Molecular Pharmaceutics最新文献

{"title":"Monitoring Sorafenib Resistance and Efficacy in Hepatocellular Carcinoma Using [¹⁸F]Alfatide II and [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography.","authors":"Guanyun Wang, Yue Pan, Lingling Zheng, Xiaojun Zhang, Huanhuan Liu, Yanfeng Xu, Wenwen Zhang, Xiaohui Luan, Xiaojie Liu, Xiaodan Xu, Shina Wu, Guangyu Ma, Ying Kan, Jinming Zhang, Ruimin Wang, Jigang Yang","doi":"10.1021/acs.molpharmaceut.4c01218","DOIUrl":"10.1021/acs.molpharmaceut.4c01218","url":null,"abstract":"<p><p>Integrin αvβ3 expression is associated with sorafenib resistance in hepatocellular carcinoma (HCC). Therefore, monitoring its expression in HCC may serve as a valuable indicator of the efficacy of sorafenib treatment. In this study, longitudinal positron emission tomography (PET) was performed to assess [¹⁸F]Alfatide II and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as suitable probes for evaluating the treatment efficacy of sorafenib in a Huh-7 human (HCC) xenograft model. Huh-7 tumor cells were used to establish both normal and sorafenib-resistant cell lines, and xenograft models were developed. The mice were categorized into four groups based on the cell type and treatment: normal nontreatment, normal treatment, sorafenib-resistant nontreatment, and sorafenib-resistant treatment. Huh-7 tumor mice received intragastric injections of sorafenib (30 mg/kg/day) or vehicle for 15 consecutive days. Tumor size and weight were assessed throughout the study. Longitudinal microPET/computed tomography (CT) scans with [¹⁸F]Alfatide II and [¹⁸F]FDG were acquired to quantitatively measure angiogenesis on days -2, 3, 7, and 14 and metabolism on days -1, 4, 8, and 15 following therapy initiation. The tumor uptake (ID%/g_mean) of each probe was calculated. No significant difference in [¹⁸F]FDG uptake was observed between the normal and sorafenib-resistant groups (<i>P</i> = 0.452); however, [¹⁸F]Alfatide II uptake differed significantly between the two groups (<i>P</i> < 0.001). Sorafenib successfully inhibited normal Huh-7 tumor growth, inducing significant differences in tumor size 9 days after sorafenib treatment (<i>P</i> < 0.05). The uptake of [¹⁸F]Alfatide II in the tumor lesions changed significantly on day 14 (<i>P</i> = 0.001). However, no change was observed in the uptake of [¹⁸F]FDG (<i>P</i> > 0.05). The PET imaging data of [¹⁸F]Alfatide II and [¹⁸F]FDG were validated through <i>ex vivo</i> immunohistochemistry analysis targeting integrin αvβ3, VEGF, and GULT-1. [¹⁸F]Alfatide II PET was more effective in monitoring sorafenib resistance and therapeutic efficacy in the Huh-7 human HCC xenograft model than [¹⁸F]FDG.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2088-2097"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481733","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":"The pH-Dependent Microspecies Dissociations in the Trade-Off of Solubility and Permeability of Vitamin B2 Eutectic Solids.","authors":"Archita Goswami, Bipul Sarma","doi":"10.1021/acs.molpharmaceut.4c01518","DOIUrl":"10.1021/acs.molpharmaceut.4c01518","url":null,"abstract":"<p><p>The microspecies-specific physicochemical properties of eutectic solids of sparingly water-soluble micronutrient, Vitamin B₂ (Riboflavin), with a few representative BCS drugs, viz., Theophylline, Theobromine, Mesalamine, and Barbituric acid are established. The interplay of solubility and drug permeation behavior is experimentally determined for the eutectic solids, and properties are corroborated with the concomitant relative concentrations of pH-dependent microspecies of Riboflavin and the drugs. Partner drug candidates are selected from different quadrants of BCS classification to apprehend the influence of their solubility on the overall efficacy of the eutectic solids. The coexistence and inseparable ionic, neutral, and/or zwitterionic microspecies are spotted, and the pH-reliant isomer-specific inflection of physicochemical and pharmacokinetic properties in such multicomponent solid formulations is demonstrated.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2246-2258"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555357","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":"Computational Approaches for Predicting Drug Interactions with Human Organic Anion Transporter 4 (OAT4).","authors":"Lucy Martinez-Guerrero, Patricia A Vignaux, Joshua S Harris, Thomas R Lane, Fabio Urbina, Stephen H Wright, Sean Ekins, Nathan J Cherrington","doi":"10.1021/acs.molpharmaceut.4c00984","DOIUrl":"10.1021/acs.molpharmaceut.4c00984","url":null,"abstract":"<p><p>Human Organic Anion Transporter 4 (OAT4) is predominantly expressed in the kidneys, particularly in the apical membrane of the proximal tubule cells. This transporter is involved in the renal handling of endogenous and exogenous organic anions (OAs), making it an important transporter for drug-drug interactions (DDIs). To better understand OAT4-compound interactions, we generated single concentration (25 μM) <i>in vitro</i> inhibition data for over 1400 small molecules against the uptake of the fluorescent OA 6-carboxyfluorescein (6-CF) in Chinese hamster ovary (CHO) cells. Several drugs exhibiting higher than 50% inhibition in this initial screen were selected to determine IC₅₀ values against three structurally distinct OAT4 substrates: estrone sulfate (ES), ochratoxin A (OTA), and 6-CF. These IC₅₀ values were then compared to the drug plasma concentration as per the 2020 FDA drug-drug interaction (DDI) guidance. Several screened compounds, including some not previously reported, emerged as novel inhibitors of OAT4. These data were also used to build machine learning classification models to predict the activity of potential OAT4 inhibitors. We compared multiple machine learning algorithms and data cleaning techniques to model these screening data and investigated the utility of conformal predictors to predict OAT4 inhibition of a leave-out set. These experimental and computational approaches allowed us to model diverse and unbalanced data to enable predictions for DDIs mediated by this transporter.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1847-1858"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668488","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":"Physiologically Based Pharmacokinetic Modeling of Phosphate Prodrugs─Case Studies: Fostemsavir and Fostamatinib.","authors":"Konstantinos Stamatopoulos, Nena Mistry, Kunal Taskar, Farzaneh Salem, James M Butler, Debra Tompson","doi":"10.1021/acs.molpharmaceut.4c01362","DOIUrl":"10.1021/acs.molpharmaceut.4c01362","url":null,"abstract":"<p><p>The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model for conversion of phosphate prodrugs to active drug via intestinal alkaline phosphatase (IAP) implementing a generalized modeling strategy. Fostemsavir and fostamatinib were chosen as model drugs since there is extensive clinical pharmacokinetic data following administration of oral formulations. LUA scripting was used to develop an \"in vitro\" to \"in vivo\" extrapolation of the conversion rate of prodrugs derived from Caco2 cell lines using an absolute IAP abundance approach. The Simcyp v23 platform was modified to generate a virtual population to reflect gastric emptying rates following administration of a moderate fat meal. The PBPK model predicted the results of three different extended-release (ER) tablets of fostemsavir under fasted and fed conditions as well as for powder in capsule and tablet immediate release (IR) formulations of fostamatinib. Retrospectively, the model was also able to assess the clinical relevance of the in vitro dissolution method to rate changes of different microcrystalline cellulose-based IR tablets of fostamatinib, observed in acidic media. All predictions were within 2-fold of the observed Cmax, AUC, and Tmax, with 81% being within 1.25-fold. The developed modeling strategy can be effectively adopted to increase the confidence of using PBPK modeling to prospectively assess the in vivo performance of phosphate prodrugs and support the development of optimal oral extended-release formulations for this class of drugs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2168-2181"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707776","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":"Prediction of Self-Association and Solution Behavior of Monoclonal Antibodies Using the QCM-D Metric of Loosely Interacting Layer.","authors":"Yusra Rahman, Siddhanth Hejmady, Reza Nejadnik","doi":"10.1021/acs.molpharmaceut.4c00656","DOIUrl":"10.1021/acs.molpharmaceut.4c00656","url":null,"abstract":"<p><p>Despite the increasing availability and success of monoclonal antibodies (mAb), early identification of candidate molecules with desirable developability attributes remains challenging due to self-association and poor solution behavior. Measuring these phenomena experimentally using the available methods is complicated in mAbs development. Quartz crystal microbalance with dissipation monitoring (QCM-D) detects a loosely interacting layer on top of the irreversibly adsorbed layer of molecules, providing information about the mAbs interaction. This work aimed to explore whether the characteristics of this layer can be used as a reliable self-association metric. QCM-D experiments showed a large frequency shift (Δ<i>f</i>) associated with loosely interacting layers for omalizumab but a small or absent layer for tocilizumab. Accordingly, the viscosity of omalizumab increased exponentially at high concentrations compared to tocilizumab. Testing eight mAbs with different self-association behaviors revealed a strong rank order correlation between the mostly used metric of self-association, i.e., diffusion interaction parameter (kD-DLS), and Δ<i>f</i>, indicating Δ<i>f'</i>s potential for predicting mAb solution behavior. The study also highlighted the robustness of the metric to impurities and temperature variations compared to the sensitive kD-DLS. Overall, we demonstrate that the loosely interacting layer provides valuable information about mAb self-association, predicting the colloidal stability and solution behavior in therapeutic development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1804-1815"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749394","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 of a Radiogallium-Labeled Heterodivalent Imaging Probe Targeting Negative Charges and Integrin on the Surface of Cancer Cell Membranes.","authors":"Takeshi Fuchigami, Kohei Shimo, Toya Hiwatashi, Yuka Andoh, Masayuki Munekane, Kenji Mishiro, Hiroaki Echigo, Hiroshi Wakabayashi, Yoji Kitamura, Seigo Kinuya, Kazuma Ogawa","doi":"10.1021/acs.molpharmaceut.4c01263","DOIUrl":"10.1021/acs.molpharmaceut.4c01263","url":null,"abstract":"<p><p>Radiopharmaceuticals targeting tumor-specific environments are powerful tools for cancer diagnosis and treatment. We previously demonstrated the considerable high tumor uptake of the cationic amphiphilic peptide, ⁶⁷Ga-NOTA-KV6, in vivo. However, because this radioligand shows a relatively rapid clearance from the tumor over time, further structural optimization is necessary. In this study, to enhance tumor accumulation and retention, we synthesized and evaluated a heterobivalent radiogallium-labeled radiotracer, [⁶⁷Ga]Ga-DOTA-KV6-Mal-c(RGDyK) ([⁶⁷Ga]<b>6a</b>), fusing the KV6 peptide targeting negatively charged sites on the cancer cell membrane and cyclic RGD peptide targeting integrin α_vβ₃ on the cancer cell membrane. Cellular uptake study revealed high accumulation of [⁶⁷Ga]<b>6a</b> in integrin α_vβ₃-expressing U-87MG cancer cells, but uptake was significantly inhibited in the presence of an excess of the cyclic RGD peptide, c(RGDyK) (<b>1</b>). Peptide <b>6a</b> exhibited integrin α_vβ₃-binding affinity comparable to those of RGD peptides <b>1</b> and DOTA-Mal-c(RGDyK) (<b>8</b>). In vivo biodistribution studies of U-87MG tumor-bearing mice revealed that [⁶⁷Ga]<b>6a</b> exhibited better accumulation and retention in tumor tissues than [⁶⁷Ga]Ga-DOTA-KV6-Mal-Et ([⁶⁷Ga]<b>6b</b>; without the RGD peptide motif) and [⁶⁷Ga]Ga-DOTA-Mal-c(RGDyK) ([⁶⁷Ga]<b>9</b>; without the KV6 peptide motif). Single-photon emission computed tomography analysis also revealed high signals of [⁶⁷Ga]<b>6a</b> in tumor tissues, which were significantly blocked in the presence of excess peptide <b>1</b>. Although reducing radiotracer accumulation in nontumor tissues, such as the kidneys, remains a challenge, our developed approach exhibits potential to enhance the selectivity and retention of radiopharmaceuticals in tumor tissues.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2053-2064"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602939","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":"Hypoxia-Targeted Responsive Delivery of Doxorubicin and Digoxin for Synergistic Treatment of Triple-Negative Breast Cancer.","authors":"Lingyan Weng, Min Zhao, Zhongping Chen, Li Zhu","doi":"10.1021/acs.molpharmaceut.4c01325","DOIUrl":"10.1021/acs.molpharmaceut.4c01325","url":null,"abstract":"<p><p>To enhance the therapeutic efficacy and safety of triple-negative breast cancer (TNBC) treatment, we developed a hypoxia-responsive drug delivery system utilizing digoxin (DIG) to inhibit HIF-1α and sensitize TNBC to doxorubicin (DOX). DIG, a cardiac steroid with a well-characterized pharmacological mechanism, was encapsulated in micelles composed of methoxy-polyethylene glycol (mPEG) and poly(lactic acid) (PLA) copolymers, incorporating an azobenzene (AZO) trigger for hypoxia-sensitive drug release. The loading ratio of DOX to DIG was optimized based on DIG's minimum effective dose. In vitro and in vivo studies demonstrated that the micelles efficiently delivered their payload to hypoxic tumor regions, enabling rapid drug release. DIG-mediated HIF-1α inhibition enhanced TNBC sensitivity to DOX, leading to significant suppression of both primary tumor growth and pulmonary metastasis. This study presents a promising and clinically feasible strategy for TNBC and other hypoxia-driven malignancies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2142-2158"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583950","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":"Miniaturized High-Throughput Amorphous Solid Dispersion Screening via Picoliter Volume 2D-Inkjet Printing of Formulation Microarrays.","authors":"Georgios Papakostas, Philip A Corner, Andrew L Hook, Stephanie C Brookes, Jonathan Booth, Jonathan C Burley, James F McCabe","doi":"10.1021/acs.molpharmaceut.4c01256","DOIUrl":"10.1021/acs.molpharmaceut.4c01256","url":null,"abstract":"<p><p>Many new drug substances exhibit poor physicochemical properties and therefore require significant time and material resources to develop into safe and efficacious medicinal products. This typically involves exploring a large amount of compositional space and may require excessive amounts of drug compounds, which may not be adequate at the early stage of drug development. Scaled-down screening methods have been used as a cost-effective approach to the early-stage formulation. However, even the most material-efficient methods used in product development require milligrams or grams of drug material, which is often not available until relatively late in the lead optimization process. Herein, we report the application of picoliter inkjet printing of drugs and polymers from solution to create addressable formulation microarrays. This allows the efficient screening of drug-polymer compositions while only requiring micrograms or less of the drug substance. A total of eight model compounds, namely, carbamazepine, griseofulvin, saccharin, theophylline, 4-aminobenzoic acid, caffeine, salicylic acid, and benzocaine, were screened against seven commonly used amorphous solid dispersion (ASD) matrix polymers at 5% w/w composition intervals in the range of 5-80% w/w, with five replicates each. Each dispensed spot contains a total of only 1 μg of material (model compound and/or polymer). Across the tested ASD formulations, we ranked the different polymers based on their ability to hinder drug recrystallization across different compositions. Also, we identified distinct physicochemical behaviors in their crystallization kinetics, such as moisture resolubilization. We expect this approach to enable the rapid time- and material-efficient development of new amorphous solid dispersion formulations in an industrial setting.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2040-2052"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571563","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":"Mechanistic Investigation into the Phase Separation Behavior of Soluplus in the Presence of Biorelevant Media.","authors":"Justus Johann Lange, Malte Bøgh Senniksen, Nicole Wyttenbach, Susanne Page, Lorraine M Bateman, Patrick J O'Dwyer, Wiebke Saal, Martin Kuentz, Brendan T Griffin","doi":"10.1021/acs.molpharmaceut.4c01140","DOIUrl":"10.1021/acs.molpharmaceut.4c01140","url":null,"abstract":"<p><p>More than a decade since its introduction, the polymeric excipient Soluplus continues to receive considerable attention for its application in the development of amorphous solid dispersions (ASDs) and its utility as a solubilizer for drugs exhibiting solubility limited absorption. While it is well-recognized that Soluplus forms micelles, the impact of its lower critical solution temperature of approximately 40 °C remains an underexplored aspect. This study investigated the phase behavior of Soluplus in fasted-state simulated intestinal fluid (FaSSIF-V1). It was demonstrated that Soluplus forms a dispersed polymer-rich coacervate phase, which coexists with Soluplus micelles at 37 °C. This behavior was confirmed by cloud point measurements, visually discernible phases after centrifugation, as well as multi-angle dynamic light scattering (MADLS) measurements, and quantitative ¹H-nuclear magnetic resonance (NMR) spectroscopy of Soluplus concentrations in the supernatant pre- and post-centrifugation. The practical relevance of these findings was contextualized by solvent shift experiments and dissolution testing of spray-dried ASD. The results demonstrated that the poorly water-soluble drug RO6897779 resided in a polymer-rich coacervate phase and was spun down during centrifugation, which resulted in an amorphous pellet exhibiting the characteristics of a viscous liquid. The entrapment of the drug within the polymer-rich phase was further analyzed by temperature- and time-dependent MADLS experiments. The findings of this study are of particular relevance for a mechanistic understanding, relevant to comprehending in vitro-in vivo relationships of Soluplus-based ASDs. Low sampled drug concentrations in FaSSIF-V1 at 37 °C may originate not only from limited drug release and precipitation but also from the formation of a drug-containing, polymer-rich Soluplus phase. Therefore, a liquid-liquid phase separation occurring from Soluplus-based formulations in a biorelevant medium can be excipient-driven, which is different from the common perception that phase separation in the solution state is triggered primarily by high drug concentrations exceeding their amorphous solubility.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1958-1972"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595857","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 Characterization of the [¹⁷⁷Lu]Lu-Labeled Anti-CDH17 Nanobody Derivative for Radioimmunotherapy in the Gastric Cancer Xenograft Model.","authors":"Chenkai Mao, Shicheng Li, Rencai Fan, Jiaqi Zhang, Xinying Fan, Zhen Shentu, Zhixiang Zhuang, Lei Gan","doi":"10.1021/acs.molpharmaceut.4c01285","DOIUrl":"10.1021/acs.molpharmaceut.4c01285","url":null,"abstract":"<p><p>Cadherin 17 (CDH17) is highly expressed in digestive system cancers, and the potential of nanobodies targeting CDH17 as imaging probes and delivery vehicles for radioactive β-particles warrants exploration for their theranostic potential in CDH17-overexpressing gastric cancer (GC). In this study, we screened an anti-CDH17 nanobody library and constructed two antibodies: anti-CDH17 VHH (recombinant nanobody fused with a polyhistidine tag) and anti-CDH17 VHH-ABD (recombinant nanobody fused with an albumin-binding domain). VHH targeting CDH17 and its derivative VHH-ABD were conjugated with DOTA and labeled with radionuclide ¹⁷⁷Lu. The pharmacokinetics and theranostic efficacy of these agents were evaluated in the GC xenograft models. [¹⁷⁷Lu]Lu-VHH and [¹⁷⁷Lu]Lu-VHH-ABD exhibited high radiochemical purity (>99%, <i>n</i> = 3) and successfully delineated CDH17-positive gastric cancer tissues on SPECT/CT imaging. Compared with the rapid renal clearance of [¹⁷⁷Lu]Lu-VHH, [¹⁷⁷Lu]Lu-VHH-ABD demonstrated prolonged circulation times with increased and sustained tumor accumulation. Survival experiments in the MKN-45 tumor model revealed that two doses of [¹⁷⁷Lu]Lu-VHH-ABD effectively suppressed tumor growth, with limited systemic biotoxicity. Histological analysis using hematoxylin and eosin (H&E) staining and Ki67 immunohistochemistry confirmed structural disruption and low tumor cell proliferative activity in the tumor tissue. In preclinical studies, [¹⁷⁷Lu]Lu-anti-CDH17 VHH-ABD demonstrated substantial antitumor efficacy with manageable toxicity, offering promising clinical potential as a viable therapeutic option for CDH17-overexpressing GC.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2077-2087"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633189","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}