Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
Intracranial Human BT12 Glioblastoma Xenograft is [F]FET PET Negative but 6-[F]Fluoronicotinic Acid PET Positive: Exploring a Novel Approach for Clinical Glioblastoma Imaging.
Ekwe D, Ayo A, Zhuang X … +11 more , Dillemuth P, Airenne TT, Bakay E, Lövdahl P, Kunnas J, Bai L, Rajander J, Salminen TA, Rosenholm JM, Laakkonen P, Li XG
Mol Pharm · 2026 Jun · PMID 42261079 · Publisher ↗
Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of less than 2 years. Radiolabeled amino acids like -(2-[F]fluoroethyl)--tyrosine ([F]FET) have tremendous value in the diagnosis a...
Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of less than 2 years. Radiolabeled amino acids like -(2-[F]fluoroethyl)--tyrosine ([F]FET) have tremendous value in the diagnosis and treatment monitoring of gliomas with positron emission tomography (PET). However, the existence of [F]FET PET negativity in 10-30% of patients with glioma underscores the need for alternative radiotracers. We recently reported that 6-[F]fluoronicotinic acid ([F]FNA) PET can clearly delineate intracranial human glioblastoma xenograft in a mouse model and that monocarboxylate transporters 1 and 2 (MCT1/2) mediate tumor uptake. This study evaluated the potential clinical utility of [F]FNA by comparing its PET imaging performance with the current clinical amino acid radiotracers, [F]FET and [C]methionine ([C]MET), as benchmarks. Orthotopic human glioblastoma xenograft models were prepared in mice for radiotracer comparisons and MCT blocking studies. Dynamic PET imaging, ex vivo biodistribution, brain tissue autoradiography, and histological staining were performed. In silico docking was also performed to analyze the interactions between MCT1 and FNA. The tumor was distinctly visualized on PET with [F]FNA, whereas [F]FET did not provide discernible tumor images in the same mice. Despite the negative [F]FET PET results, the tumor was [C]MET PET positive. In vivo blocking experiments indicated that MCT1, MCT2, and MCT4 are important transporters but may contribute in unequal measures to [F]FNA tissue uptake. In vivo blocking with AZD3965, a dual inhibitor of MCT1 and MCT2, reduced [F]FNA tumor uptake by 68-77%, while blocking MCT4 reduced uptake by 23%. In silico analysis supports ligand-protein interaction between FNA and MCT1. We were not able to visualize the human glioblastoma xenografts in mice by [F]FET PET, but tumor uptake was detected with [F]FNA and [C]MET PET. MCT1, MCT2, and MCT4 have significant roles in [F]FNA uptake in glioblastoma and other tissues. [F]FNA could be an alternative approach for clinical PET imaging of glioblastoma based on a biological mechanism completely different from current clinical approaches.
Eutectic-Driven Recrystallization of Coamorphous Bicalutamide + Niclosamide Systems: Contrasting Stability above and below .
Poloczek P, Knapik-Kowalczuk J, Klimontko J … +3 more , Han X, Kawakami K, Paluch M
Mol Pharm · 2026 Jun · PMID 42260949 · Publisher ↗
Coamorphization is a promising strategy to enhance the physical stability of poorly water-soluble drugs. However, the relationship between composition, molecular dynamics, and long-term stability remains insufficiently u...
Coamorphization is a promising strategy to enhance the physical stability of poorly water-soluble drugs. However, the relationship between composition, molecular dynamics, and long-term stability remains insufficiently understood. Here, we investigate coamorphous systems composed of bicalutamide (BIC) and niclosamide (NIC), focusing on how the eutectic composition defined in the crystalline state translates into molecular dynamics and long-term physical stability of the corresponding amorphous systems above and below the glass transition temperature (). Thermal analysis revealed a eutectic point in the close vicinity of 25 wt % NIC, enabling safe melt-based amorphization of NIC without thermal degradation. Broadband dielectric spectroscopy showed that the addition of NIC does not significantly affect the molecular mobility of amorphous BIC, as reflected by comparable values oscillating around 328 K, fragility parameters in the range of 85-92, as well as similar α-relaxation dynamics across all compositions. Despite these similarities, the physical stability of the coamorphous systems exhibits a pronounced composition dependence. Under accelerated conditions in the supercooled liquid state ( > ), the coamorphous system corresponding to the eutectic concentration displays the highest resistance to recrystallization. In contrast, long-term X-ray diffraction studies performed under glassy-state conditions ( < ) reveal a different stability ranking. These findings indicate that the stabilization observed for compositions corresponding to the eutectic point depends on the thermal regime and emphasize the importance of evaluating physical stability under both supercooled liquid and glassy state conditions.
Correction to "Pharmacokinetics, Biodistribution, Immunogenicity, and Model-Informed-Based PK/PD Model of a Next-Generation Advanced Novel Gene Therapy for Hemophilia".
Dou D, Lu J, Sangchen P … +6 more , Guo C, Li D, He F, Zhu X, Zhang X, Chen X
Mol Pharm · 2026 Jun · PMID 42260715 · Publisher ↗
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Visualizing the Spatiotemporal Redistribution of Drugs in Destabilizing Nanoemulsions: A Quantitative Solution H NMR Approach.
Ueda K, Tomita S, Sunazuka Y … +2 more , Higashi K, Moribe K
Mol Pharm · 2026 Jun · PMID 42260710 · Publisher ↗
While self-nanoemulsifying drug delivery systems (SNEDDS) spontaneously generate nanosized emulsions, they are susceptible to thermodynamic destabilization. Characterizing the spatiotemporal fate of drug molecules during...
While self-nanoemulsifying drug delivery systems (SNEDDS) spontaneously generate nanosized emulsions, they are susceptible to thermodynamic destabilization. Characterizing the spatiotemporal fate of drug molecules during this transition remains challenging due to the limited chemical resolution of conventional particle analysis. Herein, we employed solution-state H NMR to elucidate the redistribution of three model drugs, fenofibrate (FFB), felodipine (FEL), and lopinavir (LPV), during the destabilization of a Labrafac PG-based nanoemulsion. While dynamic light scattering and cryo-transmission electron microscopy confirmed the progressive phase separation of the oil carrier into large oil droplets, NMR analysis revealed that drug redistribution is highly drug-specific rather than simple oil migration. FFB exhibited a redistribution profile proportional to the degree of oil phase separation, migrating into large droplets (∼38% redistribution), reflecting its higher solubility in the oil phase compared to the other drugs. In contrast, FEL and LPV were retained within the residual smaller droplets (∼89% and ∼99% retention, respectively), despite comparable separation of the oil phase. This retention suggests a higher affinity for the surfactant-rich interface relative to the oil core, rendering the drug redistribution independent of the oil phase separation. These findings demonstrate that monitoring the physical separation of the carrier is insufficient to determine the molecular state and localization of the drug. Consequently, quantitative H NMR offers a powerful, noninvasive framework to overcome the analytical limitations of conventional methods, thereby enabling molecular-level design of robust lipid-based formulations.
Development and Evaluation of an Albumin-Binding GPC3-Targeting Peptide for PET Imaging of Hepatocellular Carcinoma.
Hu W, Feng L, Wang Y … +8 more , Lin Z, Feng Y, Wang X, Tan Y, Jiang D, Li M, Wei W, Lan X
Mol Pharm · 2026 Jun · PMID 42258609 · Publisher ↗
Accurate imaging-based diagnosis of hepatocellular carcinoma (HCC) remains clinically challenging due to the limited specificity of conventional modalities. Glypican-3 (GPC3), which is highly expressed in most HCCs but a...
Accurate imaging-based diagnosis of hepatocellular carcinoma (HCC) remains clinically challenging due to the limited specificity of conventional modalities. Glypican-3 (GPC3), which is highly expressed in most HCCs but absent in normal liver and benign lesions, represents a promising target for precision imaging. In this study, we designed and synthesized two GPC3-targeted Ga-labeled peptide PET tracers: a direct-targeting probe, [Ga]Ga-HD3, and an albumin-binding-enhanced probe, [Ga]Ga-HD4. Both probes were obtained in high radiochemical purity and demonstrated good in vitro stability. Their imaging performance was systematically evaluated in GPC3-positive and GPC3-negative xenograft models, as well as in an orthotopic HCC model. While both probes enabled GPC3-specific tumor visualization, [Ga]Ga-HD4 showed significantly higher tumor uptake and prolonged tumor retention, leading to superior tumor-to-liver (T/L) and tumor-to-muscle (T/M) ratios, particularly at delayed imaging time points. Histological analysis confirmed that tumor uptake was GPC3-specific. In line with its albumin-binding design, [Ga]Ga-HD4 showed elevated blood-pool activity and extended circulation time. Together, these results demonstrate that the incorporation of an albumin-affinity moiety effectively improves the pharmacokinetics and imaging performance of GPC3-targeted tracers. This work provides a solid practical foundation for the translational development of HCC imaging agents, with [Ga]Ga-HD4 emerging as the more promising candidate owing to its improved tumor retention and imaging contrast.
Exosome Nanotherapy Rescues Male Fertility by Delivering Integrin β1 to Repair Environmental Stress-Damaged Testes.
Meng J, Wang J, Li Z … +4 more , Li F, Yun X, Jin Y, Zhang L
Mol Pharm · 2026 Jun · PMID 42258346 · Publisher ↗
Environmental thermal-mechanical (T&M) stress threatens male fertility globally, yet no molecular therapies exist for stress-induced testicular damage. We demonstrate that macrophage-derived exosomes (Mφ-EVs) function as...
Environmental thermal-mechanical (T&M) stress threatens male fertility globally, yet no molecular therapies exist for stress-induced testicular damage. We demonstrate that macrophage-derived exosomes (Mφ-EVs) function as precision nanomedicines restoring fertility by delivering Integrin β1 (ITGB1) to repair damaged spermatogenic cytoskeletons. Using validated T&M stress models in C57BL/6 mice and GC-2 spermatocytes, we characterized severe reproductive dysfunction: 14.4% motility reduction (83.0 ± 2.0% to 71.3 ± 1.7%), 69.2% increased abnormalities (8.7 ± 2.3% to 14.7 ± 2.3%), and disrupted cytoskeletal homeostasis with Layilin (2.87-fold), Talin (3.90-fold), and Vinculin (4.24-fold) upregulation ( < 0.05). Mφ-EVs treatment achieved remarkable therapeutic efficacy: motility recovered to 80.8 ± 6.8%, abnormalities normalized to 11.6 ± 1.6% (all < 0.05). Biodistribution tracking showed that exosomes accumulate in testicular tissue (peak 8 h). Molecular docking and cellular thermal shift assays revealed exosomal ITGB1 forms high-affinity ITGA1 complexes (score -222.76), stabilizing protein structure and normalizing cytoskeletal expression. This first proof-of-concept establishes exosome-based nanotherapy as a clinically translatable, noninvasive intervention for occupational and climate-related fertility disorders, with scalable manufacturing addressing millions of men worldwide.
Synthesis and Preliminary Evaluation of the At-Labeled PARP Inhibitor [At]Talazoparib as a Targeted Alpha-Particle Emitting Therapeutic.
Zheng Y, Kong D, Huynh TT … +6 more , Zhao X, Liu Y, Banks RL, Vaidyanathan G, Feng Y, Zalutsky MR
Mol Pharm · 2026 Jun · PMID 42257398 · Publisher ↗
Poly(ADP-ribose) polymerase-1 (PARP1) has become a crucial target in cancer therapy. In recent years, derivatives of olaparib and rucaparib have been radiolabeled for noninvasive imaging of PARP1 expression and targeted...
Poly(ADP-ribose) polymerase-1 (PARP1) has become a crucial target in cancer therapy. In recent years, derivatives of olaparib and rucaparib have been radiolabeled for noninvasive imaging of PARP1 expression and targeted radionuclide therapy of PARP-expressing tumors. Motivated by the superior potency of talazoparib, we developed a novel radiolabeling approach for [At]talazoparib and report its in vitro and in vivo evaluation. The tin precursors and iodo standards were synthesized, separated on a chiral column, and [At]talazoparib and its inactive. [At]LT-674 enantiomer were synthesized in a single step from their respective tin precursor. Radiochemical yield (RCY) and radiochemical purity RCP were determined using RP-HPLC. Cell uptake and internalization were performed on PSMA-positive PC-3 PIP prostate carcinoma cells and U87MG glioma cells and cytotoxicity (MTT) was evaluated on PC-3 PIP cells. Biodistribution studies were performed in athymic mice with subcutaneous PC-3 PIP xenografts and the therapeutic efficacy of [At]talazoparib was evaluated in the same animal model. The syntheses of tin precursors and iodo standards was developed and optimized. A one-step and scalable radiolabeling method was developed for the synthesis of [At]talazoparib with 70 ± 7% (n = 10) RCY in 1 h and >95% RCP. The maximum activity of [At]talazoparib produced was 370 MBq. High cell uptake and internalization were observed for [At]talazoparib but not [At]LT-674 with PC-3 PIP cells, and [At]talazoparib was cytotoxic to PC3 PIP cells in vitro. High tumor uptake and prolonged retention, and rapid clearance from normal tissues were seen for [At]talazoparib after intratumoral injection. Tumor growth inhibition and survival benefit were observed with a single dose of intratumorally injected [At]talazoparib. Methods for the chiral separation of precursor permitted radiolabeling of [At]talazoparib without the need for separation from its inactive At-labeled enantiomer after radiolabeling, and scaled-up production was optimized. [At]talazoparib exhibited promising potential as a targeted radiotherapeutic, particularly for settings where locoregional administration is warranted.
Fluorinated Chitosan-Based Theranostic Nanocarrier System for Image-Guided Synergistic Treatment of Hepatocellular Carcinoma.
Zhao X, Wang Y, Hou N … +4 more , Shang D, Wang C, Zhang W, Zhang J
Mol Pharm · 2026 Jun · PMID 42252614 · Publisher ↗
Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC), but its application is often limited by challenges such as inadequate drug accumulation in tumor tissue, the dev...
Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC), but its application is often limited by challenges such as inadequate drug accumulation in tumor tissue, the development of drug resistance, and significant toxic side effects. To address this, this study developed a fluorinated chitosan-based theranostic nanoplatform for the codelivery of the chemotherapeutic drug paclitaxel (PTX) and the photosensitizer 5,10,15,20-[3,5-(trifluoromethyl)phenyl]porphyrin (FP) by leveraging chitosan's superior biocompatibility and degradability. Using a partial fluorination strategy, fluorinated chitosan (FCS) with a unique fluorine-19 magnetic resonance imaging (F MRI) signal was effectively synthesized. Subsequently, stable and uniform nanoparticles (PTX-FP@FCS-NPs) were constructed with pH/laser-responsive drug release, which exhibit efficient uptake, laser-triggered reactive oxygen species generation, and synergistic killing effects in HCC cells (with an IC merely half that of PTX). PTX-FP@FCS-NPs accumulated selectively in xenograft HUH7 tumors and induced local photothermal heating (ΔT ≈ 30 °C), which enabled F MRI/FLI-guided synergistic chemotherapy (Chemo), photodynamic (PDT), and photothermal (PTT) therapy of HCC with high efficacy and favorable biosafety. This study not only developed an effective and safe novel strategy for HCC theranostics but also offers a reference design for constructing multifunctional nanoparticles based on natural polysaccharides.
PET Imaging Characterization of Sphingosine-1-Phosphate Receptor 2 in a Mouse Model of Esophageal Adenocarcinoma and Metastatic Lymph Node.
Chen H, Qiu L, Zhou W … +8 more , Jiang H, Xu S, Jadhav SB, Soda AK, Peng G, Li Z, Gropler RJ, Tu Z
Mol Pharm · 2026 Jun · PMID 42250214 · Publisher ↗
Esophageal adenocarcinoma (EAC) is an aggressive cancer with a rapidly increasing incidence globally. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that interacts with five G protein-coupled S1P receptor su...
Esophageal adenocarcinoma (EAC) is an aggressive cancer with a rapidly increasing incidence globally. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that interacts with five G protein-coupled S1P receptor subtypes (S1PR1-5), regulating physiological and cellular processes. Among these receptors, S1PR2 plays a significant role in cancer cell proliferation and metastasis. It was reported that S1PR2 was involved in the invasive growth of EAC cells through conjugated bile acid (CBA)-induced activation of the S1PR2 signaling pathway. This study aims to investigate the role of S1PR2 in promoting EAC development and progression using a potent and selective S1PR2 radiotracer [F]TZ9555. Imaging data of the OE33 tumor model and metastatic lymph node (LN) were acquired using the Inveon PET/CT scanner system from 40 to 60 min after tail vein administration of [F]TZ9555. The S1PR2 inhibitor JTE013 was used to block S1PR2 activity in OE33 cells for the regulation of their biological function. Western blotting, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), immunofluorescence (IF), cell uptake assay, autoradiography, and confocal microscopy analysis were performed for biological characterization. A biodistribution study of [F]TZ9555 was conducted in OE33 tumor-bearing nude mice. Single-cell RNA-sequencing analysis was performed using a data set comprised of human EAC samples and adjacent normal tissues. The PET imaging data showed that [F]TZ9555 had average uptake (%ID/g) of 0.58 ± 0.08 and 1.38 ± 0.26 in the OE33 tumor xenograft and metastatic LN, respectively, compared to the uptake of 0.21 ± 0.06 in the corresponding muscle. The average tumor-to-muscle uptake ratio was 2.8-fold, and the average metastatic LN-to-muscle ratio was 7.0-fold. The biodistribution study demonstrated higher EAC tumor uptake. IHC confirmed elevated S1PR2 expression in OE33 tumors and metastatic LN tissues. Autoradiography showed significantly high uptake in OE33 tumors and metastatic LN tissue, which were blocked by JTE013. Single-cell analysis showed a significantly increased S1PR2 expression in fibroblasts within human EAC samples. Treatment with JTE013 decreased tumor cell proliferation and reduced S1PR2 and α-SMA expression in OE33 cells. Together, our study suggested that [F]TZ9555 has a substantial preclinical and clinical potential for assessing S1PR2 expression in predicting EAC progression.
Reversible & Microbubble Concentration-Dependent Permeabilization of an Human Endothelial Barrier to Small Molecules Using Ultrasound: Implications for Neurodegenerative Diseases Therapy.
Ea K, Pinaud M, Fouan D … +11 more , Presset A, Tartu JY, Sasaki N, Taulier N, Urbach W, Contino-Pépin C, Desgranges S, Blasco H, Corcia P, Vourc'h P, Escoffre JM
Mol Pharm · 2026 Jun · PMID 42249894 · Publisher ↗
The blood-brain barrier (BBB) is a highly selective interface that protects the brain from circulating pathogens and toxins, but this selectivity also restricts the delivery of therapeutic agents to the central nervous s...
The blood-brain barrier (BBB) is a highly selective interface that protects the brain from circulating pathogens and toxins, but this selectivity also restricts the delivery of therapeutic agents to the central nervous system. Microbubble-assisted ultrasound (MB-assisted US) has emerged as a promising noninvasive and localized strategy to modulate BBB permeability and enhance drug delivery. This study investigated the ability of MB-assisted US to permeabilize an endothelial barrier model and promote the transport of small molecules, with particular attention to the influence of MB concentration and the reversibility of permeability changes. Immortalized human cerebral microvascular endothelial hCMEC/D3 cells were cultured on Transwell® inserts to form a confluent monolayer. Vevo MicroMarker® microbubbles were added to the apical compartment, and an US sequence (1 MHz, 1 ms PRP, 5% DC, 400 kPa PNP, 2 min) was applied. Barrier integrity and permeability were assessed using transendothelial electrical resistance (TEER), lucifer yellow (LY) permeability, and propidium iodide (PI) uptake assays. Tight junction (TJ) organization was evaluated by immunofluorescence staining of zonula occludens-1 (ZO-1) and claudin-5, and cell viability was assessed using complementary cytotoxic assays. MB-assisted US induced a significant and immediate decrease in TEER, accompanied by increased LY transport and localized PI uptake above a defined MB concentration threshold. These functional changes correlated with a reversible alteration of TJ architecture. Barrier function and TJ organization progressively returned to baseline within 24-48 h, and no cytotoxic effects were observed. Overall, these results demonstrate that MB-assisted US induces a microbubble concentration-dependent and reversible endothelial permeability to small molecules in an model, highlighting its potential for controlled drug delivery strategies targeting neurodegenerative disease.
Cu-Labeled Bioorthogonal Probe for Targeted Positron Emission Tomography Imaging of Malignant Melanoma.
Song B, Hong D, Lee C … +8 more , Seo Y, Kim E, Jeong W, Choi S, Lee CS, Kwon SY, Kim DY, Pyo A
Mol Pharm · 2026 Jun · PMID 42249822 · Publisher ↗
Malignant melanoma is the most severe form of skin cancer, and its incidence is increasing worldwide. In melanoma, melanocytes overexpress melanin, which can act as a specific biomarker for early detection. The benzamide...
Malignant melanoma is the most severe form of skin cancer, and its incidence is increasing worldwide. In melanoma, melanocytes overexpress melanin, which can act as a specific biomarker for early detection. The benzamide (BZA) structure is known to bind to melanin, and it can be used as a skeletal structure for radiopharmaceuticals for visualizing malignant melanoma. In this study, we synthesized a novel BZA derivative, including a bioorthogonal chelator, and labeled it with Cu for biological evaluation. Cell uptake of the ((6-((2-(dimethylamino)ethyl)carbamoyl)pyridin-3-yl)methyl)carbamodithioic acid (MI-0201B2) pretargeted Cu treatment group was threefold higher (1.73 ± 0.17%) in melanin-expressed B16F10 (mouse melanoma) cells than in negative control cells. MicroPET imaging of the B16F10-bearing C57BL/6 mice ( = 4) showed tumor uptake of the MI-0201B2 pretargeted Cu injection group of 4.42 ± 0.52%ID/g at 1 h, with this increasing until 48 h (7.74 ± 1.10%ID/g). By contrast, when only Cu and Cu-MI-0201B2 were injected, the tumor uptakes were lower than the MI-0201B2 pretargeted Cu injection group (6.49 ± 0.48%ID/g), with values of 3.94 ± 0.09 and 4.53 ± 0.09%ID/g at 24 h, respectively. Ex-vivo biodistribution studies revealed that the MI-0201B2 pretargeted Cu injection group showed specific tumor uptake and retention for 48 h (4.92 ± 0.74%ID/g at 48 h). The novel chelator MI-0201B2 exhibited excellent melanin targeting activity, demonstrating its potential as a PET imaging agent for melanoma diagnosis utilizing a bioorthogonal strategy.
Pharmacokinetics and Dosimetry of Lu-DOTATATE in Patients with Advanced Well-Differentiated, Gastroenteropancreatic Neuroendocrine Tumors: Results from a Substudy of the Phase 3 XT-XTR008-3-01 Trial.
Ma G, Dong Y, Sun S … +10 more , Wang Y, Ji H, Xu X, Yang Q, Sun Y, Zhou H, Zhang X, Ye T, Yin A, Wang R
Mol Pharm · 2026 Jun · PMID 42244161 · Publisher ↗
This substudy presents the exploratory pharmacokinetic (PK) and dosimetry profile of XTR008, Lu-DOTATATE developed in China, from the phase 3 trial XT-XTR008-3-01. 10 patients with well-differentiated, locally advanced,...
This substudy presents the exploratory pharmacokinetic (PK) and dosimetry profile of XTR008, Lu-DOTATATE developed in China, from the phase 3 trial XT-XTR008-3-01. 10 patients with well-differentiated, locally advanced, or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) received 4 cycles of Lu-DOTATATE (7.4 GBq/cycle). Postfirst dose, whole-body planar scintigraphy (up to 7 days), abdominal SPECT/CT (24/48 h), and blood and urine sampling for PK, safety, and efficacy assessment were performed. Lu-DOTATATE peaked in blood at 15 min, then decreased with a T1/2 of 37.36 ± 16.44 h. 60.38% was excreted in urine within 16 h. For four cycles, the mean absorbed doses to kidneys and red marrow were 18.914 ± 6.242 Gy (excluding one patient with nephrolithiasis and absorbed dose to kidneys of 77.1Gy) and 1.199 ± 0.337 Gy, respectively. Two patients had absorbed doses to the kidneys higher than 23 Gy (25.9 Gy, 23.1 Gy) without renal toxicity. Hematological toxicities (mostly grade 1/2) were the most common treatment-related adverse events (TRAEs). No significant association was found between organ doses and specific toxicities. Tumor absorbed dose varied widely (0.312-9.78 Gy/GBq). An objective response rate (ORR) was 30% (3/10); tumor dose did not significantly differ between responders (2.68 ± 2.53 Gy/GBq) and nonresponders (2.93 ± 1.81 Gy/GBq, = 0.44). Tumor dose correlated moderately but nonsignificantly with size change ( = 0.016, > 0.05). PRRT with XTR008 showed favorable tolerability, PK, and dosimetry in patients with advanced GEP-NETs, supporting its use in Chinese patients with well-differentiated GEP-NETs as a new treatment option.
Enhanced Therapeutic Efficacy of Combined Photothermal Therapy and Doxorubicin Chemotherapy in Anaplastic Thyroid Carcinoma: An Innovative Treatment Approach.
Yang F, Zhou Y, Xu Y … +4 more , Zhou H, Qu J, Sun H, Lv S
Mol Pharm · 2026 Jun · PMID 42243048 · Publisher ↗
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with limited effective clinical therapies. Photothermal therapy (PTT) and doxorubicin (DOX) chemotherapy have shown potential against ATC, yet their cl...
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with limited effective clinical therapies. Photothermal therapy (PTT) and doxorubicin (DOX) chemotherapy have shown potential against ATC, yet their clinical application is hindered by limited tissue penetration and systemic toxicity, respectively. In this study, we developed an innovative combinatorial strategy integrating PTT with DOX chemotherapy. , this combined treatment markedly enhanced DOX uptake by ATC cells, inhibited cell proliferation, migration, and invasion, and effectively induced apoptosis. Additionally, it elevated intracellular reactive oxygen species levels, exacerbated DNA damage, and downregulated the expression of angiogenesis-related proteins. , the therapy significantly suppressed tumor growth, promoted the release of immunogenic cell death-associated signaling molecules, and reduced the expression of matrix metalloproteinase-9. Importantly, the treatment exhibited favorable biocompatibility and mitigated DOX-induced cardiotoxicity. Collectively, this PTT-chemotherapy combination enhances antitumor efficacy through multiple mechanisms while reducing systemic toxicity, representing a promising strategy with translational potential for ATC treatment.
Targeting NETosis in the Lung: Respiratory Delivery of Neutrophil-Specific NEBP-Liposomes for Enhanced Therapy of Acute Lung Injury.
Liu X, Liu Y, Guo W … +5 more , Li X, Han Y, Huo Q, Liu Y, Niu Y
Mol Pharm · 2026 Jun · PMID 42241382 · Publisher ↗
The activation, adhesion, and migration of neutrophils are one of the main reasons for the progression of acute lung injury (ALI) and a new therapeutic target for ALI. Although respiratory administration for ALI has the...
The activation, adhesion, and migration of neutrophils are one of the main reasons for the progression of acute lung injury (ALI) and a new therapeutic target for ALI. Although respiratory administration for ALI has the characteristics of targeted drug delivery, some issues, such as the drug's short residence time in the lungs, rapid clearance rate, and lack of specificity for neutrophils, make it difficult to maintain an effective drug concentration. Here, we designed and evaluated a neutrophil-targeting peptide NEBP-modified andrographolide liposome (N-Lip@A) that can be administered via the respiratory tract to inhibit the formation of neutrophil extracellular traps, aiming to provide a rapid, efficient, and precise intervention strategy for ALI. N-Lip@A liposomes were synthesized by the traditional thin-film hydration method. Cell immunofluorescence and scanning electron microscopy observations indicated that N-Lip@A could reduce the formation of neutrophil extracellular traps (NETs). Quantitative analysis using the PicoGreen assay showed that the release of double-stranded DNA (dsDNA) in the N-Lip@A group was reduced to 57.9% compared with the untreated PMA group, and its effect was superior to that of the nontargeted liposome formulation (Lip@A). SYTOX staining, CCK8 assay, and Calcein-AM/PI staining results demonstrated that N-Lip@A could reduce the death of PMA-stimulated neutrophils. Besides, compared with the untreated group, the supernatant from neutrophils pretreated with N-Lip@A increased the survival rate of alveolar epithelial MLE-12 cells. In a lipopolysaccharide-induced murine model of ALI, compared with the nontargeted Lip@A group or the untreated group, the pathological lung injury score decreased to 52.6% and 31.6%, respectively. Significant disease remission, including reduced pulmonary edema, restored integrity of the blood-air barrier, and improved alveolar architecture were also demonstrated through EB staining analysis, lung wet-to-dry weight ratio determination, and HE staining analysis. Collectively, N-Lip@A enables precise delivery of AGL to activated neutrophils via NEBP-mediated targeting, effectively inhibiting NETs formation and mitigating ALI-associated pathological damage. This strategy provides an expandable targeted drug delivery platform for the treatment of various acute or chronic pulmonary inflammatory diseases driven mainly by neutrophils.
Preclinical Safety Evaluation and First-in-Human Translational Study of [Lu]Lu-TEFAPI-06: An Albumin-Binding Fibroblast Activation Protein Inhibitor for Theranostics.
Tian X, Wang L, He C … +4 more , Teng Y, Zhang Y, Cui Z, Liu J
Mol Pharm · 2026 Jun · PMID 42241330 · Publisher ↗
Current quinoline-based fibroblast activation protein (FAP) inhibitors typically exhibit rapid pharmacokinetics, which limits their effective energy deposition and therapeutic efficacy in radionuclide therapy. To address...
Current quinoline-based fibroblast activation protein (FAP) inhibitors typically exhibit rapid pharmacokinetics, which limits their effective energy deposition and therapeutic efficacy in radionuclide therapy. To address this limitation, a novel albumin-binding radiopharmaceutical, [Lu]Lu-TEFAPI-06, was developed to extend circulatory half-life and enhance tumor retention. This study reports a systematic "bench-to-bedside" translational investigation of [Lu]Lu-TEFAPI-06, encompassing comprehensive preclinical toxicology evaluation and an exploratory first-in-human (FIH) trial. In the preclinical phase, safety assessment in Sprague-Dawley rats demonstrated a favorable toxicity profile; no overt adverse effects or histopathological organ damage were observed. Biodistribution studies in tumor-bearing mice confirmed prolonged tumor retention compared to conventional ligands. In the subsequent FIH trial enrolling five patients with metastatic solid tumors, [Lu]Lu-TEFAPI-06 demonstrated acceptable tolerability. The primary adverse events were mild, reversible hematotoxicity, with no signs of hepatotoxicity or nephrotoxicity detected. Dosimetric analysis identified the kidneys as the dose-limiting organ. Clinically, the radiotracer exhibited significant heterogeneity in biodistribution, displaying the most favorable kinetic profile and absorbed dose in the patient with leiomyosarcoma. Furthermore, preliminary observations of therapeutic response in this patient indicated reductions in both standardized uptake values (SUVmax) and serum tumor markers. These findings preliminarily indicate the manageable safety and translational potential of [Lu]Lu-TEFAPI-06 within this small exploratory cohort, supporting further evaluation of albumin-binding FAP-targeted therapies.
A Universal Tag To Supercharge Proteins for Cytosolic Delivery.
Quan Y, Jing W, Peng L … +2 more , Yang W, Tai W
Mol Pharm · 2026 Jun · PMID 42231647 · Publisher ↗
Supercharged proteins are some naturally occurring proteins that bear an abnormally high number of charged amino acids but can fold correctly and function normally. Owing to the nanoscale three-dimensional charge distrib...
Supercharged proteins are some naturally occurring proteins that bear an abnormally high number of charged amino acids but can fold correctly and function normally. Owing to the nanoscale three-dimensional charge distribution associated with folding, the superpositively charged proteins possess the ability to rapidly enter mammalian cells with a potency much greater than cell-penetrating peptides and protein transduction domains. To harness the advantage, some proteins have been extensively mutated at their surface-exposed residues to generate "supercharged" variants such as +36GFP. Despite its effectiveness, this approach is time-consuming and only applicable to a few proteins that can tolerate the massive mutagenesis. Here, we proposed a tagging strategy to supercharge proteins and expand its application for the cytosolic delivery of proteins. Using the pan-protein binding ability of Coomassie brilliant blue (CBB), we developed a CBB-bearing cationic peptide CBB-R8 that can anchor on the protein surface and supercharge proteins without mutagenesis. The charge density of tagged proteins can be finely tuned by varying the tag/protein molar ratio, thus achieving a superior delivery efficiency to the cytosol than the canonical +36GFP. Mechanism studies revealed that the tagged protein could instantly and directly access the cytosol with little participation of endocytic pathways, resulting in the majority of delivered proteins being located in the cytosol. Moreover, the tagged proteins were discharged in the cytosol and return to biological functions after delivery, capable of catalyzing, blocking, and manipulating diverse targets inside cells. In conclusion, this simple plug-and-charge methodology greatly facilitates the preparation of supercharged proteins and expands its application to more intracellular targets.
Ga-Labeled LLP2A for PET Imaging of Very Late Antigen-4 in Acute Cardiac Rejection.
Li H, Gai Y, Hou X … +8 more , Duan Q, Wu Y, Deng C, Long Y, Zhang L, Chen Y, Lan X, Xie M
Mol Pharm · 2026 Jun · PMID 42231105 · Publisher ↗
Acute rejection (AR) remains the most common complication after heart transplantation (HT). AR is an acute immune response mediated by lymphocytes, and very late antigen-4 (VLA-4) plays a vital role in lymphocyte differe...
Acute rejection (AR) remains the most common complication after heart transplantation (HT). AR is an acute immune response mediated by lymphocytes, and very late antigen-4 (VLA-4) plays a vital role in lymphocyte differentiation and transport, making it an attractive target for developing molecular diagnostic agents. In this study, we proposed the construction of a radionuclide probe Ga-LLP2A and explored the role of the VLA-4 receptor distribution in AR. The in vitro and in vivo targeting efficiency and specificity of the tracer were validated by the cell uptake assay of monocyte cells and cardiomyocytes, PET/CT imaging, and biodistribution of VLA-4-positive B16F10 tumor-bearing mice models, respectively. Ga-LLP2A (5.5-7.4 MBq/rat) were injected into each group of rats 5 days after transplantation, including allograft (ALL), allograft treatment (ALL-T), allograft blocking (ALL-B), isograft (ISO), and normal Lewis (NOR) rats. PET/CT images, ex vivo autoradiography, and biodistribution were performed 1 h after injection. Expression levels of VLA-4 in the hearts of rats in each group were assessed by immunochemical staining. The tracer exhibited high accumulation with good contrast in the graft heart of ALL rats in static PET/CT images, autoradiography, and biodistribution studies and lower accumulation of radioactivity in the ALL-T and ALL-B groups, while no uptake was seen in the ISO and NOR groups. Histological analysis confirmed the abundant infiltration of VLA-4-positive cells in the graft heart of ALL rats. In conclusion, Ga-LLP2A exhibited high VLA-4 targeting efficacy in vivo and could accumulate specifically in the graft heart, rendering it a promising candidate for noninvasive imaging of acute cardiac rejection.
Antitumor Immunity Mediated by Nanoreactors Based on Bacterial Membrane Vesicles.
Zhang R, Sun Y, Ding F … +6 more , Ju W, Chu Z, Ren Z, He Z, Wang X, Wang P
Mol Pharm · 2026 Jun · PMID 42228764 · Publisher ↗
Traditional cancer vaccines are designed to elicit tumor-specific immune responses against preexisting or recurrent tumors and have been widely explored in oncology. However, their clinical translation has been hampered...
Traditional cancer vaccines are designed to elicit tumor-specific immune responses against preexisting or recurrent tumors and have been widely explored in oncology. However, their clinical translation has been hampered by persistent limitations such as suboptimal immunogenicity, complex manufacturing processes, and safety concerns, underscoring the need for multifunctional cancer vaccines that simultaneously achieve high potency and favorable tolerability. Here, we present a tumor vaccine platform based on engineered bacterial membrane vesicles (E-MVs) displaying the well-defined tumor-associated antigen MUC1 VNTR. This platform integrates antigen delivery with the intrinsic adjuvant properties of E-MV biological macromolecule, thereby enabling both therapeutic antitumor immunity and durable prophylactic protection. E-MVs derived from engineered (DE3) exhibit a spherical morphology with a size distribution of 100-200 nm. Following subcutaneous administration, E-MVs rapidly accumulate in draining lymph nodes and are efficiently internalized by dendritic cells, promoting antigen processing and cross-presentation to T cells. Functionally, E-MVs induce significant infiltration of CD8 T cell into the tumor microenvironment and enhance IFN-γ production, resulting in potent tumor immune responses. This leads to suppressed tumor growth, prolonged survival, and effective prevention upon tumor challenge in both "cold tumor" (breast cancer) and "hot tumor" (melanoma) mouse models. Collectively, these results demonstrate that the E-MV-based vaccine is a versatile therapeutic and prophylactic platform, offering a simple, efficient, and clinically translatable strategy to induce durable antitumor immunity.
Differentiating and Quantifying Two Different Amorphous Phases of a Drug Substance in Tablet Formulation by N Solid-State NMR: Derisking the Drug's Chemical Liability.
Medek A, Strohmeier M, Schuchart A … +2 more , Maguire CK, Ferris L
Mol Pharm · 2026 Jun · PMID 42227700 · Publisher ↗
A sensitive solid-state N NMR method was developed to allow for differentiation and quantification of amorphous drug substance (DS) potassium salt, amorphous DS free form, and their crystalline counterparts in the presen...
A sensitive solid-state N NMR method was developed to allow for differentiation and quantification of amorphous drug substance (DS) potassium salt, amorphous DS free form, and their crystalline counterparts in the presence of excipients in a tablet formulation. To achieve the desired sensitivity, N-enriched DS crystalline potassium salt was used to prepare tablets. The tablets were stressed at multiple elevated temperature and relative humidity conditions to assess the extent of DS amorphization and ensuing salt disproportionation with the goal of determining if any free DS form (amorphous or crystalline) was generated. In contrast to the potassium salt, the free DS form was known to present a chemical degradation liability. This work confirmed the mechanism of the DS degradation being the amorphization-mediated salt disproportionation and, by evaluating the routes to amorphization, determined the risk of degradation during the life cycle of the drug product.
Correction to "Homologous Tumor Cell-Derived Delivery of Doxorubicin via Liquid Nitrogen-Treated 4T1 Cells for Targeted Breast Cancer Therapy".
Yang F, Lu Y, Lang X … +7 more , Sun L, Zou H, Zhou Z, Guo Y, Guo Y, Wang X, Han M
Mol Pharm · 2026 Jun · PMID 42223415 · Publisher ↗
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