Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
Dual-Targeted Radionuclide Therapy with Tb Instigates Anticancer Immunity in "Cold" Murine Prostate Tumor.
Sun J, Guo J, Qi X … +5 more , Yang J, Wang G, Zhou G, Meng F, Zhong Z
Mol Pharm · 2026 Jul · PMID 42397707 · Publisher ↗
Targeted radionuclide therapy (TRT) with Lu holds a huge clinical success in treating advanced prostate cancer patients. It is noted, however, that Lu with moderate radiation energy achieves effective tumor inhibition at...
Targeted radionuclide therapy (TRT) with Lu holds a huge clinical success in treating advanced prostate cancer patients. It is noted, however, that Lu with moderate radiation energy achieves effective tumor inhibition at a relatively high dose and has a low capacity to activate "cold" prostate tumor. In this study, we report that Sigma-1 receptor and prostate-specific membrane antigen (PSMA) dual-targeted peptide (S1R/PSMA-P) labeled with Tb, which emits locally high linear energy transfer (LET) Auger electrons, effectively inhibits prostate tumor and energizes anticancer immunity. Tb-S1R/PSMA-P exhibited significantly enhanced cytotoxicity and immunogenic cell death over Lu-labeled counterpart by inducing more DNA double-strand breaks and reactive oxygen species. Of note, Tb-S1R/PSMA-P achieved high tumor uptake and selectivity, induced a complete regression rate of 60% at a single dose of 7.4 MBq in RM1-PSMA/RM1 tumor model, and sensitized RM1-PSMA/RM1 tumor to αPD1 immune checkpoint blockade therapy at a dose of 3.7 MBq resulting in a cure rate of 50% and durable antitumor immunity. Overall, Tb-S1R/PSMA-P emerges as a promising theranostic agent that is capable of mitigating prostate tumor by boosting anticancer immunity.
Development of [In]In-CHX-A″-DTPA-αCD68 for ImmunoSPECT to Image Murine Macrophages.
Strong AE, Belitzky E, Vaughn Embs A … +10 more , Katz S, Cavaliere A, Djureinovic D, Roohani B, Liu M, Rothlin C, Leavenworth JW, Jilaveanu L, Kluger HM, Marquez-Nostra B
Mol Pharm · 2026 Jul · PMID 42391610 · Publisher ↗
High tumor-associated macrophage (TAM) abundance is associated with poorer prognoses across many cancers, including renal cell carcinoma (RCC). CD68 is an established clinical biomarker for macrophages in patient tissues...
High tumor-associated macrophage (TAM) abundance is associated with poorer prognoses across many cancers, including renal cell carcinoma (RCC). CD68 is an established clinical biomarker for macrophages in patient tissues and is also expressed in mouse macrophages, making it an attractive target for bridging preclinical and clinical imaging of macrophages. We developed an anti-mouse CD68 (mCD68) immunoSPECT imaging agent to noninvasively quantify TAM burden in vivo and evaluate response to macrophage-modulating treatment in a syngeneic RCC tumor model. [In]In-CHX-A″-DTPA-αCD68 was synthesized by optimizing chelator conjugation and radiolabeling conditions, then characterized for binding affinity, stability, and specificity by in vitro assays. In vivo specificity was assessed in the Renca syngeneic RCC model by comparing biodistribution of [In]In-CHX-A″-DTPA-αCD68 with that of the radiolabeled IgG isotype control. ImmunoSPECT signal was correlated with ex vivo CD68 expression measured by flow cytometry of dissociated tumors and spleens. To evaluate response to macrophage-modulating treatment, a 2 × 2 factorial study was conducted in which Renca-allografted mice received either anti-CSF1R or IgG control, followed by immunoSPECT imaging with [In]In-CHX-A″-DTPA-αCD68 or radiolabeled isotype control; organ-to-heart SUVR was correlated with ex vivo CD68 expression by flow cytometry. [In]In-CHX-A″-DTPA-αCD68 bound specifically to CD68 in bone marrow-derived macrophages, with high binding affinity (K = 7.99 ± 2.26 nM) to the CD68 protein. In Renca-allografted mice, immunoSPECT signal correlated strongly with ex vivo CD68 expression measured by flow cytometry of dissociated tumor and spleen cells ( = 0.854). Biodistribution studies confirmed specific uptake in vivo, with 2-fold, 8-fold, and 8-fold greater uptake in tumor, spleen, and bone marrow, respectively, compared with the radiolabeled isotype control. Treatment with the macrophage-depleting anti-CSF1R resulted in ∼40% lower tumor-to-heart SUVR with [In]In-CHX-A″-DTPA-αCD68 compared with the isotype control, despite no change in tumor volumes. ImmunoSPECT signal remained strongly correlated with ex vivo CD68 expression measured by flow cytometry ( = 0.952). This study demonstrates the first example of immunoSPECT imaging of CD68 in vivo. ImmunoSPECT imaging of CD68 provides a direct, noninvasive measure of total TAM burden in RCC and represents a translatable approach for monitoring response to macrophage-modulating treatments in preclinical studies.
Mechanistic Insight into Self-Gelation Involved in Prescription Design for Optimization of Tablet Performance.
Liu X, Fang W, Zhang R … +7 more , Yue W, Xiong Z, Niu B, Sun H, Chen J, Wang J, Han J
Mol Pharm · 2026 Jul · PMID 42389883 · Publisher ↗
Some drugs undergo gelation during the formulation development process, which not only poses significant challenges to the manufacturing process of solid dosage forms but also significantly restricts the drug dissolution...
Some drugs undergo gelation during the formulation development process, which not only poses significant challenges to the manufacturing process of solid dosage forms but also significantly restricts the drug dissolution and absorption. Could such gelation be utilized by designing the prescription to overcome the adverse effects and water solubility defect of drugs? Herein, this study attempted to design the self-gelation tablets of indomethacin (IND) by introducing small-molecule ligands and to explore the self-gelation mechanism. As a result, the designed tablets occurred to have spontaneous gelation with a typical 3D structure and viscoelasticity upon contact with a small amount of water, accompanied by amorphization transformation. Such a self-gelation behavior was significantly influenced by the composition ratios, storage temperatures, and medium pH values. In comparison to pure IND tablet, the designed IND-ligand tablets performed significantly increased apparent solubility (>200-fold) and intrinsic dissolution rate (>6000-fold) and maintained the long-term supersaturated dissolution with acid-base interactions, which was revealed by nucleation inhibition, fluorescence quenching, and phase solubility tests. Moreover, the self-gelled tablets significantly enhanced the membrane permeability of IND, demonstrating the potential for promoting oral absorption. Thus, this study revealed the self-gelation mechanism of the tablet combination and confirmed such prescription design involving self-gelation as an efficient solubilization strategy.
[Ga]Ga-DOTA-DP-UBI 29-41: A Novel Ga-Labeled Ubiquicidin 29-41 Derivative Containing d-Proline for Bacterial Infection PET Imaging.
Jiang Y, Han P, Qian Y … +8 more , Zhang L, Sun Y, Yin G, Ding D, Diao L, Zhao Z, Jiang J, Zhang J
Mol Pharm · 2026 Jul · PMID 42388085 · Publisher ↗
Bacterial infection poses a persistent and severe threat to human health. Accurate differentiation between bacterial infection and sterile inflammation is critical for timely clinical treatment. In this study, a novel Ga...
Bacterial infection poses a persistent and severe threat to human health. Accurate differentiation between bacterial infection and sterile inflammation is critical for timely clinical treatment. In this study, a novel Ga-labeled radiotracer ([Ga]Ga-DOTA-DP-UBI 29-41) was radiosynthesized by labeling the UBI 29-41 derivative (DOTA-DP-UBI 29-41) with Ga. This radiotracer was designed by introducing d-proline (DP) as a linker between the ubiquicidin 29-41 (UBI 29-41) targeting segment and the 1,4,7,10-tetraazacyclododecane-,',,'-tetraacetic acid (DOTA) chelating group. The radiotracer exhibited high radiochemical purity (RCP > 98%) and favorable stability in normal saline at room temperature and mouse serum at 37 °C, with hydrophilic properties (Log = -3.58 ± 0.04). bacterial experiments confirmed the specific and rapid binding of this radiotracer to , with binding reaching equilibrium within 30 min of incubation and exhibiting concentration-dependent competitive inhibition with UBI 29-41. Biodistribution studies in mouse models revealed effective accumulation of the tracer at bacterial infection sites (1.98 ± 0.66% ID/g at 30 min p.i.), significantly lower renal uptake (stabilized at ∼25% ID/g) than previous Ga-labeled UBI 29-41 derivatives, and a distinct difference in uptake between bacterium-infected and sterile inflamed muscles (an infection-to-inflammation ratio of 2.11 at 120 min p.i.). PET/CT imaging further confirmed that the tracer could clearly visualize bacterial infection foci and distinguish infection from sterile inflammation in dual-pathology mice, with rapid blood clearance kinetics, renal metabolism, and excretion. Collectively, these results indicate that [Ga]Ga-DOTA-DP-UBI 29-41 will be a promising PET tracer for the specific diagnosis of bacterial infection and differentiation from sterile inflammation.
Comparative Investigation of the Impact of Sodium Citrate Buffers on Lipid Nanoparticles of circRNA or Linear mRNA.
Zhou S, Wang Z, Xu Y … +3 more , Meng T, Barrett S, Zhu G
Mol Pharm · 2026 Jul · PMID 42384010 · Publisher ↗
Circular RNAs (circRNAs) are an emerging modality of RNA medicine. By bypassing terminal degradation, circRNA is highly stable with prolonged protein/peptide expression duration relative to its linear mRNA counterpart, w...
Circular RNAs (circRNAs) are an emerging modality of RNA medicine. By bypassing terminal degradation, circRNA is highly stable with prolonged protein/peptide expression duration relative to its linear mRNA counterpart, which may benefit its disease therapeutic or prophylactic efficacy. Currently, mRNA-delivering ionizable lipid nanoparticles (LNPs) and their formulation conditions, such as buffer, are often adopted for the delivery of circRNA delivery. However, it remains elusive whether the LNPs and their formulation methods optimized for mRNA are still optimal for the delivery of circRNA. Here, by comparing circRNA versus mRNA payloads, we investigated the impact of sodium citrate buffer concentrations on the physicochemical properties and RNA delivery efficiency of the resulting RNA-LNPs of three current FDA-approved LNPs, DLin-MC3-DMA (MC3), SM-102, and ALC-0315, respectively. First, for each LNP formulated using the same sodium citrate buffer concentration, mRNA and circRNA showed comparable physicochemical characteristics and transfection efficiency; by contrast, high-concentration sodium citrate compromised the expression of circRNA LNPs but not mRNA LNPs. Second, relative to SM-102 LNPs, MC3-LNPs showed a lower RNA expression efficiency in mice, especially for circRNA. Third, LNPs formulated using high-concentration sodium citrate buffer showed comparable integrity of mRNA and circRNA after multiday storage at room temperature. Overall, our findings underscore the differential impact of citrate buffer concentrations on different LNPs loaded with circRNA and mRNA, calling for the customized optimization of different LNPs for the delivery of mRNA and circRNA.
Preclinical Evaluation of Lu-Labeled Anti-CLDN18.2 VHH-Fc for Radioimmunotherapy in Gastric Cancer.
Wang X, Chen P, Li J … +11 more , Zhang R, Yan H, Li Z, Huang Z, Xu C, Zhang J, Zhu W, Peng Q, Xie S, Jiang D, Dong M
Mol Pharm · 2026 Jul · PMID 42381537 · Publisher ↗
PURPOSE: Claudin18.2 (CLDN18.2) has emerged as a significant therapeutic target for advanced gastric cancer. In this study, we aimed to develop a Lu-radiolabeled anti-CLDN18.2 VHH-Fc (SN-1A01) for radioimmunotherapy in g...
PURPOSE: Claudin18.2 (CLDN18.2) has emerged as a significant therapeutic target for advanced gastric cancer. In this study, we aimed to develop a Lu-radiolabeled anti-CLDN18.2 VHH-Fc (SN-1A01) for radioimmunotherapy in gastric cancer (GC) tumor-bearing models. METHODS: Immunohistochemistry (IHC) for CLDN18.2 was performed on gastric lesions induced by tumors from 37 patients with GC, as well as in a GC patient-derived xenograft (GC-PDX) tumor and GC xenograft tumors (N87-18.2 and NUCG4). The SN-1A01 was conjugated with DOTA and radiolabeled using Lu, resulting in the formation of the radioimmunoconjugate [Lu]Lu-DOTA-SN-1A01. We established a safe dosage for the application of [Lu]Lu-DOTA-SN-1A01 and evaluated the therapeutic efficacy of a single dose in GC models. Ki67 expression levels in tumors were detected via IHC following treatment with [Lu]Lu-DOTA-SN-1A01. RESULTS: IHC analysis demonstrated moderate-to-high CLDN18.2 expression in 45.9% of GC patient tumor tissues. Additionally, elevated levels of CLDN18.2 were detected in GC-PDX and N87-18.2 tumors, whereas lower expression was shown in NUGC4. A single dose of [Lu]Lu-DOTA-SN-1A01 below 300 μCi (11.1 MBq) was well tolerated. [Lu]Lu-DOTA-SN-1A01 significantly inhibited tumor growth and increased survival time in both GC-PDX and N87-18.2 models across a dose of 100 and 300 μCi. However, the tumor-suppressive effect was comparatively weaker in the NUGC4 model. Reduced Ki67 expression was evident in all [Lu]Lu-DOTA-SN-1A01-treated tumors. CONCLUSION: In preclinical studies, [Lu]Lu-DOTA-SN-1A01 demonstrated significant antitumor efficacy with acceptable toxicity, which indicated a strong potential for clinical translation in GC therapy.
The Impact of Plasticizer Polarity on the Permeability of Hydroxypropyl Methylcellulose Phthalate Films.
Jariwala N, De Kerpel S, Provinciael B … +2 more , Vermeire K, Van den Mooter G
Mol Pharm · 2026 Jun · PMID 42371735 · Publisher ↗
The aim of this study was to gain detailed insights into how different plasticizers influence the permeability of isolated hydroxypropyl methyl cellulose phthalate (HPMC-P) films. Since the migration of plasticizers from...
The aim of this study was to gain detailed insights into how different plasticizers influence the permeability of isolated hydroxypropyl methyl cellulose phthalate (HPMC-P) films. Since the migration of plasticizers from film coatings may critically affect their functionality, it is essential to monitor the impact of their leaching on the associated film properties. In this work, the leaching behavior of plasticizers from isolated HPMC-P films was estimated using their thermal properties by modulated temperature differential scanning calorimetry (MT-DSC) at varying plasticizer concentrations. The films plasticized with acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS) exhibited lower permeability compared to those plasticized with polyethylene glycol 400 (PEG 400). This reduced permeability can be attributed to the slower leaching rates of ATEC and DBS and to the persistent hydrophobic character that they impart to the films, even after prolonged aqueous exposure. In contrast, films plasticized with PEG 400 demonstrated the highest permeability because of the hydrophilicity induced in the polymeric films. However, a subsequent decline in their diffusion rate was observed once PEG 400 had leached out of the films. Furthermore, the correlation between leaching behavior and flux profiles provided an understanding of the influence of plasticizer on film permeability based on their polarity. Moreover, saturation in plasticization efficiency was noted with DBS-based films at higher plasticizer concentrations (greater than 10% w/w). Overall, our study highlights the importance of selecting appropriate plasticizers for the development of polymer films and provides insights into tailoring film permeability and drug release kinetics.
Call For Papers: Molecular Understanding and Formulation Design for Peptide Delivery.
Ling J, Chen K, Dening T … +8 more , Hageman MJ, Hetrick EM, Koo O, Nagapudi K, Qian KK, Li N, Su Y, Taylor LS
Mol Pharm · 2026 Jun · PMID 42370673 · Publisher ↗
Abstract loading — click title to view on PubMed.
Done EAZY: An Automated Procedure for Zr-Radiolabeling and Size-Exclusion Chromatography Purification of Nanoliposomal Anticancer Therapeutics.
Dubbert J, Kunkel F, Mühlenberg T … +5 more , Grunewald S, Herrmann K, Bauer S, Lückerath K, von Kiedrowski V
Mol Pharm · 2026 Jun · PMID 42367047 · Publisher ↗
Liposomal nanomedicines offer a clinically proven platform for enhanced drug delivery, yet their behavior in vivo remains difficult to characterize. Noninvasive positron emission tomography (PET) imaging with radiolabele...
Liposomal nanomedicines offer a clinically proven platform for enhanced drug delivery, yet their behavior in vivo remains difficult to characterize. Noninvasive positron emission tomography (PET) imaging with radiolabeled liposomes enables quantitative insight into their biodistribution and pharmacokinetics, supporting the rational design and clinical translation of nanocarrier-based therapeutics. Zirconium-89 ([Zr]Zr) is a positron emitter with a suitable half-life ( = 78.4 h) for tracking long-circulating nanocarriers such as PEGylated liposomes by PET imaging. However, existing manual labeling protocols often suffer from poor reproducibility, drug leakage, and limited scalability for clinical translation. Automated radiolabeling and purification of macromolecular systems, such as liposomes, antibodies, and antibody fragments, are essential for the reproducible, clinically translatable production of radiopharmaceuticals. However, these requirements necessitate larger and more complex radiosynthesizers that are often not suitable for smaller laboratories. Although automated procedures using complex synthesis modules with integrated high-performance liquid chromatography purification have been demonstrated on larger radiosynthesizers, comparable processes on simpler synthesis platforms remain scarce. To address this gap, this study aimed to develop a fully automated process for the Zr-radiolabeling and subsequent size-exclusion chromatography (SEC) purification of doxorubicin-loaded, PEGylated liposomes using the ML Eazy synthesis platform. The process was designed in a GMP-oriented manner with the goal of enabling its future application to other macromolecular radiopharmaceuticals. Using this approach, a fully automated procedure was successfully established on the ML Eazy platform, although optimization of a published labeling method was required to eliminate doxorubicin leakage and improve radiolabeling efficiency. Several system configurations were tested to optimize SEC and sterile filtration, resulting in a robust setup that enabled efficient purification and reproducible performance. Fine-tuning of reagent transfer, gradual pressure increase, and intermediate saline rinsing with subsequent air flushing reduced residual activity in tubing and connectors to <5%. The final automated process achieved consistent radiochemical yields of 67 ± 3% across eight batches prepared under GMP-oriented conditions. Overall, an automated, GMP-oriented all-in-one procedure for Zr-labeling with subsequent size-exclusion purification of liposomes has been successfully established, producing sterile-filtered formulations that support future clinical translation. The automated module may also be adapted for other radiolabeling applications using SEC, including antibody labeling.
Low-Temperature Hot Melt Extrusion: Solid-State Organization and Mechanical Performance of Lipid Filaments.
Alva C, Hink M, Doğan A … +10 more , Afonso Urich JA, Matić J, Specht F, Freichel T, Reyer S, Rillmann T, Abrahmsén-Alami S, Booth J, Spoerk M, Salar-Behzadi S
Mol Pharm · 2026 Jun · PMID 42343582 · Publisher ↗
The bioavailability of highly lipophilic, poorly soluble drugs can be improved effectively, when formulated in lipid-based systems. Solid lipids generally offer greater physical robustness than liquid lipids but slower r...
The bioavailability of highly lipophilic, poorly soluble drugs can be improved effectively, when formulated in lipid-based systems. Solid lipids generally offer greater physical robustness than liquid lipids but slower release. Hot-melt extrusion (HME) and additive manufacturing (AM) enable personalized release by tailoring composition and geometry. However, the limited availability of suitable solid lipid-based materials, particularly for processing thermolabile and lipophilic drugs, restricts their application. Polyglycerol esters of fatty acids (PGFAs) represent a promising class of lipids due to their stable α-form, tunable hydrophilicity, and printability. Nevertheless, the interplay between lipid processing, solid state, and rheological behavior remains insufficiently understood for HME and AM. In this study, felodipine (Biopharmaceutics Classification System (BCS) class II drug) was incorporated into a PGFA matrix to obtain a fully dissolved system at the minimum processing temperature. Drug loading induced melting point depression, delayed crystallization, and introduced disorder in crystal packing, thereby weakening the crystal network and enhancing filament flexibility, enabling printability. Printable filaments were achieved at 95 °C, while an undetectable crystalline drug was observed at 120 °C. This work demonstrates that drug-lipid interactions can be employed to enhance processability: while low-temperature processing of PGFA was feasible, drug modifications into the lipid solid state impacted the rheological and mechanical properties essential for additive manufacturing. Beyond this specific system, this study provides a rational proof of concept for processing solid and liquid lipids via continuous melt-based technologies.
Voices in Molecular Pharmaceutics: Meet Dr. Oisín Kavanagh, Who Manipulates Crystal Packing to Improve Drug Delivery.
Kavanagh ON
Mol Pharm · 2026 Jun · PMID 42335222 · Publisher ↗
Abstract loading — click title to view on PubMed.
Structure-Guided Pegylation of IL-1RA Preserves Fold and Antagonist Function.
Göktan I, Daǧ Ç, Gül A … +1 more , Kizilel S
Mol Pharm · 2026 Jun · PMID 42335098 · Publisher ↗
Rational design of PEGylated protein therapeutics requires mechanistic understanding of how coupling chemistry and PEG size jointly determine product homogeneity, receptor engagement, and structural integrity─the propert...
Rational design of PEGylated protein therapeutics requires mechanistic understanding of how coupling chemistry and PEG size jointly determine product homogeneity, receptor engagement, and structural integrity─the properties that collectively govern whether a conjugate is a viable candidate for further development. Anakinra (recombinant interleukin-1 receptor antagonist, IL-1Ra) is an approved anti-inflammatory biologic whose short systemic residence necessitates daily subcutaneous injection and is associated with steep peak-trough exposure fluctuations that, in chronic high-dose regimens, have been linked to IL-1Ra-derived systemic amyloidosis. PEGylation offers a chemically established route to increase the apparent molecular size of IL-1Ra and thereby reduce renal filtration and smooth exposure, but the structural and functional consequences of conjugation have never been characterized at residue resolution for this target─a gap that limits informed design choices between available chemistries. Here, we address this gap by establishing a head-to-head characterization framework comparing site-specific thiol-maleimide conjugation and random amino-coupling on a uniformly N-labeled recombinant IL-1Ra variant (M143V) that preserves all native conjugation sites and is potency-matched to Anakinra. Across a 5-20 kDa PEG ladder at a substoichiometric 0.5:1 PEG:protein feed, site-specific thiol-maleimide coupling yielded substantially higher conversion (∼81%) and a homogeneous single-species di-PEGylated (DoP 2) conjugate, whereas random amino-coupling produced heterogeneous mixtures across all PEG sizes (∼33-36% conversion, multiple degrees of polymerization). Purified single-species conjugates were benchmarked under a fixed IL-1β EC challenge in HEK-Blue reporter cells; all retained full maximal efficacy but exhibited chemistry- and size-dependent right-shifts in IC, indicating steric modulation of receptor engagement rather than loss of function. To directly establish whether PEG attachment perturbs structural integrity, 2D H-N HSQC NMR on the N-labeled thiol-PEG10 conjugate demonstrated a preserved global fold with localized chemical-shift perturbations near cysteine-proximal surface regions, confirming site-selective modification and intact binding scaffold. Together, these data establish the conjugation quality, antagonist activity, and structural integrity of the lead conjugate as the prerequisite characterization foundation for its further development and provide a transferable analytical framework for the rational design of PEGylated cytokine therapeutics.
Mapping a Ternary Carbohydrate Design Space for Stable and Dispersible Protein Dry Powders.
Xia G, Bennette N, Watts AB … +1 more , Brunaugh AD
Mol Pharm · 2026 Jun · PMID 42314049 · Publisher ↗
Optimizing inhalable protein powders requires simultaneously preserving protein structure and minimizing interparticle cohesion, yet the mechanistic links between excipient composition, drying physics, surface energetics...
Optimizing inhalable protein powders requires simultaneously preserving protein structure and minimizing interparticle cohesion, yet the mechanistic links between excipient composition, drying physics, surface energetics, and aerosol performance remain poorly defined. Here, a constrained ternary mixture design of inulin, trehalose, and mannitol was used to systematically interrogate composition-structure-function relationships in spray-dried lysozyme formulations. Protein secondary structure, glass transition temperature, humidity-dependent surface basicity (via inverse gas chromatography), and aerosol dispersibility (quantified by Wasserstein distance under controlled dispersion conditions) were measured and analyzed using linear and quadratic Scheffé mixture models. Carbohydrate composition strongly governed intermolecular β-sheet content and surface basicity, with trehalose positively associated with β-sheet formation and inulin promoting retention of surface basicity under humidity exposure. Most notably, the relative humidity at which surface basicity reached its minimum exhibited a strong inverse monotonic relationship with dispersibility (Spearman ρ = -0.86, = 0.013), indicating that early moisture-induced surface reorganization corresponds to greater deviation from complete dispersion under inhalation conditions. These findings support a two-stage mechanistic framework in which drying-stage viscosity evolution defines a finite mobility window for compositional redistribution prior to vitrification, while postdrying surface relaxation dynamics govern susceptibility to moisture-mediated cohesion. Carbohydrate composition thus encodes both protein structural outcomes and aerosol performance through coupled drying- and relaxation-stage processes, providing a mechanistic foundation for rational design of inhalable biologic formulations.
Computational Identification of Active Drug Metabolites for Human Protein Targets.
Larsson S, Mercado R, Winiwarter S … +1 more , Miljković F
Mol Pharm · 2026 Jun · PMID 42313059 · Publisher ↗
Understanding drug metabolism helps mitigate toxicity risks and anticipate pharmacological effects beyond the parent compound. Here, we explore high-confidence human bioactivity annotations from the public domain associ...
Understanding drug metabolism helps mitigate toxicity risks and anticipate pharmacological effects beyond the parent compound. Here, we explore high-confidence human bioactivity annotations from the public domain associated with a curated data set of drug-metabolite pairs. Our findings show that 26% of all drug-metabolite-target combinations contain metabolites with retained or increased bioactivity relative to their parent drugs, showing a high proportion of active metabolites with potencies below 100 nM. Moreover, these active metabolites display similar predicted physicochemical and ADME properties to their parent drugs, indicating that their biological activity may be preserved . Two key features of the identified active metabolites are noted: (1) the metabolite is more likely to be formed via an O-demethylation or an N-demethylation at a tertiary nitrogen, and (2) these drug-metabolite pairs are frequently active against the membrane receptor target class. To support further research in this area, we make our data compilation, including pairs with identified active metabolites and recorded bioactivity data, openly available.
Mechanistic PBPK Modeling of pH-Modifying Excipient Effects to Guide Formulation Design for Mitigating pH-Mediated DDIs.
Chirumamilla SK, Turner DB
Mol Pharm · 2026 Jun · PMID 42298946 · Publisher ↗
pH-modifying acidic excipients (acidulants) or basic excipients are often used in drug formulations to improve solubility and chemical stability. In particular, acidulants are being increasingly employed as a mitigating...
pH-modifying acidic excipients (acidulants) or basic excipients are often used in drug formulations to improve solubility and chemical stability. In particular, acidulants are being increasingly employed as a mitigating strategy for pH-mediated drug-drug interactions (DDI) of basic drugs. The selection of these excipients and their doses has relied largely on empirical optimization, with limited use of physiologically based pharmacokinetic (PBPK) modeling. Published modeling efforts have focused on semimechanistic approaches such as manual adjustment of physiological gastrointestinal (GI) lumen pH or direct incorporation of dissolution profiles to recover observed pharmacokinetics (PK); however, these approaches may introduce uncertainty in prospective predictions when either drug or excipient quantities change. Thus, a mechanistic mathematical model based on first principles was developed and implemented in the Simcyp Simulator to predict the effects of these excipients on media pH () or GI lumen pH (), which could in turn affect drug surface (microenvironment) pH and solubility. This model was used to predict the effect of the acidulants, tartaric acid and succinic acid, on both the dissolution and the clinical PK of two low-soluble weakly basic drugs, entrectinib and palbociclib. The model was able to predict the increase in dissolution rate when these excipients were used in the formulations. In clinical PK studies, the added acidulants were able to mitigate pH-mediated DDIs. The developed model recovered human PK with and without an acidulant in pH-DDI studies. Critical to these predictions was the ability of the model to not only predict the effect of excipients but also account for the self-buffering properties of ionizable drugs in the presence of buffers and . This study supports the model's utility in predicting the effectiveness of acidulants as pH-DDI mitigation strategies and informing formulation development.
Noninvasive Assessment of Colitis Activity by Targeted Imaging of Neutrophil Elastase with [Ga]Ga-POL6014.
Wang X, Niu M, Guo Y … +10 more , Wang J, Ou H, Xin K, Xing T, Ma T, Wang J, Ye J, Zhang M, Kang F, Wang J
Mol Pharm · 2026 Jun · PMID 42298351 · Publisher ↗
Effective management of IBD necessitates ongoing evaluation of disease activity. Molecular imaging of neutrophil elastase (NE) could address this urgent need as it mechanistically targets the early event of intestinal in...
Effective management of IBD necessitates ongoing evaluation of disease activity. Molecular imaging of neutrophil elastase (NE) could address this urgent need as it mechanistically targets the early event of intestinal inflammation. In this study, based on macrocyclic peptide POL6014, [Ga]Ga-POL6014 was developed for noninvasive assessment of colitis activity and treatment response through targeting of NE. [Ga]Ga-POL6014 exhibited high specificity and affinity for NE with the of 14.81 nM and IC of 3.02 nM. In PET imaging, [Ga]Ga-POL6014 could quickly visualize inflammation sites with colon uptake of 3.15 ± 0.63%ID/g and colon/muscle ratio of 4.92 ± 0.74 at 30 min p.i.. The specificity of [Ga]Ga-POL6014 was demonstrated by the dose-response blocking studies with POL6014. Furthermore, [Ga]Ga-POL6014 PET was used to evaluate treatment response to 5-ASA. The treatment significantly inhibited colon uptake of [Ga]Ga-POL6014 (1.71 ± 0.21 %ID/g), accompanied by a decrease in imaging contrast (2.81 ± 0.26). Immunofluorescence revealed the preservation of mucosal barrier integrity and a remarkable decrease in NE positive cells after 5-ASA treatment. Moreover, there were good correlations between PET quantification with NE expression and DAI score, indicating the reliability of [Ga]Ga-POL6014. Additionally, [Ga]Ga-POL6014 was widely distributed and cleared rapidly from nonspecific organs and blood pool, and was excreted through urinary system, suggesting its favorable pharmacokinetics. In conclusion, [Ga]Ga-POL6014 is a promising tracer that enables globally mapping of neutrophil-mediated inflammation in the entire gastrointestinal tract for early diagnosis, assessment of disease activity and evaluation of anti-inflammatory treatment response.
Quantifying Transporter Activity: An Absolute Scaling Approach Using Digoxin.
De Sousa Mendes M, Pilla-Reddy V, Shen H … +11 more , Moss DM, Chapy H, Poller B, Nakakariya M, Poetz O, Hammer HS, Tsai A, Chen B, Temesszentandrási-Ambrus C, Wisniewski JR, Neuhoff S
Mol Pharm · 2026 Jun · PMID 42294801 · Publisher ↗
Lilly Laboratories porcine kidney 1 (LLC-PK) and Madin-Darby canine kidney (MDCK) cell lines are commonly used in studying both passive and active drug transport, particularly through permeation assays, and, when transfe...
Lilly Laboratories porcine kidney 1 (LLC-PK) and Madin-Darby canine kidney (MDCK) cell lines are commonly used in studying both passive and active drug transport, particularly through permeation assays, and, when transfected with human MDR1, to assess P-glycoprotein (P-gp)-mediated drug clearance. However, the substantial variability in experimental outcomes, including P-gp activity, presents a significant challenge to drug development and transporter research. In this study, P-gp protein expression levels were quantified in 8 cell lines used across different laboratories to evaluate digoxin transfer in a Transwell assay. P-gp activity was estimated using both conventional analysis methods and an in vitro modeling approach. Parameters derived from conventional methods, such as apparent permeability () and Michaelis-Menten parameters ( and ), exhibited notable interlaboratory variability and could increase the risk of underestimating the impact of transporters and their saturation when used in a physiologically based pharmacokinetic (PBPK) model. By contrast, modeling-based estimates of P-gp activity demonstrated a strong correlation with absolute transporter abundance in the cell lines. This expression-function relationship supports the accurate scaling of the P-gp activity across tissues based on expression levels. A PBPK model for digoxin was developed incorporating P-gp activity in key organs, scaled according to measured expression. These findings underscore the importance of quantifying transporter expression in in vitro systems and integrating this information into a modeling framework to enable reliable in vitro-to-in vivo extrapolation (IVIVE).
Multi-Modal Characterization of the Interactions between a Recombinant Protein Antigen and a Liposomal Adjuvant.
Qu F, Wagner AA, Payne EM … +6 more , Pabit S, Foley DA, Bajoria S, Dick JE, Thompson DH, Kinsey C
Mol Pharm · 2026 Jun · PMID 42289982 · Publisher ↗
Subunit vaccines rely on adjuvants to enhance immunogenicity, yet antigen-adjuvant interactions in liposomal systems remain underexplored, with unknown implications that could impact the function and stability of coformu...
Subunit vaccines rely on adjuvants to enhance immunogenicity, yet antigen-adjuvant interactions in liposomal systems remain underexplored, with unknown implications that could impact the function and stability of coformulated system designs. We report a multimodal study aimed at elucidating interactions between a recombinant protein antigen, gE, and a liposomal adjuvant system, AS01, using a commercially available vaccine as a model. Quantitative binding assays revealed no significant binding for the antigen-adjuvant pair, with only weak, dose-dependent biolayer interferometry (BLI) signals suggesting transient contacts, in contrast to the strong responses observed in positive controls. Isothermal titration calorimetry (ITC) provided clear evidence of weak, transient interactions through dose-dependent exothermic signals and characteristic saturation behavior. Ultracentrifugation, electrophoresis, and chromatographic separation techniques confirmed independent distributions for the protein and liposome components, with minor migration shifts and trace coelution under rapid flow hinting at dynamic interactions. Structural analyses by cryogenic electron microscopy (cryo-EM) and dye labeling showed negligible changes in liposome properties upon antigen mixing. These findings suggest that vaccine formulations with little or no interaction between the protein and liposome components may be stable as premixed systems and underscore the importance of employing multiple tools for characterizing multicomponent vaccines during their development.
Fluorescence-Guided Surgery of Rhabdomyosarcoma Using a B7-H3 Targeted Antibody-Fluorophore Conjugate.
Gupta R, Ehrhorn EG, Pant A … +4 more , Streeter SS, Samkoe KS, Henderson ER, Mohs AM
Mol Pharm · 2026 Jun · PMID 42276839 · Publisher ↗
Resection of sarcomas is often limited by infiltrative tumor growth and microscopic residual disease, underscoring the need for targeted intraoperative imaging strategies that enhance visualization of primary lesions and...
Resection of sarcomas is often limited by infiltrative tumor growth and microscopic residual disease, underscoring the need for targeted intraoperative imaging strategies that enhance visualization of primary lesions and metastatic deposits. Here, a clinical-grade anti-B7-H3 antibody (MGA271) was conjugated to IRDye 800CW to generate MGA271-IRDye800, with an isotype control IgG-IRDye800 and unconjugated IRDye800 included as comparators. The resulting antibody-dye conjugates, MGA271-IRDye800 and IgG-IRDye800, exhibited an average dye-to-protein ratio of approximately 1. studies confirmed specific binding and strong fluorescence of MGA271-IRDye800 in six B7-H3-expressing sarcoma cell lines, with only minimal nonspecific uptake observed for control probes and in a B7-H3-negative control cell line. Based on these results, RH30 cells were selected to establish an orthotopic rhabdomyosarcoma xenograft model, in which near-infrared fluorescent imaging (NIRF) demonstrated substantially improved tumor visualization with MGA271-IRDye800 compared with IgG-IRDye800 and free IRDye800. Quantitative analysis confirmed significantly higher tumor-to-background ratios (TBRs) for MGA271-IRDye800 at 144 h (5.6 ± 2.2) compared with IgG-IRDye800 (2.7 ± 1.1) and unconjugated IRDye800 (1.0 ± 0.1), [ < 0.0001] supporting B7-H3-mediated tumor enrichment and superior contrast suitable for surgical navigation. During fluorescence-guided surgery, MGA271-IRDye800 enabled clear delineation of tumor margins, distinction of tumor from surrounding normal tissue and relevant background organs, and detection of otherwise occult micrometastatic lesions. Collectively, these findings demonstrate that B7-H3-targeted NIRF imaging with MGA271-IRDye800 offers sensitive and specific intraoperative visualization of sarcoma. This probe demonstrates strong potential for clinical translation as a molecular imaging agent to guide surgical resection, reduce residual disease, and ultimately improve outcomes for patients with B7-H3-expressing sarcomas.
Therapeutic Potential of Stearylamine-Conjugated Phenylboronic Acid-Modified Nanocarriers of 4-Allyl Pyrocatechol in Modulating Sialylation and Neuroinflammation in Scopolamine-Induced Cognitive Impairment in the Rat Model.
Katti VB, Kolusu AS, Madhana RM … +3 more , Pindiprolu SKSS, Tummala UK, Samudrala PK
Mol Pharm · 2026 Jun · PMID 42267754 · Publisher ↗
Alzheimer's disease is a progressive neurodegenerative condition and is regarded as the most prevalent type of dementia among older adults. It is characterized by the accumulation of beta-amyloid, tau protein hyperphosph...
Alzheimer's disease is a progressive neurodegenerative condition and is regarded as the most prevalent type of dementia among older adults. It is characterized by the accumulation of beta-amyloid, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, neuroinflammation, and neuronal loss, all of which contribute to the gradual decline in cognitive function. Recent research has highlighted the role of sialylation in the pathogenesis of Alzheimer's disease. Sialylation plays a critical role in the pathophysiology of Alzheimer's disease, influencing amyloid plaque formation, neuroinflammation, and synaptic function. CD33 plays a significant role in regulating immune responses, particularly in the central nervous system, and has been implicated in the progression of Alzheimer's disease. In this study, we explore the neuroprotective effect of stearylamine-conjugated phenyl boronic acid-modified 4-allyl pyrocatechol (PAPS) nanoparticles in modulating sialylation and neuroinflammation against scopolamine-induced Alzheimer's disease in rats. 4-Allyl pyrocatechol is known to possess antioxidant and anti-inflammatory activities. On the other hand, stearylamine-conjugated phenyl boronic acid (PBSA) not only is a potential vehicle for delivering drugs or therapeutic agents to the brain but also has a propensity to inhibit the interaction of sialic acid-conjugated ligands with CD33 receptors, which facilitates clearance of amyloid beta through microglia-mediated phagocytosis. A total of 36 animals were divided into 6 groups ( = 6) as control group, disease group, standard group, PBSA carrier group, 4-allyl pyrocatechol group, and PAPS group, which were treated with 5% carboxy methyl cellulose (p.o.), scopolamine 3 mg/kg (i.p.), donepezil 3 mg/kg (i.p.), stearylamine-conjugated phenyl boronic acid 2 mL/kg (p.o.), 4-allyl pyrocatechol 10 mg/kg (p.o.), and PAPS 10 mg/kg (p.o.) respectively. The study was designed for 16 days. From day 8, all the groups except the control group were administered scopolamine 3 mg/kg (i.p.) 45 min before they were given their respective treatments. Behavioral tests (open field test, novel object recognition test, -maze, and Morris' water maze) were conducted from day 8 to day 15. On day 16, animals were euthanized by cervical dislocation, brains were isolated, and the hippocampus and prefrontal cortex were separated and homogenized, followed by centrifugation at 4 °C, 10,000 rpm for 15 min. The biochemical estimations like acetylcholinesterase activity were used; oxidative and antioxidant parameters like nitric oxide, malondialdehyde, and reduced glutathione were determined; enzyme-linked immunosorbent assays for amyloid beta, inflammatory cytokines, brain-derived neurotrophic factor, and CD33 were performed. The results from behavioral and biochemical tests suggested that the PAPS formulation had a more significant impact on slowing the progression of scopolamine-induced cognitive impairment compared to the stearylamine-conjugated phenyl boronic acid carrier and 4-allyl pyrocatechol alone treatments. The histopathological studies revealed a decline in neural degeneration and showed improved neuronal morphology in the PAPS-treated group compared with the disease group. From the data obtained, the PAPS nanoparticle formulation would be an effective strategy for reducing the progression of cognitive impairment.
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