Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
Integrating PET and Fluorescence Imaging with a Novel PSMA-ICG Conjugate for Prostate Cancer Management.
Hou J, Tang L, Zhou M … +6 more , Yang J, Tang Y, Cai Y, Yang Y, Liu P, Hu S
Mol Pharm · 2026 Jun · PMID 42101325 · Publisher ↗
Prostate cancer (PCa) is a major global health burden, but current preoperative imaging modalities lack sufficient sensitivity for precise diagnosis. Thus, developing efficient novel imaging probes is urgently needed to...
Prostate cancer (PCa) is a major global health burden, but current preoperative imaging modalities lack sufficient sensitivity for precise diagnosis. Thus, developing efficient novel imaging probes is urgently needed to improve PCa diagnosis and management. In this study, a novel PET/fluorescence dual-modality probe [Ga]Ga-XY-PSMA-ICG was designed and synthesized, and its affinity, specificity, biodistribution, pharmacokinetics, and radiation dosimetry were evaluated in vitro and in vivo. PSMA-positive xenograft models were established to verify the PSMA-targeting ability of XY-PSMA-ICG and [Ga]Ga-XY-PSMA-ICG via fluorescence and PET imaging, and first-in-human studies were conducted to assess the safety, biodistribution, and PSMA imaging potential of [Ga]Ga-XY-PSMA-ICG. [Ga]Ga-XY-PSMA-ICG was successfully prepared through a 14-step synthesis and Ga labeling with good yield and stability. In PSMA-positive xenograft models, it showed rapid and specific tumor uptake, long tumor retention (up to 240 min), and favorable tumor-to-background ratios, which were significantly better than those of [Ga]Ga-PSMA-617 at 60 min ( < 0.01). Strong tumor fluorescence persisted up to 96 h, with a 72.8-fold higher intensity than free ICG. In clinical studies, [Ga]Ga-XY-PSMA-ICG mainly accumulated in the kidneys, bladder, spleen, and liver, with moderate uptake in the blood pool, parotid glands, and ureters in healthy volunteers. It exhibited excellent lesion detectability in patients, with intense accumulation in primary lesions (maximum SUV 50.15) and no adverse events. These results demonstrate that [Ga]Ga-XY-PSMA-ICG is a clinically translatable dual-modality probe, offering a promising strategy to enhance the precise diagnosis and management of prostate cancer and supporting its further clinical application.
Multinuclear Solid-State NMR and NMR Crystallography of Solid Forms of Creatine and Creatinine.
Fleischer CH, Rash VK, Dowdell ZT … +9 more , Termos S, Lin X, Gunaga SS, Mentink-Vigier F, Jimenez J, Abeykoon AMM, Senanayake S, Holmes ST, Schurko RW
Mol Pharm · 2026 Jun · PMID 42096280 · Publisher ↗
Creatine is a performance-enhancing supplement with two widely available commercial solid forms, namely, creatine monohydrate (creatine·HO) and creatine HCl, the latter of which does not have a reported crystal structure...
Creatine is a performance-enhancing supplement with two widely available commercial solid forms, namely, creatine monohydrate (creatine·HO) and creatine HCl, the latter of which does not have a reported crystal structure. Moreover, commercial formulations of creatine may contain creatinine, an undesired impurity phase resulting from the self-cyclization of creatine during manufacturing. Therefore, reliable methods for characterizing the different solid forms of creatine and detecting the presence of creatinine are essential. Herein, we address these challenges using C, N, and Cl solid-state NMR (SSNMR) spectroscopy to obtain distinct spectral fingerprints for creatine·HO and creatine HCl, along with creatinine and creatinine HCl. The acquisition of these SSNMR spectra offers a robust approach for both the rapid characterization of each solid form and the detection of the impurity phases. Additionally, quadrupolar NMR crystallography-guided crystal structure prediction (QNMRX-CSP) was applied for the crystal structure determination of creatine HCl, which was validated by the subsequently determined single-crystal X-ray diffraction (SCXRD) structure. Finally, to investigate the relationship between NMR parameters and structural features, C and N chemical shifts and Cl electric field gradient (EFG) tensors were computed from geometry-optimized structures of the four solid forms by using dispersion-corrected DFT-D2* methods. This integrative approach offers a powerful framework for advancing the structural understanding and quality control of creatine-based supplements and next-generation formulations, as well as a wide range of other solid pharmaceuticals and nutraceuticals.
Water-Stable Hydrazone-Linked Porous Organic Cage-Enhanced Nanoparticle Brachytherapy for the Treatment of Glioblastoma.
Dai J, Su K, Song Z … +10 more , Cui Z, Du A, Hu T, Niu L, Dong Q, Yin H, Bing Z, Yuan L, Yuan D, Pan Y
Mol Pharm · 2026 Jun · PMID 42091446 · Publisher ↗
Radiotherapy has played a crucial role in the treatment of glioblastoma (GBM). Continuous advancements have aimed to maximize radiation delivery to tumor regions while minimizing injury to the surrounding healthy tissues...
Radiotherapy has played a crucial role in the treatment of glioblastoma (GBM). Continuous advancements have aimed to maximize radiation delivery to tumor regions while minimizing injury to the surrounding healthy tissues. Recently, local brachytherapy has emerged as a promising approach for GBM. In this study, we developed a water-stable hydrazone-linked porous organic cage (HPOC-101) material, which possesses eight O-N-O chelation sites capable of efficiently coordinating with Lu, and can be administered via stereotactic injection to enhance brachytherapy for GBM. HPOC-101 (abbreviated as Cage) enables rapid, efficient, and stable radiolabeling with clinically established radionuclides, including Zr and Lu, even at room temperature. Following extensive grinding, smaller crystal grains can penetrate cells, thereby enhancing tumor cell-killing effects. In contrast, larger crystal grains can remain in intercellular spaces for prolonged periods, amplifying localized radiation effects. By delivering Lu via local stereotactic injection, the cage enhances local brachytherapy and extends the duration of radionuclide activity in GBM mouse models. Intracellular Lu-Cage complexes demonstrate increased efficacy in eliminating tumor cells. Furthermore, radionuclide-radiotherapy-induced immunogenic cell death (ICD) is also an important mechanism of internal radiotherapy. Our research shows that nanolabeled nuclides can activate local immune effects by accruing tumor infiltration of M1-like macrophages and recruiting CD8 effector T cells. This study thus presents a highly effective and water-stable organic molecular cage system for radionuclide chelation in brachytherapy, offering a promising strategy for the localized treatment of glioblastoma.
VEGFA-Targeted M3-F4 Ionizable Lipid Nanoparticles Improve Diabetic Retinopathy.
Liu S, Bao Y, Yilihaer Y … +6 more , Guo W, Ma C, Xue C, Yang Z, Chen Y, Xie Z
Mol Pharm · 2026 Jun · PMID 42089665 · Full text
Diabetic retinopathy (DR) is one of the leading causes of visual impairment and blindness worldwide. Current therapies for DR primarily focus on inhibiting vascular endothelial growth factor A (VEGFA); however, their eff...
Diabetic retinopathy (DR) is one of the leading causes of visual impairment and blindness worldwide. Current therapies for DR primarily focus on inhibiting vascular endothelial growth factor A (VEGFA); however, their efficacy remains limited due to drug resistance and the requirement for repeated intravitreal injections. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome-editing technology enables specific targeting and knockout of the VEGFA gene, offering a novel therapeutic approach for DR. In this study, we synthesized a novel ionizable lipid, M3, and assembled the optimal-performing M3-F4 into lipid nanoparticles (M3-F4 LNP) for codelivery of VEGFA-targeting Cas9 mRNA (mCas9) and single guide RNA (sgRNA). The optimized formulation, composed of M3:cholesterol:DSPC:DMG-PEG at a molar ratio of 45:42.5:10:2.5, exhibited a particle size below 100 nm, a PDI below 0.2, and an encapsulation efficiency above 80%. Sanger sequencing-based indel analysis confirmed VEGFA editing in HRMECs, with sgRNA1 achieving an indel frequency of approximately 28.7%. In high glucose-induced human retinal microvascular endothelial cells (HRMECs), the mCas9/sgVEGFA@M3-F4 LNP reduced cell proliferation, migration, invasion, and tube formation, while restoring endothelial barrier integrity and exerting anti-inflammatory effects. A single intravitreal injection of mCas9/sgVEGFA@M3-F4 LNP effectively inhibited pathological neovascularization and retinal leakage in both oxygen-induced retinopathy mice and streptozotocin-induced diabetic mice . Furthermore, it markedly attenuated VEGFA-induced inflammation while maintaining excellent biocompatibility. This study demonstrates M3-F4 LNP as a promising method for efficient CRISPR/Cas9 delivery and provides robust support for gene therapy strategies in DR treatment.
Potential of Low-Frequency Raman Spectroscopy for Structural Screening of Lipid-Based Drug Delivery Systems for Poorly Water-Soluble Drugs.
Be̅rziņš K, Krog LS, Boyd BJ
Mol Pharm · 2026 Jun · PMID 42084959 · Publisher ↗
Dynamic changes in the structure of lipid lyotropic liquid crystals upon mixing of different lipid systems were investigated using simultaneous low-frequency Raman (LFR) and small-angle X-ray scattering (SAXS) at a synch...
Dynamic changes in the structure of lipid lyotropic liquid crystals upon mixing of different lipid systems were investigated using simultaneous low-frequency Raman (LFR) and small-angle X-ray scattering (SAXS) at a synchrotron facility. Monoolein and phytantriol were investigated as lipids with broadly highlighted potential for drug delivery. Their dispersed cubic phase structures were perturbed by mixing with a vitamin E acetate emulsion, known to modify the mesophase structures formed by monoolein and phytantriol, in the presence or absence of a lipophilic drug (cinnarizine). This mixing strategy enabled the exploration of structurally distinct and compositionally complex scenarios to establish direct correlations between LFR spectral features and mesophase structural parameters determined by SAXS, thereby assessing how LFR can be used to sensitively track composition-driven mesophase transformations. Crucially, the concurrent LFR-SAXS approach also allowed the evaluation of the affinity for cinnarizine to favorably interact with these lipids and form specific nanostructures leading to increased drug solubilization. These results illustrate how combined LFR-SAXS measurements can inform and expand the future use of LFR as a partially independent, structure-sensitive probe of lipid mesophase dynamics.
Estimation of Various Physiological Parameters Affecting Amyloid Plaque Distribution of a Novel MRI Contrast Agent in the Brain of Alzheimer's Disease Transgenic Mice.
Salian V, Wang Z, Curran G … +2 more , Podulso JF, Kandimalla KK
Mol Pharm · 2026 Jun · PMID 42082924 · Publisher ↗
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is...
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is imperative for diagnosing AD before the onset of cognitive decline. Magnetic resonance (MR) imaging using Gd (III)-based agents for contrast enhancement and plaque targeting provides a promising avenue. However, there remains a challenge due to the limited permeability of these contrast agents across the blood-brain barrier (BBB), which restricts its delivery. Furthermore, clearance mechanisms in the brain also reduce retention of contrast agents. To identify mechanisms that limit the success of contrast agents, we investigated the pharmacokinetics and the brain distribution of contrast agent, Gd[N-4ab/Q-4ab]Aβ30, using AD transgenic mouse models and compartmental modeling. Our results demonstrate that the contrast agent is internalized by parenchymal cells, which limits its availability to bind to extracellular plaques. Sensitivity analysis conducted on the compartmental model identified systemic clearance and plasma-to-brain influx as key parameters that limit the delivery of the contrast agent to the brain. The analysis also highlights the BBB as a formidable barrier for delivery and the importance of improving BBB permeability to increase the accumulation of the contrast agent in the brain. Furthermore, model simulations revealed that glymphatic drainage contributes to the poor retention and rapid elimination of the contrast agent from the brain. By elucidating the role of these biological processes and parameters, this study contributes to understanding factors limiting contrast agent efficacy in amyloid plaque imaging in the AD brain. These findings also reveal important targets for optimizing contrast agent design to improve its brain delivery.
The In Vivo Effect of Amorphous Drug Nanoprecipitates on the Intestinal Absorption of the PROTACs ARV-110 (Bavdeglutamide) and ARV-471 (Vepdegestrant).
Niessen J, Koziolek M, Indulkar A … +5 more , Borchardt T, Sjöblom M, Hedeland M, Lennernäs H, Dahlgren D
Mol Pharm · 2026 Jun · PMID 42063283 · Full text
Targeted degradation of disease-associated proteins via proteolysis-targeting chimeras (PROTACs) is a powerful pharmacological strategy, but it requires a complex molecular architecture associated with poor intestinal ab...
Targeted degradation of disease-associated proteins via proteolysis-targeting chimeras (PROTACs) is a powerful pharmacological strategy, but it requires a complex molecular architecture associated with poor intestinal absorption. Rational development of orally bioavailable PROTACs requires a thorough understanding of their biopharmaceutical properties. This mechanistic in vivo study aimed to address the potential of colloidal particle formulations to enhance the intestinal absorption of two model PROTACs, ARV-110 and ARV-471. Dose escalation studies were conducted in rats to investigate the impact of particle size and concentration on intestinal absorption and bioavailability of the PROTACs. The contribution of colloidal amorphous drug nanoprecipitates was moreover directly quantified by comparing intestinal absorption from a colloid-forming formulation with that of an amorphous, noncolloidal counterpart. All in vivo experiments were complemented by in vitro determinations of amorphous solubility, solubilization dynamics, and characterization of the size and solid state of the emerging colloidal particles. The two PROTACs consistently formed luminally stable, amorphous drug nanoprecipitates in vivo. Dose-proportional increases in absorption were observed at concentrations up to 15-fold above their amorphous solubility. The amorphous drug nanoprecipitates directly contributed to an enhanced absorptive flux up to 7-fold compared to a noncolloidal amorphous powder. The potentiating effect was attributed to particle drifting of the nanoparticles across the aqueous boundary layer, which increased the free drug concentration at the epithelial membrane. For the less soluble ARV-110, the colloid effect was capped at doses >0.2 mg/kg due to saturation. For the more soluble ARV-471, the colloid effect persisted at doses up to 5.0 mg/kg but at a reduced rate due to the formation of larger, less mobile particles. Overall, this work provided mechanistic insight into PROTAC absorption and suggested that formulations capable of generating stable amorphous drug nanoprecipitates represent a promising strategy to enhance the oral bioavailability of low-solubility PROTACs.
Development and Preclinical Evaluation of Dual-Target Ga/Lu-Labeled FAP-Bisphosphonate Radioligands with Enhanced Osteoma Retention.
Zhao R, Deng Y, Jin W … +8 more , Xu M, Liang W, Liu S, Zhong J, Lv J, He J, Zhu L, Wang X
Mol Pharm · 2026 Apr · PMID 42053038 · Publisher ↗
Bone metastases and associated skeletal-related events (SREs) severely compromise the survival and quality of life of patients with advanced cancer. Although bisphosphonates enable efficient bone targeting, their radiola...
Bone metastases and associated skeletal-related events (SREs) severely compromise the survival and quality of life of patients with advanced cancer. Although bisphosphonates enable efficient bone targeting, their radiolabeled analogues exhibit limited uptake in osteolytic lesions due to the low hydroxyapatite content. Fibroblast activation protein, highly expressed in cancer-associated fibroblasts within the tumor microenvironment, provides tumor specificity and may enhance tracer accumulation in osteolytic bone metastases. To overcome this limitation, we developed two heterodimeric [Ga]Ga/[Lu]Lu-DOTA-FAPI-bisphosphonate radioligands ([Ga]Ga/[Lu]Lu-DFP-1/2) by integrating a FAP-targeting moiety with a bisphosphonate backbone. Both compounds were synthesized with high radiochemical purity (>95%) and excellent in vitro stability. In A549-FAP xenograft models, dynamic PET/CT imaging revealed comparable tumor uptake of [Ga]Ga-DFP-1/2 and [Ga]Ga-FAPI-04 up to 2 h postinjection, with [Ga]Ga-DFP-2 demonstrating faster clearance from nontarget organs. In tibial A549-FAP osteogenic models, [Ga]Ga-DFP-2 showed significantly higher uptake (4.88 ± 1.01% ID/mL) than mono-FAP or monobisphosphonate tracers ( < 0.05). In osteolytic A549 models, [Ga]Ga-DFP-2 uptake (3.16 ± 0.82% ID/mL) also exceeded that of monobisphosphonate tracers ( < 0.01). Biodistribution studies confirmed prolonged [Lu]Lu-DFP-2 retention (26.94 ± 4.40% ID/g at 168 h). Collectively, these findings demonstrate that [Ga]Ga/[Lu]Lu-DFP-2 possesses favorable dual bone- and tumor-targeting characteristics and holds strong translational promise as a novel theranostic agent for the imaging and treatment of lung cancer bone metastases.
Novel Covalent FAP-Targeted [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 for Improved Pharmacokinetics and Enhanced Tumor Uptake.
Jin Z, Wu T, Tang S … +12 more , Liu Y, Ai Y, Wan Q, Zhao Y, Yan S, Zeng J, Xing N, Liu Y, Chen L, Zhou Z, Chen Y, Qiu L
Mol Pharm · 2026 Jun · PMID 42052981 · Publisher ↗
Preclinical and clinical investigations have revealed the promising potential of various fibroblast-activating protein inhibitor (FAPI) radiopharmaceuticals. One strategy of particular interest involves the covalent targ...
Preclinical and clinical investigations have revealed the promising potential of various fibroblast-activating protein inhibitor (FAPI) radiopharmaceuticals. One strategy of particular interest involves the covalent targeting of these FAPI-based agents to fibroblast-activating protein (FAP) itself, which has been shown to enhance tumor uptake and retention. This study aims to optimize ligand structures through covalent binding strategies, developing an optimal radionuclide-based tracer for tumors with high FAP expression. All precursors were synthesized with DOTA-FAP-2286 as the molecular skeleton. The physicochemical properties, imaging, and biodistribution of radioactive ligands were investigated by Ga-labeling to evaluate their pharmacokinetic properties, as well as their affinity and specificity for FAP. The clinical transformation of [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 PET imaging was performed. Two novel covalent FAP-targeted ligands, DOTA-mFS-FAP-2286 and DOTA-mFS-KERERG-FAP-2286, were successfully synthesized. The values for DOTA-FAP-2286, DOTA-mFS-FAP-2286, and DOTA-mFS-KERERG-FAP-2286 are 2.8 nM, 84 nM, and 0.21 nM, respectively. In the HEK293huFAP tumor model, the tumor uptake values of [Ga]Ga-DOTA-FAP-2286, [Ga]Ga-DOTA-mFS-FAP-2286, and [Ga]Ga -DOTA-mFS-KERERG-FAP-2286 at 2 h were 15.21 ± 2.53% ID/g, 13.65 ± 1.64% ID/g, and 23.33 ± 1.96% ID/g, respectively. The biodistribution and imaging studies showed that [Ga]Ga-DOTA-mFS-FAP-2286 was excreted through both the hepatic-biliary and urinary systems, while [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 was excreted solely through the urinary system. Micro-PET/CT imaging studies revealed that [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 was observed to exhibit increased tumor uptake and retention along with reduced off-target accumulation relative to [Ga]Ga-DOTA-FAP-2286. In tumor patients' clinical translation imaging, [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 PET/CT demonstrated higher uptake and identified more small lymphatic and distant metastases than [Ga]Ga-DOTA-FAP-2286 PET/CT. The potential diagnostic value of [Ga]Ga-DOTA-mFS-KERERG-FAP-2286 lies in its design as a derivative of the DOTA-FAP-2286 scaffold, incorporating a sulfur(VI) fluoride exchange (SuFEx)-based covalent warhead and a hydrophilic polypeptide. This modification is anticipated to alter the pharmacokinetic profile, leading to enhanced tumor uptake and retention, thereby improving clinical diagnostic accuracy.
Precipitation Inhibition by Small-Molecule Analogues To Sustain Drug Supersaturation.
Roy P, Kavanagh ON
Mol Pharm · 2026 Jul · PMID 42046436 · Publisher ↗
Maintaining supersaturation during gastric-to-intestinal pH transitions can be essential to maximize the oral exposure of pH-sensitive drugs. This study demonstrates a mechanistically guided strategy to stabilize ciprofl...
Maintaining supersaturation during gastric-to-intestinal pH transitions can be essential to maximize the oral exposure of pH-sensitive drugs. This study demonstrates a mechanistically guided strategy to stabilize ciprofloxacin supersaturation using structurally related fluoroquinolone analogues as nucleation inhibitors. Structural similarity screening identified danofloxacin and levofloxacin as promising candidates, and their effects were evaluated using nucleation induction time, dynamic pH-shift dissolution, and H NMR spectroscopy. Danofloxacin produced the most significant extension of nucleation induction time and was superior to classical polymeric precipitation inhibitors (hypromellose and polyvinylpyrrolidone). During pH-shift dissolution, ciprofloxacin alone retained only ∼20% of its initial concentration after 30 min at pH 7.0, whereas danofloxacin and levofloxacin sustained ∼92% and ∼37%, respectively. Correspondingly, AUC min increased by 5.44-fold for danofloxacin and 1.65-fold for levofloxacin, with HPMC and PVP providing 2.8-fold and 1.25-fold increases. H NMR revealed concentration-dependent aromatic shielding consistent with ciprofloxacin···analogue heteroassociation, with danofloxacin producing the most substantial and most symmetric perturbations. These data sets support a kinetic mechanism in which isostructural analogues disrupt ciprofloxacin self-association, delay the formation of prenucleation aggregates, and prolong supersaturation. The findings establish small-molecule structural mimicry as a viable pathway for stabilizing supersaturation and guiding mechanism-based coformulation design.
Design and Application of Bioactive Cell-Penetrating Peptides as Effective Therapeutic Agents for Corneal Wound Healing.
Sinha M, Chugh A
Mol Pharm · 2026 Jun · PMID 42046239 · Publisher ↗
The management of corneal injuries remains a formidable global health challenge, yet current therapeutic strategies remain supportive rather than actively regenerative, primarily because current clinical standards fail t...
The management of corneal injuries remains a formidable global health challenge, yet current therapeutic strategies remain supportive rather than actively regenerative, primarily because current clinical standards fail to address the delicate biological tension between rapid re-epithelialization and the risk of permanent fibrotic scarring. To address this unmet need, we report the design, applications, and mechanisms of novel collagen-derived cell-penetrating peptides that function as dual-action bioactive agents. In human corneal epithelial cells, these peptides demonstrated efficient cell-penetrating capabilities and macromolecular cargo delivery. All-atom molecular dynamics simulations revealed that these peptides interact with membrane interfaces through distinct energetic profiles, facilitating the rapid translocation. Beyond their utility as delivery vectors, the peptides exhibited intrinsic, dose-dependent wound healing activity in vitro. Mechanistic investigations revealed that this capacity is driven by targeted transcriptional modulation. Both peptides suppressed fibrotic and matrix-degradation genes while simultaneously upregulating pathways governing migration, epithelial identity, and proliferation. These results suggest that rationally engineered peptides can navigate complex microenvironments to actively enforce tissue integrity. Furthermore, they offer a promising peptide-based strategy that promotes corneal epithelial repair through an intrinsic, nonfibrotic mechanism while offering a potential platform for intracellular cargo delivery.
GE11/RGD Dual-Ligand Copper Nanoassemblies Synchronize Cuproptosis and Photothermal Therapy for Targeted Cervical Cancer Ablation.
Yang N, Liu L, Ding L … +12 more , Chen Z, Su T, Yang Z, Xu X, Tang L, Wei Z, Du J, Gao C, Xue S, Guo X, Feng Y, Li R
Mol Pharm · 2026 Jun · PMID 42044237 · Publisher ↗
Cervical cancer remains a major global health burden. Conventional surgery, radiotherapy, and chemotherapy are limited by insufficient tumor targeting, severe systemic toxicity, and drug resistance, highlighting an urgen...
Cervical cancer remains a major global health burden. Conventional surgery, radiotherapy, and chemotherapy are limited by insufficient tumor targeting, severe systemic toxicity, and drug resistance, highlighting an urgent need for safe, precise, and combinatorial therapeutic strategies. In this work, we fabricated one-step self-assembled GE11/RGD dual-ligand-modified copper nanoassemblies (GR@Cu NPs). These nanoparticles display densely modified targeting peptides on a copper-rich surface and enable efficient tumor accumulation with minimal off-target distribution. Under 980 nm near-infrared irradiation (1.0 W/cm, 5 min), GR@Cu NPs trigger a photothermal-copper ion synergistic cascade. The rapid release of Cu promotes dihydrolipoamide S-acetyltransferase oligomerization, ferredoxin 1 (FDX1) downregulation, and mitochondrial collapse, thereby initiating cuproptosis. The leaked mitochondrial DNA (mtDNA) further activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-interferon regulatory factor 3 (IRF3) pathway, reshaping the antitumor immune microenvironment. In vitro, GR@Cu NPs are rapidly and selectively internalized by HeLa and SiHa cervical cancer cells. In a HeLa xenograft nude mouse model, a single 5 min laser irradiation (1.0 W/cm, tumor temperature ∼ 51 °C) achieves potent and long-lasting tumor suppression for 21 days, without obvious body weight loss or histological damage to major organs. By integrating dual-ligand targeting with synergistic cuproptosis and photothermal therapy, this study provides an effective, low-toxicity, and precise strategy for cervical cancer treatment.
Unveiling Solvent-Mediated Mechanochemical Cocrystallization Pathways by CLASSIC NMR Spectroscopy.
Gołkowska AM, Nowak M, Fábián L … +5 more , Iuga D, Emmerling F, Nartowski KP, Karolewicz B, Khimyak YZ
Mol Pharm · 2026 Jun · PMID 42044204 · Full text
Although mechanochemical synthesis offers a sustainable way to produce solid forms of pharmaceutical compounds, the molecular-level mechanisms that govern solvent-mediated transformations remain largely unexplored. In th...
Although mechanochemical synthesis offers a sustainable way to produce solid forms of pharmaceutical compounds, the molecular-level mechanisms that govern solvent-mediated transformations remain largely unexplored. In this study, we present an solid-state nuclear magnetic resonance (NMR) approach to directly monitor the evolution of liquid-assisted grinding reactions under magic-angle spinning conditions. Using a modified CLASSIC NMR protocol, we tracked the cocrystallization of two model systems, theophylline-benzamide and metronidazole-gallic acid, in the presence of solvents with different levels of polarity. This method allows us to observe both the solid and liquid phases within the reaction environment simultaneously, revealing transient intermediates, hydrate formation, and solvent-dependent polymorphic outcomes. Comparisons with time-resolved X-ray diffraction confirm the complementary nature of NMR in capturing mechanistic details that are otherwise inaccessible to a diffraction-based analysis. This work establishes solid-state NMR as a powerful and accessible tool for investigating the effects of solvents in mechanochemical synthesis, thereby advancing our molecular understanding of polymorphic control and reaction pathways.
Synthesis and Preclinical Evaluation of [F]AlF-NOTA-A2P-GPC3P for Imaging of GPC3.
Jie Z, Tudi K, Chen Z … +2 more , Huang J, Tang G
Mol Pharm · 2026 Jun · PMID 42037560 · Publisher ↗
To develop an effective GPC3-targeted PET probe for tumor imaging, [F]AlF-NOTA-A2P-GPC3P was synthesized by introducing the hydrophilic linker A2P into the L5 peptide scaffold. The probe was efficiently radiolabeled usin...
To develop an effective GPC3-targeted PET probe for tumor imaging, [F]AlF-NOTA-A2P-GPC3P was synthesized by introducing the hydrophilic linker A2P into the L5 peptide scaffold. The probe was efficiently radiolabeled using the [F]AlF method, exhibiting high hydrophilicity (Log = -3.11 ± 0.31) and excellent in vitro and in vivo stability. Cellular uptake assays verified that the probe was significantly more highly taken up by GPC3-positive cell lines than by GPC3-low cell lines, confirming its specific binding to GPC3-positive cells. Micro-PET/CT and biodistribution studies in GPC3-positive tumor models (ASPC1, A549-GPC3) demonstrated specific uptake, significantly improved tumor-to-background ratios (especially tumor-to-lung and tumor-to-heart ratios), and reduced hepatic accumulation compared with the reported probe. Blocking studies in GPC3-positive tumors (ASPC1) confirmed its specificity. Thus, [F]AlF-NOTA-A2P-GPC3P is a promising PET imaging agent for GPC3-positive tumor detection.
Application of Allometric Scaling and Translational Modeling to Predict Human Pharmacokinetics of mRNA-Encoded Antibodies.
Nguyen TNT, Chang PK, Panorchan P … +3 more , Şahin U, Türeci Ö, Wu SP
Mol Pharm · 2026 Jun · PMID 42035344 · Full text
Messenger RNA (mRNA)-lipid nanoparticle (mRNA-LNP) platforms enable the in vivo expression of almost any therapeutic protein, offering unprecedented flexibility for clinical translation. However, for these rapidly deploy...
Messenger RNA (mRNA)-lipid nanoparticle (mRNA-LNP) platforms enable the in vivo expression of almost any therapeutic protein, offering unprecedented flexibility for clinical translation. However, for these rapidly deployable therapies, predicting the first-in-human (FIH) dose remains a key challenge. We developed an allometric scaling framework for human pharmacokinetic (PK) prediction of antibodies expressed from intravenously administered mRNA-LNPs, leveraging preclinical and clinical data for BNT141 (encoding RiboMab01, a full IgG1) and BNT142 (encoding RiboMab02.1, a bispecific Fab-scFv-based T-cell engager). The dose-normalized Cmax (DCmax) and dose-normalized AUC (DAUC) of translated antibodies across multiple species could be described by the allometric approach, with the estimated exponents ranging from -1.29 to -1.42 for BNT141 and BNT142. We also determined generalized single-species allometric scaling exponents of -1.26 from mice and -0.75 from nonhuman primate (NHP), respectively, that enabled the human predictions of translated antibodies exposure approximately 4-fold (mice) and within 2-fold (NHP). A mechanistic cross-species translational model was further developed that integrated mRNA-specific elimination and translation efficiency parameters to characterize the exposure of the translated antibodies from mRNA-based therapeutics. The translational model could predict the human PK exposure of translated antibodies within 1.33-fold for BNT141 and BNT142 via single-species scaling from NHP parameters as well as capturing the concentration-time profiles with reasonably high fidelity. Validation with publicly available mRNA-1944 (encoding CHKV-24, full IgG1) data confirmed both the allometric scaling and translational modeling methods' robustness when scaling from NHP data. Taken together, these results support a generalized cross-species PK relationship that is independent of the molecular characteristics of the translated antibodies or antibody-like protein products. This integrated scaling and modeling framework offers a generalizable solution for accelerating FIH dose selection of mRNA-encoded therapeutic antibodies and is adaptable to other recombinant proteins of interest.
Proteomics-Informed Physiologically Based Pharmacokinetic Modeling for Aldehyde Oxidase Substrates in Colorectal Cancer Liver Metastasis.
Izat N, Vasilogianni AM, Al-Majdoub ZM … +5 more , Houston JB, Galetin A, Rostami-Hodjegan A, Barber J, Scotcher D
Mol Pharm · 2026 Jun · PMID 42028959 · Publisher ↗
Aldehyde oxidase (AO) metabolizes a broad range of compounds, including the oxidation of anticancer kinase inhibitors. Quantitative proteomics data reported in the literature for liver microsomes from colorectal liver me...
Aldehyde oxidase (AO) metabolizes a broad range of compounds, including the oxidation of anticancer kinase inhibitors. Quantitative proteomics data reported in the literature for liver microsomes from colorectal liver metastases (CRLM) indicate decreased expression of various drug-metabolizing enzymes and transporters compared to the healthy liver, although information on AO remains limited. This study aimed to investigate, for the first time, potential alterations in AO abundance in CRLM patients and prospectively predict the pharmacokinetics of six AO/dual AO-CYP substrates in CRLM patients via physiologically-based pharmacokinetic (PBPK) models. Global proteomic analysis (using high-N approach) was performed on human liver cytosols (HLCs) and microsomes (HLMs) from 16 cancerous and matched histologically normal (adjacent to the tumor) liver tissues from CRLM patients. Commercial fractions from healthy donors were analyzed as controls. After the application of physiological scaling factors (cytosolic or microsomal protein per gram of liver), a strong rank correlation (rs = 0.86, = 24) was observed in AO abundance between donor-matching HLC and HLM samples from CRLM patients. Interindividual variability was the highest within cancerous livers (CV = 95%; = 9). The total hepatic AO abundance (nmol/g liver) was 4- and 6.9-fold lower in cancerous tissues compared to those in histologically normal and healthy tissues, respectively. Hepatic CYP3A4 and AO abundance correlated well (rs = 0.76, = 22) across patient samples. A substrate-specific decrease in drug clearance was predicted for all six compounds in patients with CRLM with the proteomics-informed PBPK models. The implications of varying levels of tumor burden were explored in the developed PBPK models to enable prospective PK predictions for AO substrates in the CRLM cancer population.
Predicting Agitation Stability of Monoclonal Antibodies during Developability Assessment.
Cohrs M, Pagureva N, Ozbulak U … +6 more , De Neve W, Braeckmans K, De Smedt S, Tcholakova S, Vinarov Z, Svilenov HL
Mol Pharm · 2026 Jun · PMID 42028833 · Full text
Developability assessment facilitates the selection of antibody drug candidates with desirable pharmaceutical properties. However, it remains uncertain whether agitation-induced aggregation can be predicted from standard...
Developability assessment facilitates the selection of antibody drug candidates with desirable pharmaceutical properties. However, it remains uncertain whether agitation-induced aggregation can be predicted from standard developability parameters. Here, we investigated whether key biophysical parameters predict agitation-induced aggregation of monoclonal antibodies (mAbs). To this end, we generated a benchmark data set by characterizing the aggregation upon agitation in the presence of an air-liquid interface of ten approved mAbs reformulated in a common surfactant-free buffer. The extent of aggregation varied substantially among mAbs and was primarily dependent on antibody identity. Flow imaging microscopy combined with machine learning revealed micrometre-sized aggregates with distinct morphologies, consistent with aggregation at air-liquid interfaces. Examination of thin liquid films and foams confirmed the presence of aggregates directly at the air-liquid interface and, therefore, the critical role of this interface for antibody aggregation during agitation. We then applied fluorescence-based, light scattering, and chromatographic techniques to determine standard developability parameters for each mAb, including apparent melting temperature (), nonreversibility onset temperature (), aggregation onset temperature (), diffusion self-interaction parameter (), hydrophobic interaction chromatography retention time, and relative monomer yield after isothermal refolding from chemical denaturants. Notably, none of these parameters correlated with agitation-induced aggregation. Finally, we assessed the surface properties of the mAbs via drop shape analysis and found that the combination of surface pressure and elastic modulus yields a good correlation with the concentration of micrometre-sized aggregates formed due to agitation. Overall, these findings highlight limitations in predicting mAb interfacial stability using standard developability assays and underscore the importance of studying antibody behavior at interfaces.
Antimelanoma Activity of the Mastoparan Peptides MPX and MP1: Cellular Selectivity and Mechanism of Action.
Sansone Semerdjian A, Arcisio-Miranda M
Mol Pharm · 2026 Jun · PMID 42028705 · Full text
MPX (Mastoparan X) and MP1 (Polybia-MP1) are cationic amphiphilic peptides isolated from the venom of insects of the family. Due to their physicochemical features, these peptides show affinity for biomimetic membranes,...
MPX (Mastoparan X) and MP1 (Polybia-MP1) are cationic amphiphilic peptides isolated from the venom of insects of the family. Due to their physicochemical features, these peptides show affinity for biomimetic membranes, especially the more anionic ones. In this study, we investigated the cell-selective effects of MPX and MP1 peptides, comparing their cytotoxicity and metabolic effects on melanocytes and their respective counterparts, melanoma cells. By employing UV-vis spectroscopy and fluorescence microscopy assays, we provided mechanistic insights into these peptides' antimelanoma activity. MPX and MP1 peptides were cytotoxic to both cell lines. However, their effect was more intense in melanoma than in melanocyte cells. Both cell lines treated with MPX and MP1 peptides showed phosphatidylserine externalization. However, unlike MP1 treatment, MPX also elicited pore formation in the plasma membranes of melanoma cells. These data indicate that the mode of action of MPX and MP1 involves different processes, namely, necrosis and apoptosis, respectively. The levels of reactive oxygen species did not undergo significant changes, but intracellular calcium levels increased considerably in melanoma cells treated with MPX. Both cell lines have their mitochondrial membrane potentials decreased after peptide treatments; nonetheless, this reduction was more intense in melanoma than in melanocyte cells. Altogether, these data reveal that the MPX and MP1 peptides are selective for melanoma tumorigenic cells, reassuring their antimelanoma therapeutic potential. Despite their structural similarities, these peptides have cell-type-relatable distinct modes of action, which resonate in both plasma membrane alterations and metabolic processes, indicating that these effects are not mutually exclusive and not the same for all cells and conditions.
Silver Nanoparticle Coated with Deep Eutectic Solvent as an Effective Medium for Improving the Structural and Thermal Stability of Immunoglobulin G Antibodies.
Fatima U, Yadav P, Dhiman D … +2 more , Yang YL, Venkatesu P
Mol Pharm · 2026 May · PMID 42021599 · Publisher ↗
Immunoglobulin G (IgG), widely used in therapeutic and diagnostic applications, is prone to denaturation and aggregation, reducing bioactivity and shelf life and increasing immunogenic risks. Current methods fall short o...
Immunoglobulin G (IgG), widely used in therapeutic and diagnostic applications, is prone to denaturation and aggregation, reducing bioactivity and shelf life and increasing immunogenic risks. Current methods fall short of preserving IgG's stability, highlighting the need for innovative strategies to enhance its resilience and therapeutic reliability. In this work, we investigated choline chloride:glycerol (ChCl:Gly)-based deep eutectic solvent (DES) and silver nanoparticle coated with DES (AgNP:ChCl:Gly) as effective stabilizers for IgG. Various spectroscopic, imaging, and size-determining techniques were utilized to assess formulation-dependent changes in IgG structure and thermal response. Thermal fluorescence spectroscopy studies were performed to obtain the apparent transition temperature () in the presence of DES and AgNP coated with DES aqueous solutions. The measurements revealed a concentration-dependent increase in of IgG from 76.1 °C in buffer to 78.4 °C in the presence of DES and up to 82.9 °C with AgNP coated with DES at 0.4 mM, indicating enhanced resistance to thermal perturbation. Furthermore, dynamic light scattering showed formulation-dependent changes in the apparent hydrodynamic size () and surface charge of IgG under the studied conditions. This work highlights the potential validity of using AgNP coated with ChCl:Gly in IgG formulations, highlighting their potential utility as formulation additives for improving the thermal and structural robustness of IgG.
Dihydroartemisinin-Loaded ZIF-8 Nanoparticles Elicit Chemo-Immunotherapy against Malignant Pleural Effusion via Inhibition of OCT4/M-CSF Signaling Pathway.
You H, Li LG, Xiao CY … +7 more , Wang X, Kong C, Leng F, Bai XF, Han N, Li TF, Wang MF
Mol Pharm · 2026 May · PMID 42020944 · Publisher ↗
Malignant pleural effusion (MPE) is the most common complication of lung cancer with an extremely high lethality, for which no effective chemotherapeutic agent is available. Activation of local antitumor immunity of MPE...
Malignant pleural effusion (MPE) is the most common complication of lung cancer with an extremely high lethality, for which no effective chemotherapeutic agent is available. Activation of local antitumor immunity of MPE while selectively destroying the malignant cells represents an effective strategy in recent years. Herein, we sought to figure out whether dihydroartemisinin (DHA), whose pleiotropic antilung cancer effects have been elucidated by our team, loaded with zeolite imidazole framework-8 (ZIF-8) could serve as a novel anti-MPE chemo-immunotherapeutic strategy. The synthesized DHA@ZIF-8 nanoparticles were characterized in terms of size, potential, elemental composition, and stability, while the drug loading efficiency of DHA was calculated for further research. Based on it, human-derived MPE cells (hMPEC) were isolated, cultured, and identified, which was utilized together with lung cancer cell lines to validate the in vitro chemotherapeutic toxicity of DHA@ZIF-8. The prolonged survival of MPE mice treated with DHA@ZIF-8 was observed with reduced volume of MPE compared with the control group, as evidenced by micro-CT and ultrasonic images. More impressively, DHA@ZIF-8 effectively promoted the M1 polarization and dampened M2 polarization of macrophages in MPE, wherein the differentially expressed genes (DEGs) were enriched in the OCT4/NF-κB signaling pathway, which is the upstream of M-CSF. Further investigations presented zinc ions and DHA released from the DHA@ZIF-8, which located in lysosome, acted as a direct inhibitor of OCT4. However, overexpression of OCT4 attenuated the DHA@ZIF-8's effects on the NF-κB/M-CSF signaling. Taken together, the hMPEC and mice in situ models were constructed by our team for the first time, wherein DHA@ZIF-8 exhibits potent chemotherapeutic efficacy in these models. DHA@ZIF-8 facilitates M1 polarization of macrophages through the depression of the OCT4/NF-κB/M-CSF signaling pathway to enhance immunotherapeutic efficacy simultaneously, which provides a critical basis for DHA and bionanomaterial application in MPE treatment in the future.
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