Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
Spectroscopic and Thermodynamic Exploration of Folic Acid's Modulatory Impact on the Bimolecular Interactions of Hemoglobin with Pemetrexed.
Nakka S, Prabha R, Chahar D … +4 more , Yadav B, Mannem S, Devunuri N, Venkatesu P
Mol Pharm · 2026 May · PMID 41958042 · Publisher ↗
Pemetrexed (PEM) disrupts folate metabolism and may lead to blood-related side effects, such as anemia. Folic acid (FA) supplementation can be beneficial in reducing anemia caused by pemetrexed, as it helps replenish fol...
Pemetrexed (PEM) disrupts folate metabolism and may lead to blood-related side effects, such as anemia. Folic acid (FA) supplementation can be beneficial in reducing anemia caused by pemetrexed, as it helps replenish folate levels. FA plays a vital role in maintaining healthy red blood cells; its influence on the structural properties of hemoglobin (Hb) has not been clearly defined. This study involves the influence of the combined effects of PEM and FA on the structural and colloidal stability of Hb using spectroscopic techniques. Spectroscopic analysis indicates that PEM and FA associate with Hb without causing major changes to its structural stability. Notably, FA seems to help to maintain the secondary structure of Hb more effectively. The thermal stability assays demonstrated that Hb maintained and even improved its resilience when both PEM and FA were combined. Dynamic light scattering and transmission electron microscopy analyses demonstrate that Hb tends to aggregate when exposed to PEM, whereas it remains dispersed and does not aggregate in the presence of FA. The results show that FA counteracted the aggregation behavior of PEM on Hb's morphology. Therefore, the colloidal stability of Hb is balanced by FA in the presence of PEM. These results have proven and provided insights into how the mutual effect of PEM and FA is sufficient to protect proteins in therapeutic applications involving folate pathways, support the design of more such crucial effective drug delivery methods, and help in evolving biopharmaceutical formulations.
Downstream-Induced Destabilization of Neat Amorphous Drugs: Implications on Solid-State Stability and Performance.
Pantazos I, Kapourani A, Katsiadaki S … +1 more , Barmpalexis P
Mol Pharm · 2026 May · PMID 41955580 · Publisher ↗
Amorphous drug formulations offer a powerful strategy for enhancing the apparent solubility and bioavailability of poorly water-soluble drugs. However, their inherent physical instability, particularly the tendency to re...
Amorphous drug formulations offer a powerful strategy for enhancing the apparent solubility and bioavailability of poorly water-soluble drugs. However, their inherent physical instability, particularly the tendency to recrystallize during downstream processing, remains a significant hurdle. This study investigates the influence of pharmaceutical compaction parameters ─specifically compression pressure and dwell time─ on the stability and performance of melt-quenched amorphous formulations, using nifedipine (NIF) as a model compound. Compacts, prepared under varying pressures (50-250 MPa) and dwell times (1-60 s), were characterized by DSC, XRD, and ATR-FTIR, supported by multivariate analyses. Isothermal crystallization studies revealed that compression accelerated the amorphous-to-β-NIF transformation, with onset times significantly affected by both pressure and dwell time. A full factorial design confirmed statistically significant main and interaction effects. The subsequent NIF β → α transformation was observed during long-term storage under both low and high humidity, with faster polymorphic conversion under high humidity conditions. Intrinsic dissolution rate (IDR) measurements showed that higher compaction generally reduced dissolution, though under the most extreme compression conditions (i.e., 250 MPa and 60 s), a modest increase in IDR was observed. Porosity measurements revealed a partial correlation between matrix densification and reduced dissolution or recrystallization resistance, though exceptions indicated the involvement of additional structural phenomena. Compared to previous findings on celecoxib, NIF exhibited a more pronounced and consistent sensitivity to both mechanical pressure and dwell time, despite sharing similar glass forming ability (GFA) classification and physicochemical properties. These findings emphasize the compound-specific nature of amorphous drug compression-induced destabilization and highlight the need for tailored assessment strategies during downstream processing of such amorphous drug formulations.
Encapsulation of Glucose Oxidase in Porous Cu(II)-Doped Zinc Phosphate@polydopamine Nanoparticles for Triple-Combination Therapy of Cancer.
Fan M, Wen X, Zhang J … +4 more , Li R, Chen X, Song X, Li S
Mol Pharm · 2026 May · PMID 41948866 · Publisher ↗
Designing multifunctional nanotherapeutic platforms that integrate multiple therapeutic capabilities with enhanced tumor specificity and low systemic toxicity has emerged as a promising strategy for cancer therapy. Herei...
Designing multifunctional nanotherapeutic platforms that integrate multiple therapeutic capabilities with enhanced tumor specificity and low systemic toxicity has emerged as a promising strategy for cancer therapy. Herein, we put forward a simple and clear route to construct multifunctional nanoparticles (NPs) integrating chemodynamic therapy (CDT), starvation therapy (ST), and photothermal therapy (PTT) by using polydopamine as a protective layer to coat Cu-doped zinc phosphate loaded with glucose oxidase (designated as Cu-ZnP@GOx/PDA/PEG NPs) for optimizing therapeutic efficacy. The obtained Cu-ZnP@GOx/PDA/PEG NPs utilize porous Cu-doped ZnP to provide sufficient space for efficient GOx loading, while the PDA shell coated on the surface acts as a "gatekeeper" to prevent enzyme leakage and provides photothermal conversion capabilities. When Cu-ZnP@GOx/PDA/PEG NPs accumulate at tumor sites, the slightly acidic tumor microenvironment triggers the degradation of Cu-ZnP@GOx/PDA/PEG NPs, thereby releasing loaded GOx and doped Cu. The released Cu is reduced to Cu by glutathione (GSH), subsequently catalyzing HO decomposition to generate highly cytotoxic hydroxyl radicals (OH) for effective CDT. The released GOx can cut off glucose metabolism in tumor cells to realize ST, and the substances produced during the process of glucose oxidation can improve the microenvironment for better CDT. Under near-infrared irradiation, the generated heat by the photothermal effect of PDA can not only be applied for PTT but also enhance the catalytic efficiency of Fenton-like reactions and the enzymatic activity of GOx, achieving the goal of trimodal synergistic therapy of CDT/ST/PTT. Importantly, in vivo studies using tumor-bearing mice demonstrate that the combined therapy via Cu-ZnP@GOx/PDA/PEG NPs effectively suppresses tumor growth, and no obvious systemic toxicity can be observed. Taken together, the construction of Cu-ZnP@GOx/PDA/PEG NPs can provide a feasible strategy for a safe and efficient cancer therapy.
Correction to "Development of Novel Peptide-Based Ga-Labeled Radiotracers for Detecting ROR1 Expression in Tumors".
Huang S, Tian T, Qi M … +3 more , Li M, Wu X, Huang R
Mol Pharm · 2026 May · PMID 41940953 · Publisher ↗
Abstract loading — click title to view on PubMed.
Formulation Screening of Lipid Nanoparticles Enhances mRNA Delivery to Retina.
Yu J, Ma Z, Tong H … +9 more , Li Y, Li D, Zhu Q, Shi H, Zhou L, Tian C, Li B, Cheng C, Lv P
Mol Pharm · 2026 May · PMID 41931102 · Publisher ↗
Inherited retinal diseases (IRDs) are a group of genetically heterogeneous neurodegenerative disorders that cause progressive vision loss. Gene therapies based on adeno-associated virus vectors have achieved notable prog...
Inherited retinal diseases (IRDs) are a group of genetically heterogeneous neurodegenerative disorders that cause progressive vision loss. Gene therapies based on adeno-associated virus vectors have achieved notable progress in IRDs, but their limited packaging capacity and potential long-term toxicity constrain broader applications. Lipid nanoparticles (LNPs) have been clinically validated as nonviral delivery vehicles for nucleic acid therapeutics. Previous ocular studies have primarily focused on strategies such as surface modification and polyethylene glycol lipid engineering, which have provided valuable insights. However, systematic exploration of core formulation parameters, such as lipid component ratios, has received comparatively limited attention. In this study, we applied a design of experiments strategy to construct and evaluate LNP libraries for ocular delivery. Systematic screening identified formulation B11, which produced 2.6-fold and 3.0-fold reporter gene expression following intravitreal administration compared with benchmark SM-102 and MC3 formulations. Mechanistic analyses revealed that LNP B11 is internalized predominantly through caveolae-mediated endocytosis and macropinocytosis. , LNP B11 mediated mRNA expression localized to the retinal pigment epithelium, as demonstrated by mCherry expression. Furthermore, Cre mRNA delivery using B11 formulation induced tdTomato activation in Ai14 reporter mice more effectively than standard SM-102 and MC3 formulations, indicating that B11 supports functional protein expression in retinal tissue. Together, these findings identify B11 as a promising optimized LNP formulation for retinal mRNA delivery, highlighting the critical role of systematic formulation optimization in advancing nucleic acid therapeutics for retinal diseases.
Development and Preclinical Evaluation of a Selinexor-Derived Radiotracer [Ga]Ga-NOTA-Selinexor for Imaging XPO1 Expression in Multiple Myeloma.
Zhong X, Yan J, Su C … +7 more , Xu W, Wang X, Pan D, Xu Y, Wang L, Chen C, Yang M
Mol Pharm · 2026 May · PMID 41926313 · Publisher ↗
Selinexor, an FDA-approved XPO1 inhibitor for relapsed or refractory multiple myeloma (MM), has been explored as a precursor for isotopologically 18F-labeling to enable PET imaging of XPO1 expression in MM. However, low...
Selinexor, an FDA-approved XPO1 inhibitor for relapsed or refractory multiple myeloma (MM), has been explored as a precursor for isotopologically 18F-labeling to enable PET imaging of XPO1 expression in MM. However, low tumor-to-muscle (T/M) ratio and poor imaging contrast were observed due to high tracer's lipophilicity. In the present study, selinexor was conjugated to a NOTA chelator via an amide-linked two-carbon (ethylene) spacer to generate the target compound NOTA-selinexor. Subsequent radiolabeling with Ga successfully yielded [Ga]Ga-NOTA-selinexor in over 95% radiochemical yield (RCY) and approximately 96% radiochemical purity (RCP), as well as a molar activity of 12.08 ± 1.37 GBq/μmol. Molecular docking analysis confirmed that the unlabeled precursor retained binding affinity toward XPO1. Furthermore, the radiotracer possessed a hydrophilic profile (log = -0.91 ± 0.07) and demonstrated favorable stability under physiological conditions. In vivo PET imaging in MM xenograft models demonstrated that [Ga]Ga-NOTA-selinexor achieved superior imaging contrast and a significantly higher T/M ratio (∼4.4) compared to previously reported [F]selinexor (∼2.1). Taken together, these findings suggest that [Ga]Ga-NOTA-selinexor serves as a valuable PET tracer for noninvasively evaluating XPO1 expression in vivo, highlighting its potential for both precise diagnosis and treatment assessment in MM.
Injected Eye, Fellow Eye and Systemic Pharmacokinetic Modeling of Intravitreally Administered Bevacizumab.
Franz M, Jairam RK, Ma G … +5 more , Rist W, Fuchs H, Kuepfer L, Hanke N, Rimpelä AK
Mol Pharm · 2026 May · PMID 41925314 · Full text
Simulation of retinal drug concentrations after intravitreal administration is still challenging, due to knowledge gaps in ocular physiology such as the molecule-dependent permeability of ocular segments and the mechanis...
Simulation of retinal drug concentrations after intravitreal administration is still challenging, due to knowledge gaps in ocular physiology such as the molecule-dependent permeability of ocular segments and the mechanisms determining a drugs' diffusion through the vitreous. Current models consider the eye as an isolated organ, however, especially if we are striving for predictions that rely on only plasma data, it is crucial to understand the blood-ocular barrier to draw conclusions for drug exposure in the eye. The aim of this study was (1) to examine large molecule disposition within the rabbit injected eye as well as in the systemic circulation and the uninjected fellow eye using bevacizumab as a tool compound, (2) to show gaps in the current understanding of physiological processes governing drug distribution in the eye and (3) to identify model parameters relevant for eye-plasma drug exchange. We developed a semimechanistic ocular compartmental model to describe large molecule disposition in injected eye, plasma and fellow eye, following intravitreal bevacizumab administration in rabbit, based on literature data. Observations in the fellow eye add additional value to the developed model as they provide valuable new information about the blood-ocular barrier. Starting with a base model building on literature assumptions, we refined the structural model and parameter estimates (e.g., by adjusting the retinal volume) to better describe the observed data in the fellow eye. The simulated concentration-time profiles from our refined model adequately described observed concentrations in the injected eye, plasma and fellow eye. The retinal volume fraction accessible for bevacizumab was estimated at 41% and the retinal pigment epithelium permeability at 5.9 · 10 cm·s, which is in close agreement with the values obtained from in vitro experiments. The introduction of a backflow from the plasma compartment to the aqueous chamber (0.024 mL·day) yielded improved predicted aqueous concentrations in the fellow eye. The developed model increases our knowledge of ocular drug pharmacokinetics within a systemic context, with a more physiological representation of the retinal compartment and new insights into the processes involved at the blood-ocular barrier.
EGFR-Targeted and MMP-Activated Membranolytic Peptides Kill Cancer Cells Specifically In Vitro and Reduce Tumor Growth In Vivo.
Pramanik A, Booth A, Kobza D … +4 more , Brackenbury WJ, Connell SD, Beales PA, Hughes TA
Mol Pharm · 2026 May · PMID 41920242 · Full text
Membranolytic peptides are potential cancer therapeutics, although targeting cancer cells specifically remains an unmet challenge. We have modified the membranolytic peptide MP1, from , to direct its action specifically...
Membranolytic peptides are potential cancer therapeutics, although targeting cancer cells specifically remains an unmet challenge. We have modified the membranolytic peptide MP1, from , to direct its action specifically to some cancer cells, thereby improving its cancer therapeutic characteristics and reducing its nonspecific toxicity. MP1 was modified by addition of sequences allowing binding to the cancer biomarker EGFR, with or without sequences directing cleavage by the cancer biomarker MMP-2. Toxicity was assessed in human breast cell lines and was correlated with EGFR expression and MMP-2 activity. Efficacy as an antitumor agent was assessed in MDA-MB-468 xenograft models. C-terminal addition of targeting sequences generally reduced cellular toxicities of peptides relative to wildtype MP1. Cell lines that retained the highest sensitivities to these fusion peptides expressed the highest EGFR and/or MMP-2 levels, supporting specific cytotoxic activity directed to these biomarkers. Treatment with an MMP-2 inhibitor significantly reduced the cell-killing activity of peptides containing MMP-2 cleavage sites, further supporting specific targeting. Fusion peptides significantly induced apoptosis and reduced survival in EGFR/MMP-2 high cancer cells, while sparing EGFR/MMP-2 low cells in standard tissue culture and 3D-spheroids. Systemic treatment with the EGFR-MMP-MP1 fusion significantly reduced tumor size in MDA-MB-468 xenograft models, confirming in vivo efficacy against cancer cells and acceptable systemic toxicity. We conclude that EGFR-MMP-MP1 peptides represent a novel cancer therapeutic for further development.
Anticancer Efficacy of HPPH-PDT Synergies with BCG-Immunotherapy or COX-2 Inhibitor in Treating Bladder Cancer.
Durrani FA, Cacaccio J, Potter W … +9 more , Dukh M, Ghazaeian M, Hussein AA, Ibrahim OM, Kalinski P, Prasad PN, Baumann H, Guru KA, Pandey RK
Mol Pharm · 2026 Apr · PMID 41920055 · Publisher ↗
Among the photosensitizers (PSs) developed in our laboratory, 3-(1'-hexyloxy) ethyl-3-devinyl pyropheophorbide-a (HPPH) is undergoing Phase-II multicenter clinical trials for the treatment of head and neck and esophageal...
Among the photosensitizers (PSs) developed in our laboratory, 3-(1'-hexyloxy) ethyl-3-devinyl pyropheophorbide-a (HPPH) is undergoing Phase-II multicenter clinical trials for the treatment of head and neck and esophageal cancers. The PS exhibits absorption at 665 nm (in vivo) and shows desired pharmacokinetics with limited skin phototoxicity in patients, compared to FDA-approved Photofrin. This study determined the effect of HPPH-PDT in vitro and in vivo on human bladder cancer (BCa) tissue grown in immune-deficient mice. We observed high tumor uptake/retention of HPPH at 24 h post injection. The anticancer activity of HPPH-PDT was associated with undesirable induction of COX-2, the key enzyme enhancing the production of prostaglandin E2 (PGE2), a pathway we previously found accompanying tumors associated with immune suppression and tumor progression. Combination of COX-2 inhibition with PDT or with BCG-immunotherapy showed an improved rate of tumor cures. Hence, HPPH-PDT in combination with COX-2 inhibitors not only reduces the expression of COX-2, IL-6, VEGF, and PGE2 but also enhances long-term tumor cure.
Correction to "Endplate Chondrocyte Derived Exosomal miR-133a-3p Alleviates Intervertebral Disc Degeneration by Targeting the NF-κB Signaling Pathway through the miR-133a-3p/MAML1 Axis".
Li Q, Guo R, Zhao C … +3 more , Chen X, Wang H, Shen C
Mol Pharm · 2026 May · PMID 41914908 · Publisher ↗
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Polysaccharide and αGalCer Synergistically Act as Dual Adjuvants to Enhance Humoral and Cellular Immune Responses.
Liu J, Wang J, He Y … +5 more , Huang Y, Quan W, Mu H, Gou J, Peng X
Mol Pharm · 2026 May · PMID 41914345 · Publisher ↗
Adjuvants are indispensable for subunit vaccines. However, the development of safe and effective adjuvants remains a major challenge. Polysaccharides derived from traditional Chinese medicine (TCM) have recently emerged...
Adjuvants are indispensable for subunit vaccines. However, the development of safe and effective adjuvants remains a major challenge. Polysaccharides derived from traditional Chinese medicine (TCM) have recently emerged as promising sources of novel vaccine adjuvants. In this study, we investigated the adjuvant activity of polysaccharide (PSP) in combination with the glycolipid α-galactosylceramide (αGalCer or αGC). , PSP significantly promoted the activation of RAW264.7 and DC2.4 cells. , the PSP/αGC dual adjuvant group elicited markedly stronger cytokine production and a more robust humoral immune response compared with the single adjuvant groups. Moreover, it induced a strong cellular immune response with a balanced Th1/Th2 response and enhanced memory T-cell responses. The dual-adjuvant system also demonstrated a good biocompatibility and safety in mice. To our knowledge, this is the first report of a dual-adjuvant system combining a plant-derived polysaccharide with an iNKT cell agonist, highlighting PSP/αGC as a promising platform for next-generation vaccine design.
Evolution of Particle Radiotherapy: From Physical to Dual Targeting in Precision Medicine.
Yao H, Zheng F, Zhong Y … +7 more , Tian H, Li Z, Zhu H, Yang Z, Zhang H, Tian M, Zeng W
Mol Pharm · 2026 May · PMID 41913578 · Publisher ↗
As cancer remains a formidable global health challenge, radiotherapy is evolving toward unprecedented levels of precision. Particle radiotherapy (PRT), utilizing charged particles such as protons and carbon ions, has eme...
As cancer remains a formidable global health challenge, radiotherapy is evolving toward unprecedented levels of precision. Particle radiotherapy (PRT), utilizing charged particles such as protons and carbon ions, has emerged as a superior alternative to conventional photon-based approaches. While proton therapy (PT) achieves superior physical targeting the Bragg peak and carbon ion radiotherapy (CIRT) adds biological potency through high linear energy transfer (LET), both modalities are fundamentally constrained by their primary reliance on spatial/macroscopic dose distribution. Against this backdrop, boron neutron capture therapy (BNCT) stands out as an innovative dual-targeting strategy in precision oncology. BNCT combines biochemical selectivity (achieved tumor-specific boron-10 agents) with cellular-scale physical precision (realized by neutron-irradiation-triggered, locally confined high LET particles). This review delineates the latest progress in particle radiotherapy, specifically highlighting the crucial transition from the established physical targeting of PT and CIRT to the burgeoning dual-targeting innovation of BNCT. We provide an in-depth analysis of mechanistic principles, technological advancements in accelerator-based sources, the pharmacological evolution of boron delivery systems, and the resulting clinical applications. Future directions for the entire particle radiotherapy field center on reducing operational costs, optimizing therapeutic accuracy, conducting robust randomized trials, and exploring synergistic therapies. Critically, BNCT, with its unique dual-targeting mechanism, represents a potentially transformative precision therapy with significant potential for intractable malignancies.
Advanced Age-Related Changes in Intestinal Drug Transporters and Metabolising Enzymes: A Targeted Proteomics Study.
Harder F, Brouwers J, Vanuytsel T … +2 more , Oswald S, Augustijns P
Mol Pharm · 2026 May · PMID 41910159 · Publisher ↗
This study examines the influence of aging on the protein abundance of key drug transport proteins (DTPs) and drug-metabolizing enzymes (DMEs). Duodenal and colonic biopsies were collected from 58 volunteers aged 19-85 y...
This study examines the influence of aging on the protein abundance of key drug transport proteins (DTPs) and drug-metabolizing enzymes (DMEs). Duodenal and colonic biopsies were collected from 58 volunteers aged 19-85 years who underwent routine endoscopic procedures. Targeted mass spectrometry-based proteomics was used to quantify the abundance of major ATP-binding cassette (ABC) and solute carrier (SLC) transporters, as well as cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes involved in drug disposition. Multiple regression analysis was employed to assess the effects of age, sex, and sex-specific age effects on DTP and DME expression, providing insight into potential age-related variability in intestinal drug metabolism and transport. The analysis revealed significant age-related changes in duodenal protein abundance, with age coefficients ranging from -0.36 to 0.51. Specifically, a decrease in duodenal abundance with age was observed for carboxylesterase 2 (CES2), peptide transporter 1 (PEPT1), and villin-1. Additionally, a significant age-dependent increase in the duodenal abundance of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins 1, 3, 4 (MRP1, MRP3, MRP4) and permeability-glycoprotein (P-gp) was observed. No significant impact of sex or sex-specific age effects was detected. These findings provide novel insights into the aging human proteome and may inform future research in this area.
Cationic Nanogel Coated Norovirus VLP Nasal Vaccine Induces Neutralizing Mucosal IgA and Serum IgG Antibodies.
Yuki Y, Kurokawa S, Yamanoue T … +11 more , Tsuchihashi T, Tamiya S, Sawada SI, Uchida Y, Sugiura K, Nakahashi-Ouchida R, Sakon N, Tokuhara D, Akiyoshi K, Sato S, Kiyono H
Mol Pharm · 2026 Apr · PMID 41887203 · Full text
Although norovirus can affect people of any age, the majority of deaths and illnesses occur in children under one year old and people over the age of 55. Currently, there is no vaccine or medication available. Previously...
Although norovirus can affect people of any age, the majority of deaths and illnesses occur in children under one year old and people over the age of 55. Currently, there is no vaccine or medication available. Previously, we developed a nasal vaccine drug delivery system (DDS) for a small protein antigen by using cationic cholesteryl pullulan (cCHP) nanogels, in which the vaccine antigen was embedded in the nanogel structure through hydrophobic interactions. Here, we developed and tested a virus-like particle (VLP)-based nasal vaccine system that is coated in nanogel. We used VLPs (diameter, approximately 40 nm) of the GII.4 (Sydney_2012) genotype of norovirus, a globally prevalent strain. By using a molar ratio of 1:10 or 1:100 VLPs to nanogel, we successfully covered the VLPs with cationic nanogel by electrostatic force. Following nasal immunization in mice, the nanogel-covered VLPs bound continuously to the nasal epithelium, effectively enabling mucosal dendritic cells to take them up and initiate systemic antigen-specific IgG and IgA antibody responses as well as antigen-specific IgA antibodies in mucosal compartments such as the airways and intestinal tract. The antibodies induced by nasal immunization with the nanogel-covered VLP vaccine neutralized the GII.4 (Sydney_2012) genotype of norovirus. These results provide proof of concept for advancing the development of adjuvant-free cCHP-nanogel-based VLP nasal vaccines.
Covalent versus Dimeric Optimization of Nectin-4-Targeted Peptide Radiotracers: A Head-to-Head Comparison in Triple-Negative Breast Cancer Mice Models.
Pei Y, Zhou X, Gao F … +8 more , Sun M, Qiu S, Qin X, Qu C, Wen K, Du J, Hu J, Cheng Z
Mol Pharm · 2026 Apr · PMID 41883057 · Publisher ↗
Nectin-4 is highly expressed in several malignancies, including triple-negative breast cancer, and it represents an attractive target for molecular imaging and therapy. In this study, we report the first head-to-head com...
Nectin-4 is highly expressed in several malignancies, including triple-negative breast cancer, and it represents an attractive target for molecular imaging and therapy. In this study, we report the first head-to-head comparison of two structural optimization strategies for Nectin-4-targeted peptide radiotracers: peptide dimerization (for the development of Ga-DOTA-HTA-DM) and sulfonyl fluoride modification (for the development of Ga-DOTA-HTA-SF). The dimeric peptide DOTA-HTA-DM achieved a pronounced affinity gain (SPR apparent ≈ 0.37 nM), consistent with the bivalent binding mode predicted by docking and molecular dynamics simulations. In contrast to the lead compound N188, the sulfonyl fluoride-modified peptide DOTA-HTA-SF retained low-nanomolar affinity, and the Ga radiolabeled probe exhibited markedly higher tumor uptake at early time postinjection (∼5% ID/g at 30 min) and sustained tumor retention (>4% ID/g at 2 h), resulting in superior tumor-to-background contrast. Both radiotracers were predominantly cleared through the renal system, and blocking studies confirmed their Nectin-4-mediated tumor accumulation. Taken together, these findings demonstrate that dimerization enhances molecular recognition through multivalency, while sulfonyl fluoride modification prolongs tumor residence and improves imaging contrast. The complementary advantages of these two strategies establish a rational framework for the design of next-generation Nectin-4-targeted radiotracers.
Addressing the Release and Permeation Challenges of High- Drugs in Amorphous Solid Dispersions.
Shah DD, Xu Z, Knipp GT … +5 more , Yang W, Marden S, Wu D, Zhou L, Taylor LS
Mol Pharm · 2026 Apr · PMID 41877608 · Publisher ↗
The goal of the current study was to assess the release rate of model high glass transition temperature () drugs from amorphous solid dispersions (ASDs) as a function of drug loading, and then to evaluate the permeation...
The goal of the current study was to assess the release rate of model high glass transition temperature () drugs from amorphous solid dispersions (ASDs) as a function of drug loading, and then to evaluate the permeation rate of the resultant solutions using Caco-2 cells. Ivacaftor and ARV-825 were selected as model drugs and were formulated as ASDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Release was found to be very slow or not detectable at higher drug loadings. Dramatically improved release was observed upon addition of 10 wt % glyceryl tributyrate to the ASDs, which reduced . Nanosized drug-rich amorphous droplets, generated upon dissolution of ivacaftor ASDs, enhanced the Caco-2 membrane permeation rate, likely by partitioning into the unstirred water layer (UWL) at the surface of the membrane and reducing the concentration gradient across the UWL. The extent of improvement was correlated with the size of droplets: smaller droplets resulted in faster permeation rates. Addition of glyceryl tributyrate, while increasing the release rate, decreased the permeation rate due to formation of larger droplets. In conclusion, the addition of a plasticizer to an ASD containing a high drug led to an improvement in release rate but increased the size of drug-rich nanodroplets produced via the release process with unknown potential implications for in vivo performance.
Anti-EGFR Aptamer-Conjugated Erythrocyte Membrane-Derived Nanoparticles for Targeted Doxorubicin Delivery.
Lee DH, Choi K, Lee JW … +3 more , Kim MW, Park YS, Choi MJ
Mol Pharm · 2026 Apr · PMID 41877526 · Publisher ↗
Conventional nanomedicines frequently suffer from rapid systemic clearance via the mononuclear phagocytic system (MPS) and off-targeting, which severely limits their therapeutic index. Recently, new attempts using cell m...
Conventional nanomedicines frequently suffer from rapid systemic clearance via the mononuclear phagocytic system (MPS) and off-targeting, which severely limits their therapeutic index. Recently, new attempts using cell membrane-derived nanoparticles (CDNs) have been proposed as a novel platform of drug carriers. To address these challenges, we report a biomimetic drug delivery platform utilizing erythrocyte-derived nanoparticles (EDNs) that leverage the actual "self" signaling of erythrocyte cell membranes. But many ligand functionalizations often rely on monoclonal antibodies, which are frequently hampered by antidrug antibody (ADA) response and limited tumor penetration due to their bulky size. In this study, we engineered a next-generation biomimetic nanocarrier by conjugating anti-EGFR targeting aptamers onto EDNs. And we successfully encapsulated doxorubicin (DOX) into EDNs using an optimized phosphate gradient method, achieving a high loading efficiency of 38% while preserving the structural integrity of membrane proteins. The size of Apt-EDNs-DOX was measured by the dynamic light scattering (DLS) method, 215 nm in diameter. Furthermore, assays confirmed that the aptamer-mediated targeting significantly enhanced intracellular drug delivery and selective cytotoxicity in MDA-MB-231 (EGFR+) compared to MDA-MB-453 (EGFR-). therapeutic evaluation in a tumor xenograft mouse model demonstrated significant tumor growth inhibition and a favorable safety profile compared with the free drug. These findings suggest that substituting antibodies with aptamers represents a crucial advancement in developing more stable, less immunogenic, and highly efficient targeted nanomedicines for clinical translation in cancer therapy.
Influence of the Binding Valency of Anti-HER2 Biparatopic Antibodies on Biodistribution in an SK-OV-3 Tumor Xenograft Model.
Akiba H, Nakashima K, Ichinose T … +2 more , Watanabe H, Ono M
Mol Pharm · 2026 Apr · PMID 41873858 · Publisher ↗
Biparatopic antibodies (BpAbs) are an attractive format of engineered therapeutic antibodies that bind to two distinct epitopes of a single antigen. Accelerated cell internalization is anticipated in many developmental c...
Biparatopic antibodies (BpAbs) are an attractive format of engineered therapeutic antibodies that bind to two distinct epitopes of a single antigen. Accelerated cell internalization is anticipated in many developmental campaigns, and both bivalent and tetravalent forms have been developed for this purpose. However, their pharmacokinetic properties have not been understood systematically; thus, optimization approaches for BpAbs have been limited. In this study, we conducted a comparative biodistribution analysis of bivalent and tetravalent BpAbs using the same variable fragments. Two different pairs of epitopes of human epidermal growth factor receptor 2 (HER2) were targeted, and their distribution was evaluated in a tumor xenograft model by In-labeling. Bivalent BpAbs showed higher accumulation in tumors than tetravalent BpAbs in both cases. However, epitope-dependent differences in biodistribution did not correlate with those of the original monoclonal antibodies. In addition, cell internalization during the early stages of incubation was higher for tetravalent BpAbs. These results suggest the advantage of bivalent BpAbs over tetravalent BpAbs in pharmacokinetics; however, the design may require optimization depending on the mechanism of action of the BpAb of interest.
Lipid Nanoparticle-Mediated Delivery of 27-Hydroxycholesterol for Targeting Rhinovirus-Induced Respiratory Diseases.
Repellin M, Costantino M, Francese R … +5 more , Dugas PY, Poli G, Lembo D, Civra A, Lollo G
Mol Pharm · 2026 Apr · PMID 41861355 · Publisher ↗
Human rhinovirus (HRV) is a highly widespread pathogen, the most frequent cause of the common cold, and often associated with asthma exacerbation. To date, attempts to develop direct-acting antivirals (DAAs) have proved...
Human rhinovirus (HRV) is a highly widespread pathogen, the most frequent cause of the common cold, and often associated with asthma exacerbation. To date, attempts to develop direct-acting antivirals (DAAs) have proved unsuccessful, also due to their tendency to select resistant variants when challenged with HRV quasispecies. 27-hydroxycholesterol (27OHC), a cholesterol-derived host-targeting antiviral (HTA), inhibits HRV replication and is less prone to selecting resistant variants than the DAAs pleconaril and rupintrivir. In the present study, we developed and evaluated a lipid nanoparticle (LNP)-based formulation for the nasal delivery of 27OHC. The antiviral efficacy of 27OHC-loaded LNPs was assessed on HeLa cells by focus reduction assays and yield reduction assays. The effect on cell viability and the cytotoxicity were determined via MTS and LDH assays to calculate the 50% cytotoxic concentration (CC50). Efficacy and biocompatibility of 27OHC were further validated in a physiologically relevant 3D model of reconstituted human nasal epithelia derived from healthy donors. Cellular uptake and internalization kinetics of LNPs were assessed on HeLa cells with the use of fluorochrome-tagged LNPs and indirect immunofluorescence. Our results demonstrate that 27OHC-loaded LNPs strongly inhibit HRV infectivity at 50% effective concentration (EC50) in the low micromolar range and are characterized by a selectivity index (SIs = CC50/EC50) above 150. Importantly, the adopted formulation suppressed viral replication in the nasal epithelium without cytotoxic effects. The uptake experiments show that LNPs enter cells and are clearly detectable intracellularly at 24 h post-treatment. These findings highlight the therapeutic potential of 27OHC delivered via LNPs as a promising host-targeting strategy against HRV and provide a rationale for further studies aiming to explore its potential in a preclinical setting.
Covalent Radiopharmaceuticals: Precision Imaging and Therapy for Cancer.
Klauser PC, Wang L
Mol Pharm · 2026 Apr · PMID 41860087 · Full text
Covalent radiopharmaceuticals are emerging as a powerful new class of agents for cancer imaging and therapy, offering durable target engagement that overcomes the key limitations of conventional, reversible tracers. By f...
Covalent radiopharmaceuticals are emerging as a powerful new class of agents for cancer imaging and therapy, offering durable target engagement that overcomes the key limitations of conventional, reversible tracers. By forming covalent bonds with nucleophilic residues on or near disease-relevant proteins, covalent radiopharmaceuticals can achieve prolonged tumor retention, improved target selectivity, and enhanced imaging contrast, or therapeutic efficacy. This strategy is particularly well-suited to addressing biological challenges such as rapid internalization, low target abundance, and tumor heterogeneity, where noncovalent agents often underperform. Recent advances have demonstrated the versatility of covalent radiopharmaceuticals across a range of molecular formats, including small molecules, protein binders, and peptidomimetics. These agents have been engineered with diverse covalent targeting moieties that enable selective and stable binding under physiological conditions. In preclinical and early clinical studies, covalent tracers have shown superior tumor retention and, in some cases, improved performance over standard-of-care agents. Importantly, covalent design also allows for greater alignment between tracer pharmacokinetics and radionuclide decay, improving dosimetry and expanding therapeutic windows. While challenges remain in optimizing covalent handle reactivity and minimizing off-target effects, ongoing innovations in synthetic chemistry and protein engineering are rapidly advancing the field. As the mechanistic and translational advantages of covalency become increasingly clear, covalent radiopharmaceuticals are poised to redefine molecular imaging and therapy. They are not merely specialized tools but are foundational components of next-generation precision oncology.
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