Molecular Pharmaceutics最新文献

{"title":"Development of a Novel 68Ga-Labeled Radiotracer Targeting Carbonic Anhydrase IX for the Diagnosis of Clear Cell Renal Cell Carcinoma","authors":"Tao Liu,&nbsp;Hongchuang Xu,&nbsp;Xueqi Chen,&nbsp;Kai Cui,&nbsp;Jingcheng Zhou,&nbsp;Lin Cai,&nbsp;Yizhou Wang,&nbsp;Jianhua Zhang,&nbsp;Xing Yang,&nbsp;Kan Gong","doi":"10.1021/acs.molpharmaceut.6c00150","DOIUrl":"10.1021/acs.molpharmaceut.6c00150","url":null,"abstract":"<p>Carbonic anhydrase IX (CAIX) is highly expressed in mostclearcell renal cell carcinomas (ccRCCs), making it an attractive candidatefor the development of a molecular imaging target. This study investigatedthe preclinical performance and clinical feasibility of ⁶⁸Ga–C1, a novel developed CAIX-targeted bicyclic peptide PETtracer. The binding characteristics and biological properties of ⁶⁸Ga–C1 were first assessed through <em>in vitro</em> experiments. Subsequently, their imaging performance was evaluatedin CAIX-expressing ccRCC cell lines and xenograft mouse models. Apilot translational study was then conducted in individuals suspectedof renal cell carcinoma (RCC) and in ccRCC patients undergoing evaluationfor disease recurrence or metastatic progression. In preclinical investigations, ⁶⁸Ga–C1 demonstrated strong affinity for CAIX, selectiveaccumulation in CAIX-positive tumor cells and xenografts, favorablepharmacokinetic behavior, and an acceptable safety profile. Clinically,five patients presenting with newly detected renal masses and sevenccRCC patients after nephrectomy who were suspected of recurrenceor metastasis underwent ⁶⁸Ga–C1 PET imaging. Highuptake of ⁶⁸Ga–C1 was detected in nine ccRCC patientsand in one angiosarcoma patient with positive CAIX expression, whereasa pathologically confirmed non-ccRCC lesion showed negligible traceraccumulation. These findings support its potential as a noninvasivePET tracer for the detection, characterization, and restaging of CAIX-positiverenal malignancies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4123–4132"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429347","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":"First-in-Class CD146-Targeting Peptide Probes for Noninvasive PET Imaging of Melanoma","authors":"Qian Zhang,&nbsp;Xiaoyi Guo,&nbsp;Siqi Hao,&nbsp;Qian Chen,&nbsp;Yang Jiang,&nbsp;Yan Zhang,&nbsp;Huanhuan Cao,&nbsp;Hua Zhu,&nbsp;Zhi Yang,&nbsp;Teli Liu","doi":"10.1021/acs.molpharmaceut.6c00184","DOIUrl":"10.1021/acs.molpharmaceut.6c00184","url":null,"abstract":"<p>The transmembrane glycoprotein CD146,overexpressed insolid tumorsand tumor vasculature, is a compelling target reinforced by CD146-targetingantibody-drug conjugates (ADCs) in clinical trials. This developmentunderscores the unmet need for noninvasive imaging tools to guidepatient selection. Here, we report the first [⁶⁸Ga]Ga-labeledpeptide-based molecular imaging agents targeting CD146: [⁶⁸Ga]Ga-DOTA-P1 and [⁶⁸Ga]Ga-DOTA-P2. Both probes were reliablysynthesized with radiochemical yield &gt;90% within 15 min and radiochemicalpurity exceeding 95% (<em>n</em> = 5). [⁶⁸Ga]Ga-DOTA-P1and [⁶⁸Ga]Ga-DOTA-P2 have good <em>in vitro</em> stability, and high affinity for CD146-positive cell, with <em>K</em>_d values of 152.3 nM and 205.1 nM, respectively. <em>In vitro</em> cellular assays demonstrated specific binding,and fluorescence imaging with the analog FITC-P1 visually confirmedrobust CD146-mediated cellular uptake. <em>In vivo</em> PET/CTimaging demonstrated rapid tumor uptake and tissue excretion. A375model showed a higher tumor-to-muscle ratio (5.33  ±  0.58)with [⁶⁸Ga]Ga-DOTA-P1 at 30 min, whereas [⁶⁸Ga]Ga-DOTA-P2 produced lower contrast (2.55  ±  0.58)due to its slower blood clearance; in addition, the imaging abilityof [⁶⁸Ga]Ga-DOTA-P1 was also verified in another CD146-positivemodel (SK-Mel-28). An immunohistochemical test was performed to assessCD146 distribution, showing low expression in normal tissues versuspositive membrane-localized expression in A375 and SK-Mel-28 tumors.This work establishes [⁶⁸Ga]Ga-DOTA-P1 as a rapid, high-contrastimaging tool for CD146-expressing malignancies, offering a practicalstrategy for noninvasive patient stratification in the era of targetedCD146 therapies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4155–4165"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395608","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":"Rescuing Dendritic Cells from Adjuvant Toxicity: Liposomal Ginsenoside Rh2 as a Dual-Action Strategy for Enhanced Vaccine Potency","authors":"Qingqing Nie,&nbsp;Liping Chen,&nbsp;Wenqiang Cao,&nbsp;Zhijie Chen,&nbsp;Xue Wang,&nbsp;Wang Gong,&nbsp;Xiaoli Yu,&nbsp;Yanna Liu,&nbsp;Shuai Zhang,&nbsp;Yuchen Yang,&nbsp;Yuehong Zou,&nbsp;Yinxiu Huang,&nbsp;Jinquan Zhang,&nbsp;Ziyan Meng","doi":"10.1021/acs.molpharmaceut.6c00787","DOIUrl":"10.1021/acs.molpharmaceut.6c00787","url":null,"abstract":"<p>Antigen-presentingcell (APC)-associated cytotoxicity is consideredone of the bottlenecks restricting the development of novel vaccineadjuvants. Our present study suggested that liposome-encapsulatedginsenoside Rh2 (LP-Rh2) may effectively alleviate APC injury elicitedby diverse cytotoxic immunostimulants. Combined transcriptomic andmetabolomic profiling together with cellular functional assays revealedthat LP-Rh2 could ameliorate mitochondrial dysfunction triggered byliposomal simvastatin (LP-SIM). Likely via elevating mitochondrialmembrane potential and promoting ATP production, LP-Rh2 appears torestrain the early stage apoptosis of dendritic cells and therebyrelieve statin-caused DC damage. In vivo animal observations indicatedthat coadministration of LP-Rh2 and LP-SIM tends to boost APC activationwithin draining lymph nodes. Preliminary findings demonstrated thatLP-Rh2 may achieve synergistic immunostimulatory effects with LP-SIMby preserving dendritic cell (DC) homeostasis, which consequentlyhelps strengthen both humoral and cellular immune responses. Meanwhile,no apparent toxic pathological changes were observed according toserum biochemistry and histopathological assessments of vital organs.In summary, preliminary data presumably confirmed that LP-Rh2 conferscellular protection through the regulation of mitochondrial functionand apoptotic cascades, which renders it a promising candidate protectiveadjuvant for improving the biosafety and immune performance of cytotoxicimmunostimulants.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4360–4376"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395533","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":"Improving Pharmacokinetics of PSMA/GRPR-Targeting Radiolabeled Heterodimer through Enhanced Albumin Binding","authors":"Shohei Tsuchihashi,&nbsp;Kazuma Nakashima,&nbsp;Hiroyuki Watanabe,&nbsp;Masahiro Ono","doi":"10.1021/acs.molpharmaceut.6c00209","DOIUrl":"10.1021/acs.molpharmaceut.6c00209","url":null,"abstract":"<p>Radiolabeledheterodimers targeting prostate-specific membraneantigen (PSMA) and gastrin-releasing peptide receptor (GRPR) havebeen extensively investigated to overcome heterogeneous target expressionin prostate cancer. However, low tumor retention and high kidney uptakeremain major challenges. In this study, we designed and synthesizeda novel albumin binder (ALB)-modified PSMA/GRPR-targeting heterodimer,PADA, to improve tumor retention and tumor-to-kidney ratios. [¹¹¹In]In-PADA exhibited marked binding ability to albumin,PSMA, and GRPR <em>in vitro</em>. In biodistribution studies,the tumor retention of [¹¹¹In]In-PADA was improved by theintroduction of ALB in both PSMA-positive and GRPR-positive tumor-bearingmice. Overall, the tumor AUC values and tumor-to-kidney AUC valueratios of [¹¹¹In]In-PADA were higher than those of a controlagent without an ALB moiety in both model mice. In single-photon emissioncomputed tomography (SPECT) imaging studies, [¹¹¹In]In-PADAcould be used to successfully visualize both PSMA-positive and GRPR-positivetumors and exhibited enhanced tumor-to-kidney contrast due to theintroduction of ALB. These results suggest that [¹¹¹In]In-PADAexhibits favorable pharmacokinetics as a PSMA/GRPR-targeting heterodimer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4166–4180"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443513","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":"Fluorescence-Guided Nanobomb for Triple-Action Tumor Annihilation Based on Fe/Mn Porphyrin MOFs","authors":"Aiai Wang,&nbsp;Hui Xu,&nbsp;Zhihui Xin,&nbsp;Yaru Li,&nbsp;Rong Wang,&nbsp;Xiaoliang Chen,&nbsp;Lu Zhao,&nbsp;Yunfeng Bai,&nbsp;Feng Feng","doi":"10.1021/acs.molpharmaceut.6c00313","DOIUrl":"10.1021/acs.molpharmaceut.6c00313","url":null,"abstract":"<p>Porphyrin bimetallic metal–organic frameworks(BMOFs) havepromising applications in photodynamic therapy (PDT) and chemodynamictherapy (CDT) for tumor therapy. However, their therapeutic effectis restricted by the insufficient reactive oxygen species generatedby BMOFs. Herein, a nanobomb, Fe-TCPP(Mn)/DOX/PEG/Apt-M (FTMDPA),with pH-responsive properties, was designed for fluorescence imaging-guidedtriple-action tumor annihilation. First, a novel Fe/Mn porphyrin BMOF,Fe-TCPP(Mn) (FTM), was assembled by a solvothermal method to achieveenhanced tumor therapy through ROS amplification. Under 660 nm laserirradiation, TCPP(Mn) could act as a photosensitizer to activate PDT.Significantly, TCPP(Mn) and Fe³⁺ exhibit peroxidase-likeand Fenton-like activities, catalyzing the generation of •OHfrom H₂O₂, which effectively amplifies CDT.Besides, FTMDPA exhibits pH-responsive DOX release capability, whichcould achieve chemotherapy (CHT), and could efficiently accumulateat the tumor site with the aid of an aptamer. Importantly, FTMDPAexhibits fluorescence imaging, which has potential applications indetection and image-guided precision therapy. Therefore, the designednanobomb integrates targeted delivery, pH responsiveness, fluorescenceimaging, and amplified PDT-CDT-CHT triple-action tumor annihilationinto a single system, providing a promising strategy for tumor diagnosisand treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4227–4239"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560215","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":"Predicting pHmax and Salt Disproportionation Risk for Basic Drugs","authors":"Xin Yao,&nbsp;Mengqi Yu,&nbsp;Fei Chen,&nbsp;Siqi Du,&nbsp;Leah C. Kallemeyn,&nbsp;Joel Bergman,&nbsp;Michael W. Lesslie,&nbsp;Shuang Chen,&nbsp;Ahmad Y. Sheikh","doi":"10.1021/acs.molpharmaceut.6c00644","DOIUrl":"10.1021/acs.molpharmaceut.6c00644","url":null,"abstract":"<p>Pharmaceutical salts are commonlyused to enhance the bioavailabilityof poorly water-soluble drugs. The maximum solubility in water andthe physical stability of a salt are closely linked to its pH_max, the pH at which both the free form (acid or base) andthe salt can coexist. However, several aspects related to pH_max are only partially addressed or unexplored: (1) before salt screening,which usually consumes significant materials and efforts, whetherpH_max can be predicted based on molecular properties; (2)whether salt disproportionation proceeds via a solid-state or water-mediatedmechanism; and (3) whether disproportionation risk can be graded systematicallyand predicted. In this work, the relationship between pH_max and the physical properties of the basic compounds was examined,and a regression model was constructed based on their correlations.The pH_max values of 106 monosalts for 35 basic drugs werecompiled from the literature. In the data set examined, the pH_max is strongly correlated with the p<em>K</em>_<em>a</em> of the drug (2–10), but not significantlywith the p<em>K</em>_<em>a</em> of the counter-acid(−8 to 5), and is slightly influenced by the molecular weightsof the drug and counter-acid. Accordingly, before salt screening,pH_max of a monosalt can be predicted as a function of thedrug p<em>K</em>_<em>a</em> and the relevantmolecular weights. Across a pH range of 1–11, for the 106 monosaltsstudied, 74% of the predicted pH_max values were found tobe within experimental errors. To determine whether disproportionationbetween pharmaceutical salts of basic drugs and basic excipients isa solid-state reaction or not, differential scanning calorimetry (DSC)is performed. The results showed that a solid-state reaction did notoccur even at high temperatures where the excipient either meltedor was liquefied above its glass transition temperature. Disproportionationrisk levels were systematically defined based on development requirementsand were exemplified using model HCl salts (sertraline, prazosin,phenazopyridine, and pioglitazone) across a wide pH_max range.The risk level shows a strong correlation with the pH difference betweenthe equilibrium pH of the excipient (pH_ee) and the pH_max of the salt. Notably, the risk level increases more sharplywith the pH difference (pH_ee – pH_max)for highly hygroscopic excipients. A prediction workflow for disproportionationrisk level is proposed based on the above correlation and the self-disproportionationtype of pharmaceutical salts.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4298–4310"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560184","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":"Done EAZY: An Automated Procedure for 89Zr-Radiolabeling and Size-Exclusion Chromatography Purification of Nanoliposomal Anticancer Therapeutics","authors":"Justin Dubbert,&nbsp;Falk Kunkel,&nbsp;Thomas Mühlenberg,&nbsp;Susanne Grunewald,&nbsp;Ken Herrmann,&nbsp;Sebastian Bauer,&nbsp;Katharina Lückerath,&nbsp;Valeska von Kiedrowski","doi":"10.1021/acs.molpharmaceut.6c00129","DOIUrl":"10.1021/acs.molpharmaceut.6c00129","url":null,"abstract":"<p>Liposomal nanomedicines offer a clinically proven platformforenhanced drug delivery, yet their behavior in vivo remains difficultto characterize. Noninvasive positron emission tomography (PET) imagingwith radiolabeled liposomes enables quantitative insight into theirbiodistribution and pharmacokinetics, supporting the rational designand clinical translation of nanocarrier-based therapeutics. Zirconium-89([⁸⁹Zr]Zr) is a positron emitter with a suitable half-life(<em>t</em>_1/2 = 78.4 h) for tracking long-circulatingnanocarriers such as PEGylated liposomes by PET imaging. However,existing manual labeling protocols often suffer from poor reproducibility,drug leakage, and limited scalability for clinical translation. Automatedradiolabeling and purification of macromolecular systems, such asliposomes, antibodies, and antibody fragments, are essential for thereproducible, clinically translatable production of radiopharmaceuticals.However, these requirements necessitate larger and more complex radiosynthesizersthat are often not suitable for smaller laboratories. Although automatedprocedures using complex synthesis modules with integrated high-performanceliquid chromatography purification have been demonstrated on largerradiosynthesizers, comparable processes on simpler synthesis platformsremain scarce. To address this gap, this study aimed to develop afully automated process for the ⁸⁹Zr-radiolabeling andsubsequent size-exclusion chromatography (SEC) purification of doxorubicin-loaded,PEGylated liposomes using the <span>ML</span> Eazy synthesis platform.The process was designed in a GMP-oriented manner with the goal ofenabling its future application to other macromolecular radiopharmaceuticals.Using this approach, a fully automated procedure was successfullyestablished on the ML Eazy platform, although optimization of a publishedlabeling method was required to eliminate doxorubicin leakage andimprove radiolabeling efficiency. Several system configurations weretested to optimize SEC and sterile filtration, resulting in a robustsetup that enabled efficient purification and reproducible performance.Fine-tuning of reagent transfer, gradual pressure increase, and intermediatesaline rinsing with subsequent air flushing reduced residual activityin tubing and connectors to &lt;5%. The final automated process achievedconsistent radiochemical yields of 67 ± 3% across eight batchesprepared under GMP-oriented conditions. Overall, an automated, GMP-orientedall-in-one procedure for ⁸⁹Zr-labeling with subsequentsize-exclusion purification of liposomes has been successfully established,producing sterile-filtered formulations that support future clinicaltranslation. The automated module may also be adapted for other radiolabelingapplications using SEC, including antibody labeling.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4112–4122"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343492","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 Long-Acting FAPI Dimer Albb-2FAPI for Diagnosis and Therapy of FAP-Positive Tumors","authors":"Mengqi Shi,&nbsp;Xuejun Wen,&nbsp;Yucen Tao,&nbsp;Jingjing Zhang,&nbsp;Xiaoyuan Chen","doi":"10.1021/acs.molpharmaceut.6c00178","DOIUrl":"10.1021/acs.molpharmaceut.6c00178","url":null,"abstract":"<p>Fibroblast activation protein (FAP)-targeted radiotheranosticsshow strong promise for cancer imaging and therapy, yet their clinicaltranslation is limited by the trade-off between rapid tumor targetingand insufficient systemic residence time. To address this challenge,we report the design and evaluation of ¹⁷⁷Lu-Albb-2FAPI,a long-acting dimeric FAPI derivative that integrates FAPI-02 dimerizationwith an Evans Blue-based reversible albumin-binding motif to achieveimproved tumor targeting while preserving a favorable pharmacokineticprofile. Molecular docking revealed enhanced FAP binding via avidity-drivenstabilization without compromising albumin interaction. <em>In vitro</em> studies confirmed rapid, FAP-specific cellular uptake,while <em>in vivo</em> SPECT/CT imaging and biodistributionanalyses demonstrated higher and more sustained tumor accumulation,together with improved early tumor-to-background contrast, comparedwith the monomeric analogue Albb-1FAPI. In the Panc02 tumor model,characterized by moderate FAP expression, ¹⁷⁷Lu-Albb-2FAPIexhibited durable tumor retention and induced rapid tumor regressionwhile preserving hematological safety. By coupling dimerization-enhancedtarget engagement with controlled albumin binding, ¹⁷⁷Lu-Albb-2FAPIovercomes key diagnostic and therapeutic limitations of existing long-actingFAP radioligands, establishing a refined molecular design strategyfor next-generation FAP-targeted radiotheranostics with strong translationalpotential.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4144–4154"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467814","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":"An Innovative Strategy for the Redox Balance in Breast Cancer with Wool Keratin-Stabilized Copper Nanozyme","authors":"Qikuan He,&nbsp;Hongji Wu,&nbsp;Meilin Guo,&nbsp;Ruifan Ye,&nbsp;Yonghua Tang,&nbsp;Hong Li","doi":"10.1021/acs.molpharmaceut.6c00316","DOIUrl":"10.1021/acs.molpharmaceut.6c00316","url":null,"abstract":"<p>Breast cancer, particularly the triple-negative subtype,posesa significant clinical challenge due to its aggressive behavior andlack of effective therapeutic targets. Current treatments are generallylimited by drug resistance and systemic toxicity. This study developeda WK peptide-guided copper-based nanozyme that targets the redox balancein tumor lesions. Functionally, this nanozyme exhibits peroxidase-likeactivity, converting endogenous hydrogen peroxide into cytotoxic radicalswhile depleting glutathione, thereby disrupting redox homeostasisthrough a dual mechanism. Mechanistically, <em>in vitro</em> and <em>in vivo</em> experiments demonstrate that the nanozymeeffectively induces a ROS burst in breast cancer cells, inhibits thePI3K-AKT-mTOR signaling pathway, and triggers apoptosis, leading tosignificant tumor suppression. In summary, this work translates nanozymetechnology into a promising therapeutic strategy with the potentialto overcome treatment resistance in breast cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"23 8","pages":"4240–4250"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148496850","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":"Radiosynthesis and Preclinical Evaluation of Enantiopure (<i>R</i>)-[¹⁸F]Fluorolactate for PET Imaging of Metabolic Processes.","authors":"Xiaoqing Zhuang, Jenni Virta, Negar A Samani, Tomi T Airenne, Maxwell W G Miner, Heidi Liljenbäck, Aino Latva-Rasku, Mitra Gerami, Jesse Ponkamo, Nea Läpinen, Pyry Dillemuth, Johan Rajander, Tiina A Salminen, Sven Enerbäck, Pirjo Nuutila, Xiang-Guo Li, Anne Roivainen","doi":"10.1021/acs.molpharmaceut.6c00236","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.6c00236","url":null,"abstract":"<p><p>L-Lactate is a key substrate in energy metabolism and a potential biomarker for cancer and metabolic disorders. We developed an enantiomerically pure positron emission tomography (PET) tracer, (<i>R</i>)-[¹⁸F]fluorolactate, to mimic natural L-lactate. (<i>R</i>)-[¹⁸F]Fluorolactate was synthesized via nucleophilic ring-opening of benzyl (<i>S</i>)-oxirane-2-carboxylate, optimized to yield >91% radiochemical purity, > 95% enantiomeric excess, pH 6, and >5.56 GBq/μmol molar activity. PET/computed tomography (CT) imaging, biodistribution, autoradiography, and stability analyses were conducted in fasted and nonfasted rats and in mice bearing subcutaneous Lewis lung carcinoma (LLC) tumors. In rats, tracer uptake was highest in the kidneys and liver, with fasting further increasing renal and hepatic uptake. In mice, (<i>R</i>)-[¹⁸F]fluorolactate accumulated in tumors. The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 significantly reduced tracer uptake in normal tissues and LLC tumors, and increased renal excretion, confirming MCT1-mediated transport. More than 80% and 90% of the tracer remained intact in plasma at 70 min postinjection in rats and tumor-bearing mice, respectively. <i>In silico</i> structural analyses supported the experimental findings. (<i>R</i>)-[¹⁸F]Fluorolactate is a metabolically stable, MCT1-sensitive PET tracer suitable for noninvasive assessment of lactate transport and metabolism and shows promise for imaging MCT1-dependent lactate transport in cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589502","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}