguzel, Tyler M Corts, Yong Liu, Yuejie Zhao, Wei Xu, Jing Ling, Allen C Templeton, Bodhisattwa Chaudhuri, Marian Gindy, Angela Wagner, Yongchao Su","doi":"10.1021/acs.molpharmaceut.4c01437","DOIUrl":"10.1021/acs.molpharmaceut.4c01437","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) have emerged as the premier drug delivery system for oligonucleotide vaccines and therapeutics in recent years. Despite their prosperous advancement in research and clinical applications, there is a significant lack of mechanistic understanding of the assembly of lipid particles at the molecular level. In our study, we utilized a combination of solution and solid-state NMR, together with molecular dynamics simulations, to elucidate local structures and interactions of chemical components across multiple motional regimes. Our results comprehensively evaluated the impact of formulation components and engineering process factors on the particle formation and identified the interplay of phospholipids (DSPC), poly(ethylene glycol) (PEG) lipid conjugates, and cholesterol in governing the particle size and lipid dynamics from a structural perspective, using static ³¹P NMR techniques. These studies provide novel insights into the impact of particle engineering on the molecular properties of the LNP envelope membrane. Additionally, molecular interactions and compositional distribution play a critical role in particle engineering and the consequent stability and potency. In this study, we have identified intermolecular contacts among the lipid components using one-dimensional ¹H-¹³C cross-polarization magic angle spinning experiments, ¹H relaxation measurements, and two-dimensional ¹H-¹H correlation methods, providing a structural basis for the lipid assembly. Interestingly, the cationic and ionizable lipids, conventionally regarded as stabilizing agents primarily located within the core of LNPs, were found to interact with PEG lipids and coexist in the outer layer of the particles. We suggest that LNPs examined here are comprised of an outer layer rich in lipid components surrounding a core region. Our high-resolution findings offer insightful structural and dynamic details pertaining to the individual chemical components in the lipid particles and their interactions influence lipid complex structure and stability in particle engineering.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2193-2212"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered Turmeric-Derived Nanovesicles for Ulcerative Colitis Therapy by Attenuating Oxidative Stress and Alleviating Inflammation.","authors":"Guihong Lu, Shanming Lu, Haibing Dai, Fan Zhang, Xiaotian Wang, Weiqun Li, Lin Mei, Hui Tan","doi":"10.1021/acs.molpharmaceut.4c01328","DOIUrl":"10.1021/acs.molpharmaceut.4c01328","url":null,"abstract":"<p><p>Inflammation and oxidative stress are important features of traumatic ulcerative colitis (UC). Turmeric has been used as a dietary and functional ingredient for its potent anti-inflammatory effects in UC therapy. However, its practical effectiveness is hindered by limited reactive oxygen species (ROS) elimination properties. To address this, we constructed a unique treatment agent by growing cerium oxide (CeO₂) nanocrystals on the membranes of turmeric-derived nanovesicles (TNVs), named as TNV-Ce. The resulted TNV-Ce could suppress inflammation and exhibit exceptional ROS-scavenging activity, which was validated both in lipopolysaccharide-induced macrophages and dextran sulfate sodium salt-induced chronic colitis mouse model. Following oral administration, TNV-Ce significantly accumulated at inflamed sites, effectively eliminating ROS and inhibiting pro-inflammatory cytokines for synergistic action against UC.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2159-2167"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Multifunctional Peptide-Decorated Nanofibers for Targeted Delivery of Temozolomide across the Blood-Brain Barrier.","authors":"Rosa Bellavita, Teresa Barra, Simone Braccia, Marina Prisco, Salvatore Valiante, Assunta Lombardi, Linda Leone, Jessica Pisano, Rodolfo Esposito, Flavia Nastri, Gerardino D'Errico, Annarita Falanga, Stefania Galdiero","doi":"10.1021/acs.molpharmaceut.4c01125","DOIUrl":"10.1021/acs.molpharmaceut.4c01125","url":null,"abstract":"<p><p>A nanoplatform based on self-assembling peptides was developed with the ability to effectively transport and deliver a wide range of moieties across the blood-brain barrier (BBB) for the treatment of glioblastoma. Its surface was functionalized to have a targeted release of TMZ thanks to the targeting peptide that binds to EGFRvIII, which is overexpressed on tumor cells, and gH625, which acts as an enhancer of penetration. Furthermore, the on-demand release of TMZ was achieved through matrix metalloproteinase-9 (MMP-9) cleavage. Nanofibers were characterized for their stability, critical aggregation concentration, and morphology. Next, the effect on both 2D and 3D glioblastoma/astrocytoma (U-87) and glioma (U-118) cell lines was evaluated. The Annexin V/Propidium iodide showed an increase in necrotic and apoptotic cells, and the morphological analysis allowed to discover that both U-118 and U-87 spheroids are smaller in surface, perimeter, and Feret's diameter when treated with NF-TMZ. The developed nanofiber was demonstrated to permeate the BBB <i>in vitro</i> in a 3D spheroidal biodynamic BBB model. Finally, there were no cytotoxic effects of nanofibers without the drug on spheroids, while a significant decrease in viability was observed when NF-TMZ was used. Overall, these results open new opportunities for the evaluation of the efficacy and safety of this nanoplatform in <i>in vivo</i> studies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1920-1938"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipopolysaccharide Induces Resistance to CAR-T Cell Therapy of Colorectal Cancer Cells through TGF-β-Mediated Stemness Enhancement.","authors":"Min Tao, Mengmeng Xue, Daoyu Zhou, Luyao Zhang, Xiaojuan Hou, Xinyu Zhu, Shiyao Feng, Haixin Yan, Xiaofeng Qian, Lixin Wei, Chen Zong, Xue Yang, Li Zhang","doi":"10.1021/acs.molpharmaceut.4c00264","DOIUrl":"10.1021/acs.molpharmaceut.4c00264","url":null,"abstract":"<p><p>Chimeric antigen receptor-T (CAR-T) cell therapy is a cellular immunotherapy that has emerged in recent years, and increasing studies showed that therapeutic resistance to CAR-T cell therapy presents in colorectal cancer patients. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is known to preserve a high concentration in the colon. Whether LPS is a contributing factor to the development of resistance in colorectal cancer cells against CAR-T cell therapy remains unclear. For <i>in vivo</i> experiments, colorectal cancer cells COLO205 were pretreated with LPS for 24 h and then were injected into nude mice through the tail vein, followed by CAR-T cells transplantation one day later. Later, the number of tumors in the lung tissues of the mice was observed. The <i>in vitro</i> experiments were performed on COLO205 cells, which were treated with LPS for 24 h. The effect of LPS on the stemness of COLO205 and SW620 cells was observed by using the colony formation assay and spheroidization experiments. The effect of LPS on the expression of stemness-related genes, including CD44, SOX2, and NANOG, was observed by qRT-PCR assay, Western blotting assay, and immunofluorescence staining. Inhibitors of TGF-β and the MYD88 inhibitor were used to study the mechanisms by which LPS induces the stemness enhancement and resistance to CAR-T cell therapy of COLO205 cells. The correlation between <i>MYD88</i> and <i>TGFB1</i>, as well as the correlation between <i>TGFB1</i> and stemness-related genes was analyzed using the TCGA database. Both the <i>in vivo</i> assay of nude mice and the <i>in vitro</i> assay showed that LPS pretreatment could induce resistance to CAR-T cell therapy of colorectal cancer cells. LPS could enhance COLO205 and SW620 cells stemness presented by upregulation of CD44, SOX2, and NANOG. The reverse interfering assay using the TGF-β inhibitor indicated that the autosecretion of TGF-β induced by LPS played a critical role in the stemness enhancement of colorectal cancer cells. The TCGA database analysis revealed a strong positive correlation between <i>MYD88</i> and <i>TGFB1</i>. Additionally, <i>TGFB1</i> has been found to upregulate the expression of genes associated with stemness. Further mechanism studies showed that the TLR4/MYD88 pathway medicates LPS-induced TGF-β expression. Our results suggested that LPS-induced resistance to CAR-T cell therapy of colorectal cancer cells through stemness enhancement. TLR4/MYD88 signal pathway-dependent TGF-β expression was involved in stemness enhancement and CAR-T cell therapy resistance. In conclusion, our findings help us to understand the underlying mechanisms of CAR-T cell therapy resistance and indicate that inhibitors of TGF-β and MYD88 are promising targeting candidates to promote a therapeutic effect of CAR-T cell therapy in colorectal cancer in the clinic.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1790-1803"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid Nanoparticles and PEG: Time Frame of Immune Checkpoint Blockade Can Be Controlled by Adjusting the Rate of Cellular Uptake of Nanoparticles.","authors":"Andrew S Choi, Taylor J Moon, Anubhuti Bhalotia, Aarthi Rajan, Laolu Ogunnaike, Diarmuid W Hutchinson, Inga Hwang, Aaditya Gokhale, Justin N Kim, Timothy Ma, Efstathios Karathanasis","doi":"10.1021/acs.molpharmaceut.4c01039","DOIUrl":"10.1021/acs.molpharmaceut.4c01039","url":null,"abstract":"<p><p>The engineerability of lipid nanoparticles (LNPs) and their ability to deliver nucleic acids make LNPs attractive tools for cancer immunotherapy. LNP-based gene delivery can be employed for various approaches in cancer immunotherapy, including encoding tumor-associated antigens and silencing of negative immune checkpoint proteins. For example, LNPs carrying small interfering RNAs can offer several advantages, including sustained and durable inhibition of an immune checkpoint protein. Due to their tunable design, modifying the lipid composition of LNPs can regulate the rate of their uptake by immune cells and the rate of gene silencing. Controlling the kinetics of LNP uptake provides additional flexibility and strategies to generate appropriate immunomodulation in the tumor microenvironment. Here, we evaluated the effects of polyethylene glycol (PEG) content ranging from 0.5 to 6 mol % on the cellular uptake of LNPs by immune cells and gene silencing of PD-L1 after intratumoral administration. We evaluated the cellular uptake and PD-L1 blockade in vitro in cell studies and in vivo using the YUMM1.7 melanoma tumor model. Cell studies showed that the rate of cell uptake was inversely correlated to an increasing mol % of PEG in a linear relationship. In the in vivo studies, 0.5% PEG LNP initiated an immediate effect in the tumor with a significant decrease in the PD-L1 expression of immune cells observed within 24 h. In comparison, the gene silencing effect of 6% PEG LNP was delayed, with a significant decrease of PD-L1 expression in immune cell subsets being observed 72 h after administration. Notably, performance of the 6% PEG LNP at 72 h was comparable to that of the 0.5% PEG LNP at 24 h. Overall, this study suggests that PEG modifications and intratumoral administration of LNPs can be a promising strategy for an effective antitumor immune response.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1859-1868"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multitask Deep Learning Models of Combined Industrial Absorption, Distribution, Metabolism, and Excretion Datasets to Improve Generalization.","authors":"Joseph A Napoli, Michael Reutlinger, Patricia Brandl, Wenyi Wang, Jérôme Hert, Prashant Desai","doi":"10.1021/acs.molpharmaceut.4c01086","DOIUrl":"10.1021/acs.molpharmaceut.4c01086","url":null,"abstract":"<p><p>The optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of compounds is critical to the drug discovery process. As such, machine learning (ML) models for ADME are widely used for prioritizing the design and synthesis of compounds. The effectiveness of ML models for ADME depends on the availability of high-quality experimental data for a diverse set of compounds that is relevant to the emerging chemical space being explored by the drug discovery teams. To that end, ADME data sets from Genentech and Roche were combined to evaluate the impact of expanding the chemical space on the performance of ML models, a first experiment of its kind for large-scale, historical ADME data sets. The combined ADME data set consisted of over 1 million individual measurements distributed across 11 assay end points. We utilized a multitask (MT) neural network architecture that enables the modeling of multiple end points simultaneously and thereby exploits information transfer between interconnected ADME end points. Both single- and cross-site MT models were trained and compared against single-site, single-task baseline models. Given the differences in assay protocols across the two sites, the data for corresponding end points across sites were modeled as separate tasks. Models were evaluated against test sets representing varying degrees of extrapolation difficulty, including cluster-based, temporal, and external test sets. We found that cross-site MT models appeared to provide a greater generalization capacity compared to single-site models. The performance improvement of the cross-site MT models was more pronounced for the relatively \"distant\" external and temporal test sets, suggesting an expanded applicability domain. The data exchange exercise described here demonstrates the value of expanding the learning from ADME data from multiple sources without the need to aggregate such data when the experimental methods are disparate.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1892-1900"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation and First-in-Human Study of [⁶⁸Ga]Ga-αvβ6-2: A Novel Dimeric Integrin αvβ6-Targeted PET Probe for Pancreatic Cancer Imaging.","authors":"Xiao Pang, Yan Zhao, Xiaolin Chen, Xinming Zhao, Mengjiao Wang, Xiaoshan Chen, Huiqing Yuan, Yuhan Sun, Jingya Han","doi":"10.1021/acs.molpharmaceut.5c00051","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00051","url":null,"abstract":"<p><p>Integrin αvβ6 is highly expressed in pancreatic cancer, making it an ideal target for molecular imaging diagnosis. Multimerization is considered an effective strategy to increase the accumulation of molecular probes in tumors. Here, we synthesized monomeric and dimeric αvβ6-targeting molecular probes, labeled with ⁶⁸Ga, and designated them [⁶⁸Ga]Ga-αvβ6-1 and [⁶⁸Ga]Ga-αvβ6-2, respectively. Both in vitro and in vivo studies were conducted using human pancreatic cancer BxPC-3 cells and BxPC-3 tumor-bearing mice. Additionally, positron emission tomography/computed tomography (PET/CT) imaging with [⁶⁸Ga]Ga-αvβ6-2 was performed in three patients with pancreatic cancer. In vitro studies demonstrated that [⁶⁸Ga]Ga-αvβ6-2 exhibited greater binding affinity, cellular uptake, and internalization than did [⁶⁸Ga]Ga-αvβ6-1. Micro-PET/CT imaging and biodistribution studies revealed the superior imaging performance of [⁶⁸Ga]Ga-αvβ6-2. Furthermore, the first-in-human evaluation highlighted the favorable in vivo distribution and diagnostic efficacy of [⁶⁸Ga]Ga-αvβ6-2 in pancreatic cancer. These results underscore the effectiveness of the multimerization strategy in the application of αvβ6-targeted molecular probes, suggesting that [⁶⁸Ga]Ga-αvβ6-2 may possess favorable clinical translation potential.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Evaluation of ⁶⁸Ga-Labeled TMTP1-Based Cyclic Peptide Probes for Targeting Hepatocellular Carcinoma.","authors":"Yesen Li, Yanjie Wang, Yaoxuan Wang, Jinxiong Huang, Zhide Guo","doi":"10.1021/acs.molpharmaceut.4c01123","DOIUrl":"10.1021/acs.molpharmaceut.4c01123","url":null,"abstract":"<p><p>This study focused on the development and evaluation of four [⁶⁸Ga]-labeled cyclic TMTP1 peptide-based probes for targeting highly metastatic hepatocellular carcinoma (HCC). The probes─[⁶⁸Ga]Ga-N-G-NVvRQ, [⁶⁸Ga]Ga-c[K(N)NVvRQ], [⁶⁸Ga]Ga-c[K(N)NVVRQ], and [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂─were designed using a head-to-tail cyclization strategy to enhance their stability, improve tumor targeting, and reduce uptake in nontarget organs. The microPET imaging results showed that although tumor uptake for all four probes was similar at each time point, renal evaluation revealed that [⁶⁸Ga]Ga-c[K(N)NVvRQ] had the lowest value at 15 min (1.90 ± 0.87%ID/g), significantly outperforming linear analog [⁶⁸Ga]Ga-N-G-NVvRQ (2.87 ± 0.86%ID/g) and dimeric peptide, [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂ (3.92 ± 0.68%ID/g), and the probe exhibited the lowest physiological uptake across major organs. At 30 min, the liver uptake of [⁶⁸Ga]Ga-c[K(N)NVvRQ] was 0.29 ± 0.08%ID/g, with a tumor-to-liver (T/L) ratio of 2.45 ± 0.03. This low nonspecific uptake in normal organs contributed to high-contrast PET imaging, facilitating the diagnosis of small tumor lesions. In addition, the probe demonstrated sustained low renal radioactivity retention, which may offer potential benefits for minimizing additional radioactive damage to the kidneys. Overall, [⁶⁸Ga]Ga-c[K(N)NVvRQ] achieved a good balance between strong tumor uptake and low nonspecific uptake in organs (especially in kidneys), making it an ideal candidate for further investigation in HCC imaging applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1901-1910"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}