{"title":"Smart Nanometals: An Approach to Transform Brain Cancer Diagnosis and Therapy.","authors":"Anam Arora, Neha Jain, Manisha Pandey, Shreya Kaul, Rupali Verma, Bapi Gorain","doi":"10.1021/acs.molpharmaceut.5c00504","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00504","url":null,"abstract":"<p><p>Cancer is responsible for a great proportion of deaths globally and requires urgent attention. Even with the most recent advanced technologies in diagnosis and interventions, the management and cure of cancer patients are limited. However, novel drug delivery tools with innovative technologies have been shown to deliver chemotherapeutics to cancer cells with minimal interaction with healthy cells. Among them, metallic nanoparticles (MNPs) such as gold, silver, copper oxide, and iron oxide have garnered attention owing to their higher surface area-to-volume ratio, multifunctionality, and tunable optical characteristics, making them suitable for therapeutic, diagnostic, and theranostic purposes in brain carcinoma. It has also been demonstrated that MNPs can maintain significant therapeutic concentrations in target cells through site-specific and continued release. Due to their immense potential, the current review focused on exploring MNPs for improved diagnosis and management of brain tumors. Specifically, this review aimed to understand the interaction of MNPs with the brain tumor microenvironment to overcome impediments such as the blood-brain barrier, efflux pump presence, and the invasive nature of brain tumors. Additionally, the regulatory aspects, existing gaps in research, toxicity concerns, and remediation strategies were addressed to replace traditionally available brain cancer treatment strategies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688328","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}
Liyan Wang, Li Yang, Kaili Liang, Bo Liu, Qing Luo, Wei Wang, Ding Zhang, Qing Wang
{"title":"Cannabidiol-Loaded Nanostructured Lipid Carriers for Nose to Brain Delivery: An Effective Therapeutic Approach against Epilepsy.","authors":"Liyan Wang, Li Yang, Kaili Liang, Bo Liu, Qing Luo, Wei Wang, Ding Zhang, Qing Wang","doi":"10.1021/acs.molpharmaceut.5c00452","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00452","url":null,"abstract":"<p><p>The presence of first-pass metabolism and the obstacle of the blood-brain barrier may reduce the effectiveness of oral antiepileptic medications. Nasal drug delivery has been considered a promising selective route to the brain for drugs with low aqueous solubility in the treatment of CNS disease. The purpose of our study was to improve the bioavailability as well as brain targetability of cannabidiol (CBD) by encapsulating it in nanostructured lipid carriers (NLCs) and delivering the formulation via the nasal route. CBD-NLCs were effectively prepared with the appropriate particle sizes and polydispersity index for the nasal route (77.71 nm± 0.79 and 0.23 ± 0.00, respectively). These particles demonstrated a high entrapment efficiency and drug loading of 99.24% ± 0.07 and 8.73% ± 0.56 w/w, respectively. According to the FTIR, XRD, and DSC data, CBD was either in the amorphous state or distributed molecularly in the lipid matrix. The absorption of CBD-NLCs in the nasal cavity was significantly superior to pure CBD (the rate constants were 9.02 ± 1.64 and 2.10 ± 0.25 μg/min, respectively). Compared to the intravenous administration of CBD, CBD-NLCs showed a drug targeting efficiency of 277.82% after nasal administration, indicating a more efficient brain targeting. In a rat model where seizure activity was induced by PTZ, intranasal administration of CBD-NLCs significantly prolonged seizure latency and decreased the Racine score. All of the results suggest CBD-NLCs administered intranasally might be a promising alternative to traditional epilepsy treatments.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688327","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}
Christopher I Williams, Farbod Mahmoudinobar, David C Thompson, J Wade Davis, Sandeep Kumar
{"title":"A Pharmacophore-Based Method for Rapid and Accurate Virtual Screening of Antibody Libraries against Antigens.","authors":"Christopher I Williams, Farbod Mahmoudinobar, David C Thompson, J Wade Davis, Sandeep Kumar","doi":"10.1021/acs.molpharmaceut.5c00250","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00250","url":null,"abstract":"<p><p>Antibody-based biotherapeutics make up an important class of biopharmaceuticals. However, their discovery requires resource- and time-consuming laboratory processes. To ameliorate this situation, several computational methods were used to predict the structures of antibody:antigen complexes (Ab:Ag) and identify potential binders, in-silico. However, there is still a general lack of rapid virtual screening methods capable of screening large antibody libraries against a given antigen or group of antigens. In this work, we explore the application of a successful small-molecule drug discovery strategy and adapt pharmacophore-based virtual screening to the world of antibody discovery. Using a nonredundant data set of 874 Ab:Ag complexes, we have developed an automated method to create pharmacophores from the antibody complementarity determining regions. Our method is 98.6% (862 out of 874) successful at reproducing the ground truth, i.e., it can recapitulate the parental antibody:antigen complexes. In a benchmarking comparison with cognate docking, using 33 Ab:Ag complexes of <i>therapeutic interest</i>, the pharmacophore method was not only much faster than cognate docking but also recovered all the native interfacial contacts. In addition, it can also find additional putative antibody binders to a given antigen within clusters of Ab:Ag complexes with similar interfacial structures. Our method has significant implications toward accelerating biotherapeutic drug discovery as well as drug repurposing research. This method was implemented in MOE 2024 and is available to the scientific community.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688326","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":"A Semimechanistic Ocular Pharmacokinetic Model for ADVM-022 Gene Therapy Describing the Dose-Exposure Relationship in Monkeys and the Scaling to Human.","authors":"Florian Hugi, Jannik Vollmer, Lionel Renaud, Matthias Machacek","doi":"10.1021/acs.molpharmaceut.5c00155","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00155","url":null,"abstract":"<p><p>Gene therapies are emerging as a new treatment modality. Due to their novelty, general pharmacological properties have yet to be established. For example, the translation from animal models to humans for first-in-human dose selection and the dose-exposure relationship remain poorly characterized. A mechanistic and quantitative framework would improve preclinical program design, enable more robust first-in-human dose predictions, and support more rigorous dose adjustments during clinical development. This study establishes a semimechanistic mathematical model for aflibercept expression and pharmacokinetics (PK) following intravitreal (IVT) ADVM-022 administration in monkeys and humans, drawing on the preclinical and clinical data presently available. ADVM-022 is an AAV2.7m8-based viral vector that delivers the gene encoding aflibercept, an antivascular endothelial growth factor (VEGF) fusion protein. It was developed as a gene therapy for treating wet age-related macular degeneration (wAMD) and is administered through a single IVT injection. The proposed model incorporates established ocular PK for intravitreally administered proteins, along with an expression component that links AAV dose to aflibercept production. Based on pooled PK data from monkey studies, the model suggests that transduction occurs not only in the retina but also in other ocular tissues bordering the vitreous, contributing to the observed intraocular aflibercept levels. Increasing doses within the lower range of preclinical studies (3 × 10<sup>10</sup>-2 × 10<sup>13</sup> vg/eye) lead to increased transduction and expression, plateauing at upper limits of approximately 12.7 μg/day·cm<sup>3</sup> for the retina, and 0.785 μg/day for extra-retinal tissues at higher doses. Assuming similar transduction efficiency between humans and monkeys, with adjustments for anatomical differences, the model provided predictions of ocular aflibercept concentrations that aligned with observations from the two dose groups in the phase 1 OPTIC clinical trial, supporting the utility of this approach.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673364","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 of Dual-Functionalized Intranasal Nanovesicles Embedded with Thymoquinone for Targeted Modulation of the PI3K/AKT Pathway in Glioblastoma Therapy.","authors":"Sagar Trivedi, Rishabh Agade, Veena Belgamwar","doi":"10.1021/acs.molpharmaceut.5c00764","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00764","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, known for its invasiveness, therapy resistance, and the challenge posed by the blood-brain barrier (BBB). This study presents a novel, dual-functionalized nanovesicular system for intranasal delivery of thymoquinone (TH), encapsulated in PEGylated chitosan-coated NVs and conjugated with lactoferrin (Lf). This formulation (TH-Lf-PEG-CS-NVs) was optimized using a central composite design and exhibited high entrapment efficiency (96.28 ± 0.65%), a particle size of 129.82 ± 0.53 nm, and coating efficiency of 91.72 ± 0.22%. In vitro and ex vivo studies demonstrated superior cellular uptake (84.01 ± 3.78%) and a ∼3.16-fold increase in permeability (<i>P</i><sub>app</sub>: 0.57 ± 0.072 μg/cm<sup>2</sup>/min) compared to free TH. Mechanistic assays confirmed modulation of the PI3K/AKT pathway, with reduced Bcl-2 (56.91 ± 2.98%), COX-2 (31.22 ± 2.19%), and increased caspase-3 (75.9 ± 3.01%) expression. In vivo pharmacokinetics revealed a peak cerebrospinal fluid concentration (<i>C</i><sub>max</sub>) of 51.72 ± 1.22 μg/mL at 24 h and sustained release for 36 h. Histopathological evaluations affirmed safety and biocompatibility. This multifunctional nanocarrier facilitates targeted delivery, effective BBB penetration, and prolonged cerebral retention, offering a noninvasive, efficient strategy for GBM treatment. The findings support its potential as a translational therapeutic platform for central nervous system malignancies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673365","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}
Yuta Yagi, Takanatsu Hosokawa, Takuro Yamada, Teruki Nii, Takeshi Mori, Yoshiki Katayama
{"title":"Intravenous Administration of Antisense Oligonucleotide Incorporated into PLGA Nanoparticles Alters the Pattern of Organ Distribution and Gene Knockdown Effects.","authors":"Yuta Yagi, Takanatsu Hosokawa, Takuro Yamada, Teruki Nii, Takeshi Mori, Yoshiki Katayama","doi":"10.1021/acs.molpharmaceut.5c00414","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00414","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) were recently approved for treating diseases that are unable to be treated by conventional modalities. However, the approved ASOs target limited organs, particularly the liver, as a result of their pharmacokinetic nature. Here, we report a detailed analysis of the biodistribution and gene knockdown (KD) activity of ASO in organs in the whole body by using ASO incorporated into nanoparticles (NPs). Biodegradable poly(lactide-<i>co</i>-glycolic acid) was used as a matrix of NPs and the <i>Malat1</i> gene, which is expressed in many organs, was selected as a target of ASO. NPs enabled dramatically high accumulation of ASO in the liver, spleen, lung, and heart compared with that of naked ASO in mice. Notably, high accumulation in the organ did not always result in the KD effect because of the difference of susceptibility to the KD effect in cells that take up NPs. While we used 1 order of magnitude lower dose of ASO compared with conventional naked ASO treatments, NPs showed KD effects not only in the heart but also in the lung and kidney, where naked ASO did not show KD effects. Here, we clarify the unique biodistribution and KD effects of ASO incorporated in NPs. These findings will contribute to the development of an ASO delivery system to target atypical organs with reduced side effects.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666649","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}
Scott A Southern, Vijith Kumar, Victor Terskikh, David L Bryce, Andreas Brinkmann
{"title":"NMR Crystallographic Investigation Coupled with Molecular Dynamics Simulations Reveals the Nature of Disorder in Chlorpromazine Hydrochloride Solvatomorphs.","authors":"Scott A Southern, Vijith Kumar, Victor Terskikh, David L Bryce, Andreas Brinkmann","doi":"10.1021/acs.molpharmaceut.5c00269","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00269","url":null,"abstract":"<p><p>Chlorpromazine, a widely used antipsychotic medication formulated as a hydrochloride salt, has been a significant active pharmaceutical ingredient (API) for the treatment of schizophrenia for much of the last century. This work presents a comprehensive investigation into the nature of the structural disorder of chlorpromazine hydrochloride solvatomorphs using a combination of nuclear magnetic resonance (NMR) crystallography and molecular dynamics simulations. We focus on understanding the structural characteristics and stability of chlorpromazine hydrochloride and its hydrate, particularly the disorder in the dimethylaminopropyl side chain. This work provides a detailed analysis of the structural characteristics influencing this disorder, advancing the understanding of drug development and the design process for APIs that exhibit similar types of disorder.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666650","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}
Wenhui Fu, Zhequan Fu, Dai Shi, Tingting Yang, Pengcheng Ma, Hongxing Su, Fangchao Tong, Hui Tan, Qingyu Lin, Dengfeng Cheng
{"title":"Evaluation of [<sup>18</sup>F]F-PTTP as a Positron Emission Tomography Radioligand for Imaging P2X7 Receptors in Epileptic Rats.","authors":"Wenhui Fu, Zhequan Fu, Dai Shi, Tingting Yang, Pengcheng Ma, Hongxing Su, Fangchao Tong, Hui Tan, Qingyu Lin, Dengfeng Cheng","doi":"10.1021/acs.molpharmaceut.4c01458","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01458","url":null,"abstract":"<p><p>Patients with epilepsy often face significant challenges, with one-third of them being resistant to available antiseizure medications, leading to drug-resistant epilepsy (DRE). The P2X7 receptor (P2X7R), a mechanistic and inflammatory biomarker, exhibits increased expression during epileptogenesis. P2X7R antagonists effectively reduce the severity of seizure and neuronal death, highlighting this receptor as a potential therapeutic target. Precise detection of P2X7R is essential for guiding the treatments. Herein, we prepared the P2X7R-targeting probe [<sup>18</sup>F]F-PTTP and evaluated its efficacy in positron emission tomography (PET) imaging of epileptic rats. [<sup>18</sup>F]F-PTTP was synthesized via the cleavage of the trifluoromethylsulfonyl group with a radiochemical yield of 10-17% (end of synthesis, EOS), molar activity of 56.12 ± 6.06 GBq/μmol (EOS), and radiochemical purity exceeding 99%. [<sup>18</sup>F]F-PTTP PET imaging was performed on epileptic rats induced via intrahippocampal kainic acid (KA) injection across three disease progression stages: acute (1 day), latent (1 week), and chronic (1 month). PET results revealed specific [<sup>18</sup>F]F-PTTP binding to the epileptic brain, particularly in the right hippocampus (KA-injected site), with the highest standardized uptake value ratio observed at 1 week (1.34 ± 0.11). Autoradiography and histological analyses confirmed P2X7R overexpression in the epileptic brain, associated with microglia and astrocyte activation. Our findings suggest that [<sup>18</sup>F]F-PTTP PET imaging is a promising tool for visualizing P2X7R expression during epileptogenesis, which may facilitate neuroinflammation assessment, P2X7R-targeted therapy, and treatment monitoring in epilepsy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657900","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}
Yao-Hua Lu, Fan Leng, Si-Yuan Chen, Chen-Yu Wang, Chang-Long Gou, Ting-Ting Yu, Liu-Gen Li, Hai-Tao Li, Min Yan, Qiufang Zhang, Tong-Fei Li, Jian Yin, Yuan-Jian Hui, Jun Hu
{"title":"Using Metal-Organic Framework Nanoparticles for Targeted Codelivery of Bortezomib and Iron Ions to Mitochondrial TOM20 to Induce Ferroptosis for Colorectal Cancer Treatment.","authors":"Yao-Hua Lu, Fan Leng, Si-Yuan Chen, Chen-Yu Wang, Chang-Long Gou, Ting-Ting Yu, Liu-Gen Li, Hai-Tao Li, Min Yan, Qiufang Zhang, Tong-Fei Li, Jian Yin, Yuan-Jian Hui, Jun Hu","doi":"10.1021/acs.molpharmaceut.5c00489","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00489","url":null,"abstract":"<p><p>Targeted promotion of iron ion accumulation and inhibition of outer membrane protein function in mitochondria contribute to ferroptosis, thereby boosting anticolorectal cancer (CRC) efficacy. Based on our previous study, the anticancer agent bortezomib (BTZ) was loaded in an iron-derived metal-organic framework (MOF), which was further modified by rhodamine B (RhB), yielding BTZ@RhB-MOF for targeted CRC treatment. Physicochemical characterization results indicated successful preparation of BTZ@RhB-MOF, which had the framework structure and nanosize properties with BTZ and iron ion release under acidic conditions. Further measurements indicated that BTZ@RhB-MOF could be distributed more effectively in tumor tissues, owing to its targeted characteristics. BTZ@RhB-MOF was mainly localized at the mitochondrial outer membrane, where it bound to TOM20 and subsequently destroyed the mitochondria of CRC cells. Then, BTZ@RhB-MOF released the iron ions it was carrying, increasing the concentration of intracellular iron ions and inducing vigorous ferroptosis. Finally, in vitro and in vivo experiments demonstrated that BTZ@RhB-MOF could suppress CRC cells and tumor grafts in CRC cell-bearing mice with favorable safety. Thus, the targeted codelivery of BTZ and iron ions using MOF to the mitochondria of CRC cells was achieved. Therefore, BTZ@RhB-MOF can effectively induce ferroptosis by suppressing TOM20 and increasing iron ion concentrations after the agents are unloaded, offering a potentially targeted strategy for CRC chemotherapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647921","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":"Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging.","authors":"Hongmei Yuan, Haiyang Li, Tongtong Wu, Sufan Tang, Yinwen Wang, Zhicong Yang, Yang Liu, Wenlu Zheng, Nan Liu, Yue Chen, Zhijun Zhou","doi":"10.1021/acs.molpharmaceut.5c00464","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00464","url":null,"abstract":"<p><p>Fibroblast activation protein (FAP), highly overexpressed in cancer-associated fibroblasts (CAFs), is crucial in tumor pathogenesis and progression, making it an important target for diagnosis and therapy. This study presents the design of a series of FAP inhibitors (FAPIs) derived from UAMC-1110 derivative, modified with zwitterions and polyethylene glycol (PEG). The novel <sup>68</sup>Ga-labeled tracers show improved pharmacokinetics compared to <sup>68</sup>Ga-FAPI-04. Small animal positron emission tomography/computed tomography (micro-PET/CT) on U87MG tumor-bearing nude mice revealed that <sup>68</sup>Ga-FAPI-BN-1, incorporating boron trifluoride zwitterion, and <sup>68</sup>Ga-FAPI-P8PN, with phosphate zwitterion and PEG8 modifications, demonstrated high tumor uptake and minimal normal tissue uptake. Biodistribution studies confirmed their excellent tumor accumulation and tumor-to-normal tissue ratios (T/NT). Specifically, <sup>68</sup>Ga-FAPI-BN-1 exhibited a tumor uptake of 49.31 ± 2.76%ID/g at 1 h, with a tumor/muscle ratio of 24, while <sup>68</sup>Ga-FAPI-P8PN showed a tumor uptake of 42.19 ± 3.21% ID/g at 0.5 h, with a tumor/muscle ratio of 23. These results indicate that these tracers hold promise as effective molecular imaging agents targeting FAP.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647920","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}