Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
CD64-Targeted Polymer-Drug Conjugates Exploit Cathepsin K-Dependent Payload Release for Selective Elimination of Immunosuppressive Macrophages.
Musil D, Krhutová M, Blažková K … +13 more , Kramná A, Brázdová A, Výmolová B, Houdová Megová M, Hadzima M, Kryštůfek R, Šubr V, Kostka L, Etrych T, Ormsby T, Šácha P, Abramson J, Konvalinka J
Mol Pharm · 2026 May · PMID 42013459 · Full text
Selective depletion of immunosuppressive macrophages in the tumor microenvironment is a promising strategy in cancer therapy. CD64 is broadly expressed on myeloid cells, including both pro-inflammatory M1-like and immuno...
Selective depletion of immunosuppressive macrophages in the tumor microenvironment is a promising strategy in cancer therapy. CD64 is broadly expressed on myeloid cells, including both pro-inflammatory M1-like and immunosuppressive M2-like macrophages that resemble tumor-associated macrophages (TAMs), and thus represents an attractive entry receptor for targeted payload delivery. We developed HPMA-based CD64-targeted polymer-drug conjugates (CD64-TPDCs) that combine multivalent receptor engagement with enzyme-responsive payload release. These copolymers are decorated with the CD64-binding cyclic peptide cp33 and carry the cytotoxic payload mertansine (DM1) bound via cathepsin-cleavable peptide linkers. Multivalent cp33 presentation on the polymer markedly increased the apparent affinity for human CD64, resulting in subnanomolar binding and selective recognition of CD64-expressing cells, significantly improving the binding potency of monovalent cp33 peptide. In polarized M2-like human monocyte-derived macrophages (MDMs), we showed that cytotoxic Gly-Phe-Leu-Gly-DM1 CD64-TPDCs selectively induced apoptosis. In contrast, M1-like MDMs were largely spared despite expressing higher levels of CD64. In M2-like MDMs, CD64-TPDCs rapidly accumulated in lysosomes, whereas in M1-like cells, they remained largely confined to endosomes. To elucidate the basis of this selectivity, we profiled expression of cathepsins in polarized MDMs. We found that M2-like MDMs display substantially higher levels of cathepsin K, establishing a model in which cathepsin K is the major protease responsible for Gly-Phe-Leu-Gly linker cleavage and DM1 release in M2-like macrophages. These findings demonstrate that CD64-TPDCs can be engineered to exploit subset-specific trafficking and cathepsin K-dependent linker cleavage for the selective elimination of M2-like macrophages. This work provides a generalizable design principle for stimuli-responsive PDCs that may actively target immunosuppressive myeloid cells in tumors.
Near-UV and Visible Light Promote Iron-Catalyzed Site-Specific Radical Transformation of Threonine to Alanine in a Monoclonal Antibody Fc Domain (IgG1-Fc).
Espinoza Ballesteros M, Solis Rodriguez M, Tolbert TJ … +1 more , Schöneich C
Mol Pharm · 2026 May · PMID 42011714 · Publisher ↗
Near-UV and visible-light photodegradation is a concern for the development of stable and efficacious protein therapeutics, but mechanistic information on the underlying processes is scarce. We previously reported on the...
Near-UV and visible-light photodegradation is a concern for the development of stable and efficacious protein therapeutics, but mechanistic information on the underlying processes is scarce. We previously reported on the photoconversion and photofragmentation of IgG1-Fc, IgG1, and an IgG1-based fusion protein in the CH domain. Here, we report a novel site-specific photodegradation mechanism, converting Thr into Ala catalyzed by Fe(III). Site-directed mutagenesis and spin-trapping in conjunction with high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis reveal that this novel photoconversion proceeds via the generation of intermediary protein glycyl and methyl (CH) radicals analogous to metal-catalyzed cross-coupling reactions observed in synthetic organic processes.
Combination Gene Therapy with AAV-Based Vectors Ameliorates the Phenotype of Type 2 Diabetes in Diet-Induced Obese and db/db Mice.
Rajendiran R, Pathak S, Kumar A … +4 more , Bhaumik S, Amit S, Pydi SP, Jayandharan GR
Mol Pharm · 2026 May · PMID 42011518 · Publisher ↗
Type 2 diabetes mellitus (T2DM) has significant treatment challenges due to its complex pathophysiology and associated comorbidities. In recent years, hepatokine fibroblast growth factor 21 (FGF21) has gained significant...
Type 2 diabetes mellitus (T2DM) has significant treatment challenges due to its complex pathophysiology and associated comorbidities. In recent years, hepatokine fibroblast growth factor 21 (FGF21) has gained significant attention for treatment of metabolic disorders. Its translation potential is hindered by a short half-life and adverse effects on skeletal muscle. To address this, we developed an engineered AAV8 vector encoding codon-optimized human () transgene either alone or in combination with AAV9-miR411 to sustain FGF21 expression and to preserve muscle function. Our analysis over a 41 week follow-up period in diet-induced obese (DIO) mice showed that gene therapy led to a substantial reduction in body weight (∼38%), improved glycemic profile (blood glucose 80-108 vs 116-150 mg/dL, in control vector group), preserved glucose-stimulated insulin secretion, and attenuated hepatic steatosis. The combination of co.hFGF21 and miR-411 enhanced insulin responsiveness and muscle histology. To further validate the therapeutic efficacy of , we used diabetic /J (/) mice. gene therapy controlled obesity (body weight reduction of ∼31%), reversed hyperglycemia, and improved insulin sensitivity over a 30 week period. Additionally, co.hFGF21 expression significantly improved energy expenditure in / mice without any adverse effects on skeletal muscles. These findings support the use of optimized AAV8 human codon-optimized FGF21 as a viable, long-lasting therapeutic strategy for T2DM.
Sorafenib-Loaded Mesoporous Fe-Hematoporphyrin Complex for Ferroptosis-Enhanced Photodynamic Therapy of Colorectal Tumor.
Zhang C, Bai Y, Zhang Y … +4 more , Ye Y, Lin C, Lan M, Zhang Y
Mol Pharm · 2026 May · PMID 42011059 · Publisher ↗
Current colorectal cancer (CRC) therapies (e.g., surgery and radiotherapy) face challenges of invasiveness, drug resistance, and limited efficacy. Photodynamic therapy (PDT), a noninvasive modality, generates cytotoxic r...
Current colorectal cancer (CRC) therapies (e.g., surgery and radiotherapy) face challenges of invasiveness, drug resistance, and limited efficacy. Photodynamic therapy (PDT), a noninvasive modality, generates cytotoxic reactive oxygen species (ROS) via photosensitizers, offering a promising approach to overcome resistance. However, CRC and other solid tumors exhibit a hypoxic microenvironment with elevated glutathione (GSH) levels that scavenge ROS, severely compromising PDT efficacy. Developing advanced PDT systems to enhance ROS generation and overcome these microenvironmental barriers (e.g., hypoxia and GSH overexpression) is thus critical to improve CRC treatment outcomes and clinical translation. Herein, we report that a mesoporous Fe-hematoporphyrin complex (FeCP) was synthesized via covalent coordination of Fe with hematoporphyrin. The FeCP exhibits a high surface area and tunable porosity, enabling efficient encapsulation of the ferroptosis inducer sorafenib (SOR) with a loading efficiency of 29.8%, as quantified by UV spectroscopy. Both in vitro and in vivo evaluations demonstrated that FeCP@SOR exhibited biocompatibility and synergistically enhanced photodynamic therapy (PDT) efficacy through dual redox modulation mechanisms. Mechanistically, FeCP@SOR significantly downregulated SLC7A11 expression, triggering substantial lipid peroxidation (LPO) and malondialdehyde (MDA) accumulation, as well as significant depletion of glutathione (GSH), ultimately inducing ferroptosis and alleviating tumor hypoxia. Concurrently, the amplified reactive oxygen species (ROS) generation disrupted intracellular redox homeostasis, intensifying tumor cell death and suppressing tumor growth. The FeCP@SOR nanocomposite demonstrated synergistic therapeutic effects against colorectal tumors, thereby offering a novel and reliable material platform for clinical photodynamic therapy (PDT) in colorectal cancer (CRC) management.
Combining PC-SAFT and ML to Access Unknown API Solubilities.
Habicht J, Sadowski G, Brandenbusch C
Mol Pharm · 2026 May · PMID 42009311 · Full text
Predicting the solubility of active pharmaceutical ingredients (APIs) is essential throughout drug development. However, state-of-the-art modeling approaches require system-specific data sets for parameter estimation and...
Predicting the solubility of active pharmaceutical ingredients (APIs) is essential throughout drug development. However, state-of-the-art modeling approaches require system-specific data sets for parameter estimation and are resource intensive. This work introduces a new method that integrates adaptive machine learning (ML) methods with PC-SAFT modeling to vastly reduce requirements of experimental data. Instead of extensive experimental campaigns of solubility measurements, only the molecular structure and melting properties of the API are needed - information onten available in literature or easily measured. The ML framework applied in this work supplies PC-SAFT parameters for APIs. With solvent parameters already available from literature, this novel approach provided highly accurate solubility estimations for 21 APIs in pure solvents ( = 0.83 without using any binary data and = 0.98 using a single binary data point), as well as for mixed solvents, closely matching literature data. Compared to prior models, this hybrid method is more generalizable, consistent, and efficient, streamlining the workflow and providing reliable predictions with minimal experimental effort. By making a thermodynamic-based solubility assessment available early in process development, it outperforms state-of-the-art models that demand significantly more experimental input. The results of this work indicate that the newly developed ML framework can be efficiently applied to provide PC-SAFT parameters for APIs with minimal need of or even without using any experimental solubility data, which can be used to achieve thermodynamics-based access to API solubility in a very early stage of process development. This approach does not only provide solubility data in pure solvents but also in solvent mixtures.
Smart Magnetic Nanozyme for Multimodal Dynamic Regulation to Reverse Multidrug Resistance in Breast Cancer.
He J, Gong S, Liu Y … +6 more , Chen H, Ashraf K, Sajid S, Gallo J, Guo M, Mohsin A
Mol Pharm · 2026 May · PMID 42007566 · Publisher ↗
Intratumoral redox homeostasis is often implicated in the development of multidrug resistance (MDR), which compromises the oxidative cytotoxicity of anthracycline chemotherapeutics such as doxorubicin (DOX). To overcome...
Intratumoral redox homeostasis is often implicated in the development of multidrug resistance (MDR), which compromises the oxidative cytotoxicity of anthracycline chemotherapeutics such as doxorubicin (DOX). To overcome the redox homeostasis-driven MDR, we analyzed the transcriptomes of 216 breast cancer patients, revealing a noteworthy association between the (a regulator of redox homeostasis) overexpression and drug resistance. Moreover, a smart magnetic nanozyme, HADAF (HA@Anti-@DOX@Au@FeO), was rationally designed to target and reverse MDR. HADAF nanozyme integrates Au@FeO nanosheets with DOX, antisense oligonucleotides of and hyaluronic acid (HA). Notably, the dynamic regulation of HADAF is triggered spatiotemporally by a controllable low-frequency vibrational magnetic field (VMF) and near-infrared (NIR) laser irradiation. In vitro and in vivo experiments showed that HADAF effectively inhibited the /PI3K/mTOR/MCL-1 signaling pathway, promoting apoptosis and ferroptosis, and achieving a 90% inhibition rate in MCF-7/ADR cells. As a result of this engineered therapeutic approach, the combination therapy reduced the IC of DOX by 87.7-fold compared to free DOX. In summary, this multimodal nanozyme provides a novel strategy to target redox homeostasis and overcome MDR in cancer therapy.
Multifunctional Cannabidiol-Loaded Nanoparticles Based on Herbal-Derived Bioactive Materials Provide Enhanced Neuroprotection against Ischemic Stroke.
Yang MY, Quan HY, Yu YW … +5 more , Liu T, Ruan J, Li DL, Wu J, Fan HY
Mol Pharm · 2026 May · PMID 42003696 · Publisher ↗
The ischemic cascade is central to the pathophysiology of ischemic stroke, making single-target strategies often inadequate. An ideal neuroprotective approach should therefore target multiple key components of the ischem...
The ischemic cascade is central to the pathophysiology of ischemic stroke, making single-target strategies often inadequate. An ideal neuroprotective approach should therefore target multiple key components of the ischemic cascade. Herbal-derived bioactive materials offer dual "carrier and therapeutic" functions, providing unique advantages for addressing current treatment challenges. This study aims to develop a new multifunctional biomimetic nanoparticle using such herbal macromolecular materials. This nanoformulation (designated as CBDNPs) integrates polysaccharide for immunomodulation, apigenin for cardiovascular protection, and CBD for neuroprotection into a unified therapeutic strategy for the treatment of ischemic stroke. Biomimetic nanoparticles were produced with macrophage membrane (MM) coating on the surface of CBDNPs. MM/CBDNPs were characterized for physical properties and assessed for biological functions in vitro, with therapeutic efficacy evaluated in a middle cerebral artery occlusion (MCAO) model. The biomimetic CBD nanoformulation possessed favorable physicochemical properties and biological functions. Macrophage membranes can prevent drug-loaded nanoparticles and be engulfed by macrophages, and facilitate these nanoparticles to accumulate in the injured brain, while reducing ROS generation and stabilizing the mitochondrial membrane potential. In the MCAO rat model, administration of MM/CBDNPs reduced brain tissue damage and neuroinflammation and decreased neuronal apoptosis, exhibiting increased efficiency and neuroprotection. The underlying mechanism of anti-inflammation and neuroprotection of MM/CBDNPs was associated with the inhibition of NLRP3/NF-κB signaling pathway. These results demonstrate that MM/CBDNPs exhibited favorable neuroprotection and biocompatibility. This discovery offers new insights into the application of CBD and polymeric nanoparticles in the treatment of cerebral stroke.
Effect of Drug-Polymer Interaction on Solid-State Stability and In Vitro Drug Flux of Amorphous Solid Dispersions.
Kumar NSK, Jankovsky C, Zimny E … +2 more , Thakral NK, Suryanarayanan R
Mol Pharm · 2026 May · PMID 42003393 · Publisher ↗
Polymers play a pivotal role in amorphous solid dispersion (ASD) formulations. An ideal polymer must possess several attributes: it must maintain solid-state stability (retention of drug in the amorphous state), sustain...
Polymers play a pivotal role in amorphous solid dispersion (ASD) formulations. An ideal polymer must possess several attributes: it must maintain solid-state stability (retention of drug in the amorphous state), sustain the drug in a supersaturated state in the GI fluids (following administration), and have no detrimental effect on the drug permeation potential. In this study, indomethacin (IMC) ASDs were prepared with each hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone vinyl acetate) (PVPVA), or amino methacrylate copolymer (Eudragit E PO, EPO) were evaluated for their solid-state stability, dissolution behavior, and in vitro drug permeation using the parallel artificial membrane permeability assay (PAMPA). Solid-state stability was investigated through Flory-Huggins interaction parameters, and the molecular mobility was quantified using dielectric spectroscopy. Additionally, water-solid interactions and stability under accelerated conditions provided an assessment of the impact of drug-polymer interactions. Stability was rank ordered: IMC-EPO > IMC-PVPVA > IMC-HPMCAS, with IMC-EPO demonstrating superior resistance to crystallization. With respect to achieving supersaturation, the rankings were: IMC-HPMCAS > IMC-PVPVA > Amorphous IMC > IMC-EPO. While PVPVA and HPMCAS helped achieved the highest supersaturation, EPO was comparable to the amorphous drug. The rank ordering with respect to drug flux was: IMC-PVPVA > IMC-HPMCAS > Amorphous IMC ≈ IMC-EPO > Crystalline IMC. Thus, IMC-PVPVA offered a favorable compromise between physical robustness and permeation efficiency. These findings highlight the importance of polymer selection in ASD design─not only for maintaining physical stability, but also for ensuring effective drug dissolution and permeation.
Facile Fabrication of Multifunctional Metal-Phenolic Network Nanoparticles for Bacterial Keratitis Treatment.
Wang M, Qin C, Wang Y … +4 more , Cheng P, Zhu W, Chen H, Lin Q
Mol Pharm · 2026 May · PMID 41992746 · Publisher ↗
The management of methicillin-resistant (MRSA) keratitis remains highly challenging due to escalating antibiotic resistance and the severe, vision-threatening damage driven by uncontrolled inflammation. In this work, EG...
The management of methicillin-resistant (MRSA) keratitis remains highly challenging due to escalating antibiotic resistance and the severe, vision-threatening damage driven by uncontrolled inflammation. In this work, EGCG-Zn-VAN nanoparticles (NPs) were engineered as a multifunctional metal-phenolic network (MPN)-based platform to overcome these limitations through three integrated mechanisms: enhanced ocular retention, infection microenvironment-responsive antibiotic release, and synergistic anti-inflammatory activity. The carrier, formed by coordination-driven self-assembly of (-)-epigallocatechin gallate (EGCG) and Zn, enabled high vancomycin loading and provided prolonged precorneal residence. A checkerboard assay confirmed potent pharmacological synergy between the MPN matrix and vancomycin, while the platform exhibited robust pH-responsive behavior for preferential drug release under acidic infectious conditions. In a rat keratitis model, EGCG-Zn-VAN NPs combined potent bactericidal efficacy with effective modulation of the oxidative and inflammatory milieu. Notably, despite delivering a substantially lower antibiotic dose (∼14.9 μg/mL), the nanoparticle formulation significantly outperformed a clinical standard-of-care comparator (5% free vancomycin), achieving >95% reduction of MRSA burden and suppressing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) toward near-baseline levels. Quantitative histomorphometry confirmed that treatment led to the preservation of corneal transparency, epithelial integrity, and physiological stromal thickness. These outcomes arise from the cooperative interplay between vancomycin and the ROS-scavenging EGCG-Zn network, establishing EGCG-Zn-VAN NPs as a versatile, stimuli-responsive nanotherapeutic platform capable of addressing both microbial burden and host pathology. This platform provides a promising dose-sparing strategy for the clinical management of drug-resistant bacterial keratitis and other inflammation-associated ocular infections.
mRNASyner: An Integrative Framework for Full-Length mRNA Sequence Optimization via Multimodule Synergistic Design.
Gu Z, Wang GA, Feng Z … +4 more , Sun C, Li S, Zhang K, Li H
Mol Pharm · 2026 May · PMID 41991479 · Publisher ↗
Messenger RNA (mRNA) technology holds great promise in biomedicine; however, its therapeutic efficacy relies heavily on translation efficiency and the in vivo stability of mRNA sequences, both of which are governed by dy...
Messenger RNA (mRNA) technology holds great promise in biomedicine; however, its therapeutic efficacy relies heavily on translation efficiency and the in vivo stability of mRNA sequences, both of which are governed by dynamic interactions between the coding and noncoding regions. Existing optimization approaches typically focus on individual sequence components and lack the capacity for global, synergistic optimization. Moreover, their performance is often limited when processing long sequences or supporting iterative sequence refinement. To overcome these challenges, we propose a unified and interpretable in silico framework for full-length mRNA sequence design, integrating CDS optimization, UTR generation, and degradation modeling. In silico case studies based on respiratory syncytial virus (RSV) vaccine design demonstrated that mRNASyner achieved a favorable balance between translational accessibility and structural stability. mRNASyner thus enables the design of full-length mRNA sequences, supports long-sequence optimization, and offers a novel solution for the development of personalized mRNA therapeutics.
Development of Liposomal Formulations Composed of Thermoresponsive Polymers to Enhance Tumor Accumulation in Combining with Local Tumor Heating.
Fukada T, Sano K, Nakata M … +2 more , Yamasaki T, Mukai T
Mol Pharm · 2026 May · PMID 41988805 · Publisher ↗
Liposomes, nanosized vesicles consisting of a lipid bilayer membrane, have been widely investigated as versatile drug delivery systems. Clinically, several liposomal formulations have been used as anticancer drug carrier...
Liposomes, nanosized vesicles consisting of a lipid bilayer membrane, have been widely investigated as versatile drug delivery systems. Clinically, several liposomal formulations have been used as anticancer drug carriers owing to their enhanced permeability and retention (EPR) effects. Nevertheless, the accumulation of conventional liposomes in tumors remains insufficient to achieve optimal therapeutic efficacy. Therefore, the development of innovative liposomes with improved tumor selectivity and delivery efficiency is required. In this study, we designed and evaluated novel liposomes prepared from thermoresponsive polyoxazoline (POZ)-lipid conjugates (DSPE-POZ), cholesterol, and hydrogenated soybean phosphatidylcholine (HSPC). The obtained liposomes had a particle size of 50-60 nm and a slightly negative ζ-potential. POZ has a lower critical solution temperature (LCST), which enables liposomes to alter their physicochemical properties in response to mild hyperthermia. The fixed aqueous layer thickness (FALT) of the DSPE-POZ liposomes dramatically decreased above the LCST, indicating increased hydrophobicity of the liposomal surface. A cellular uptake study using mouse colon cancer cells (Colon26) demonstrated that DSPE-POZ liposomes containing POZ with an LCST of 37-38 °C were significantly highly taken up by tumor cells at 43 °C (above LCST) compared to 37 °C. Furthermore, biodistribution studies using Colon26 tumor-bearing mice revealed that DSPE-POZ liposomes were cleared from the blood and preferentially accumulated in heated tumors, achieving a 7-fold higher uptake than in nonheated tumors. These results indicate that liposomes composed of POZ-lipid conjugates represent a promising drug delivery platform capable of improving tumor accumulation when combined with local tumor heating.
Parallel-Competitive Absorption-Presystemic Metabolism Model for Subcutaneous Bioavailability Prediction of Monoclonal Antibodies.
Milewski M, Cueto MA, Murashov M … +2 more , Kapoor Y, Alidori S
Mol Pharm · 2026 May · PMID 41985526 · Publisher ↗
Monoclonal antibody therapeutics are often administered subcutaneously rather than intravenously to improve patient compliance and reduce healthcare costs. However, systemic absorption after a subcutaneous injection is o...
Monoclonal antibody therapeutics are often administered subcutaneously rather than intravenously to improve patient compliance and reduce healthcare costs. However, systemic absorption after a subcutaneous injection is often incomplete and variable. The bioavailability prediction model applied herein utilized a two-compartment pharmacokinetic framework in conjunction with parallel-competitive absorption and presystemic metabolism pathways. This study aimed to broaden the former validation of human bioavailability prediction by including linear and nonlinear-pharmacokinetics compounds. Validation was significantly expanded using a data set from 79 monoclonal antibodies (mAbs), spanning a bioavailability range of 29-100% (and a geometric mean bioavailability of 66%). By applying a single absorption rate constant alongside compound-specific estimates of presystemic metabolism rates, proportional to systemic clearance parameters, human subcutaneous bioavailability predictions were generated with a root-mean-square error (RMSE) of 13.1%. This mechanistic predictive method offers a preliminary estimate of subcutaneous bioavailability solely on the basis of pharmacokinetic data, which can be derived from intravenous administration.
Targeting of VISTA with Cyclic Peptide-Based PET Tracers for Immune Checkpoint Imaging.
Feng H, Tian X, Li X … +5 more , Duan L, Li B, Wu X, Gao Y, Wang X
Mol Pharm · 2026 May · PMID 41978961 · Publisher ↗
Given the distinct roles of VISTA in immune regulation, a better visualization of VISTA expression could clarify the tumor immune status and predict the responses to immunotherapy. However, only a few targeted probes are...
Given the distinct roles of VISTA in immune regulation, a better visualization of VISTA expression could clarify the tumor immune status and predict the responses to immunotherapy. However, only a few targeted probes are in development and insufficient to fulfill clinical demands. In this study, based on cyclic peptide antagonist AP1049, three novel radiotracers, [Ga]Ga-AP1049, [Ga]Ga-AHX-AP1049, and [Ga]Ga-Pip-AP1049, were designed and developed for targeting and imaging VISTA in cancers. Molecular dynamics simulation revealed the better binding of NOTA-Pip-AP1049 for VISTA protein than that of NOTA-AP1049 and NOTA-AHX-AP1049. Protein binding assays demonstrated their high specificity and affinity with IC values of 58.10, 23.34, and 17.56 nM, respectively. The B16-F10 tumor uptake of three tracers was significant and decreased over time within 120 min, with tumor uptake values of 1.02 ± 0.21, 1.56 ± 0.21, and 1.89 ± 0.29 %ID/cc and tumor/muscle ratios of 2.36 ± 0.36, 3.10 ± 0.51, and 4.06 ± 0.71 at 30 min post-injection, respectively. Their specificity were verified by blocking studies. Furthermore, [Ga]Ga-Pip-AP1049 PET could detect varying VISTA expression in B16-F10, 4T1, MC38, and CT26 xenograft models with tumor uptake values of 2.71 ± 0.43, 2.32 ± 0.44, 1.17 ± 0.30, and 0.85 ± 0.17 %ID/cc, which were in consistent with percentages of VISTA cells ( = 0.8712, < 0.0001). Biodistribution data suggested their renal excretion and favorable pharmacokinetics. In conclusion, [Ga]Ga-Pip-AP1049 is a promising tracer for PET imaging of VISTA expression in tumor microenvironment, indicating its potential as a companion diagnostic of immunotherapy.
Biotin-Decorated Inulin-Based Polymeric Micelles Unveil Their Dual-Targeting Ability for the Potential Treatment of Glioblastoma Multiforme through the and Investigations.
Riccobelli P, Cannone E, Filiberti S … +8 more , Ribaudo G, Bonini SA, Grigoletto A, Massardi ML, Codenotti S, Schiavone M, Ronca R, Mandracchia D
Mol Pharm · 2026 May · PMID 41973041 · Full text
This study evaluated biotinylated-inulin vitamin E micelles (INVITE-BIO) as a carrier for the hydrophobic drug curcumin and their biotin-mediated dual-targeting ability to the Blood-Brain Barrier (BBB) and Glioblastoma M...
This study evaluated biotinylated-inulin vitamin E micelles (INVITE-BIO) as a carrier for the hydrophobic drug curcumin and their biotin-mediated dual-targeting ability to the Blood-Brain Barrier (BBB) and Glioblastoma Multiforme (GBM) cells by and studies. We previously demonstrated that INVITE-BIO micelles are long-circulating carriers upon i.v. administration, remaining in the body for up to 48 h, making these nanosystems potentially useful for receptor-mediated targeted drug delivery. Here, we first report the physicochemical characterization of curcumin-loaded INVITE-BIO micelles, which revealed a nanosized and spherical shape, as evaluated by DLS and TEM. Moreover, INVITE-BIO micelles showed high loading capacity and good ability to release the payloaded curcumin, which is located in the core of micelles, as demonstrated by H NMR study. The bioavailability of biotin on the micelle's surface was demonstrated by HABA/avidin binding assay. Second, biological studies on GBM U87MG cells indicated that empty micellar carriers did not reveal any significant cytotoxicity and that the encapsulation of curcumin within the carrier can enhance the curcumin's efficacy, potentially by improving its bioavailability. Furthermore, confocal microscopy and flow cytometry studies revealed that the presence of biotin moieties is pivotal to enhancing the cellular uptake and retention of the INVITE nanosystems. In conclusion, INVITE-BIO micelles enhanced both the crossing of BBB and drug accumulation in GBM tumor cells overexpressing the receptor for biotin through receptor-mediated endocytosis, demonstrating the great potential of biotinylated INVITE micelles as a promising dual-targeted approach for i.v. administration of antitumoral drugs for the treatment of Glioblastoma Multiforme.
Ionizable Polymeric Micelles Targeting Transferrin Receptor 1 Enhance Systemic mRNA Delivery to the Brain.
Norimatsu J, Mizuno HL, Mochida Y … +4 more , Fukushima S, Uchida S, Cabral H, Anraku Y
Mol Pharm · 2026 May · PMID 41972602 · Full text
mRNA-based therapies hold immense potential for treating a plethora of diseases. However, their application to central nervous system (CNS) disorders remains limited due to biological barriers, such as rapid degradation...
mRNA-based therapies hold immense potential for treating a plethora of diseases. However, their application to central nervous system (CNS) disorders remains limited due to biological barriers, such as rapid degradation in circulation, restricted brain access, and endosomal entrapment within cells. To address these challenges, we developed a polymeric micelle-based nanocarrier capable of systemically delivering mRNA to the brain. This system employed triphenylphosphonium (TPP) as a cationic moiety to stably complex with mRNA and prolong its blood circulation. TPP was introduced into a PEG-polyaspartamide derivative bearing diethylenetriamines, whose pH-responsive ionizable amines facilitated endosomal escape. For brain targeting, antibody fragments against transferrin receptor 1 were conjugated to the PEG shell at a controlled density via click chemistry. This rational, multifaceted design enabled robust in situ protein production in the brain following systemic administration, achieving around a 10-fold increase compared to our initial formulation, while exerting lower impact on off-target expression in other organs. Our system offers a promising platform for systemic mRNA delivery to the brain, opening new avenues for treating CNS disorders.
g-CN Nanosheets as a Ferroptosis-Targeted Nanoprobe: Mitigating Iron Overload and Restoring Male Fertility Nrf2 Pathway Activation.
Wang L, Yang F, Ye Z … +5 more , Lu R, Wei J, Liu M, Chen G, Ding W
Mol Pharm · 2026 May · PMID 41964938 · Publisher ↗
Ferroptosis induced by iron overload has been recognized as a critical factor in germ cell damage and subsequent male infertility. However, current ferroptosis inhibitors are often constrained by systemic side effects an...
Ferroptosis induced by iron overload has been recognized as a critical factor in germ cell damage and subsequent male infertility. However, current ferroptosis inhibitors are often constrained by systemic side effects and limited targeting. Herein, we developed graphitic carbon nitride (g-CN) nanosheets as a multisite iron chelation strategy to inhibit iron overload-induced ferroptosis and prevent male reproductive dysfunction. Characterized by excellent stability and intrinsic fluorescence, the g-CN nanosheets enable specific iron ion (Fe and Fe) sequestration, exhibiting iron-responsive fluorescence quenching with remarkable selectivity and sensitivity. Both and studies confirmed that iron overload induces significant germ cell damage, whereas g-CN nanosheets treatment targeted ferroptosis the Nrf2 pathway, thereby preserving male reproductive function. Moreover, g-CN exhibited excellent biosafety, with minimal cytotoxicity and no adverse effects . These findings highlight the potential of g-CN nanosheets as a promising therapeutic platform for the treatment of ferroptosis-related diseases.
Nanostructured Lipid Carriers Enhance Brain Delivery and Antioxidant Efficacy of a Small-Molecule MAO B Inhibitor for Neurodegenerative Disease Therapy.
Mastrogiacomo R, Miniero DV, Rullo M … +12 more , Rizzi F, Minervini G, Panniello A, Striccoli M, Fanizza E, Comparelli R, Curri ML, Catto M, Liuzzi GM, Pisani L, Latronico T, Depalo N
Mol Pharm · 2026 May · PMID 41962139 · Full text
Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, urgently require new therapeutic strategies. Monoamine oxidase B (MAO B), a mitochondrial enzyme involved in oxidative stress and neurotransmit...
Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, urgently require new therapeutic strategies. Monoamine oxidase B (MAO B), a mitochondrial enzyme involved in oxidative stress and neurotransmitter metabolism, has emerged as a promising target for neuroprotection. A 5-substituted-1-indazole derivative (here referred to as compound ) has been recently identified as a potent and safe MAO B inhibitor with antioxidant and neuroprotective properties. Unfortunately, compound suffers from poor aqueous solubility and chemical stability under hydrolytic conditions, thereby limiting its therapeutic potential. To overcome these drawbacks, nanostructured lipid carriers (NLCs) were developed as delivery systems for compound . The coloading of luminescent carbon dots (CDs) together with compound within NLCs further enabled investigation into NLCs' ability to permeate through the artificial blood-brain barrier (BBB) model, allowing a quantitative evaluation of crossing efficiency. Delivery via NLCs resulted in a markedly higher fraction of compound crossing the BBB (∼26%) compared with the free molecule (∼2.6%). Encapsulation also retained antioxidant efficacy in SH-SY5Y cells, while the nanoformulations exhibited a good degree of cell tolerance, with viability remaining above 60% across the tested concentration range. These in vitro findings suggest that the proposed nanoformulation represents a promising strategy to enhance delivery of the investigated small molecule to the central nervous system (CNS), highlighting its potential application in neurodegenerative diseases (NDs).
Novel Gold-Functionalization of Liposomes and Its Impact on Cellular Uptake and Trafficking.
Margielewska A, Łuków K, Laroui A … +5 more , Marcinkowska M, Michlewska S, Gorzkiewicz M, Półtorak Ł, Klajnert-Maculewicz B
Mol Pharm · 2026 May · PMID 41960788 · Full text
Liposomes decorated with gold nanoparticles (AuNPs) represent multifunctional nanocarriers that combine high drug-loading capacity with the unique physicochemical properties of metallic nanoparticles. Here, we report a s...
Liposomes decorated with gold nanoparticles (AuNPs) represent multifunctional nanocarriers that combine high drug-loading capacity with the unique physicochemical properties of metallic nanoparticles. Here, we report a simple one-pot strategy for the controlled surface attachment of citrate-stabilized AuNPs to liposomes, based on the synergistic action of electrostatic and covalent interactions. This was achieved by incorporating two functional lipids: the cationic lipid DOTAP, providing a permanent positive surface charge that promotes electrostatic attraction toward negatively charged AuNPs, and the thiol-containing lipid DPSH, possessing a functional group known for stable Au-S bond formation. Simple mixing of AuNPs with DOTAP&DPSH liposomes resulted in a hydrodynamic diameter increase corresponding approximately to twice the AuNP diameter, a reduction in ζ-potential, and a red shift of the AuNP plasmon absorption maximum, confirming nanoparticle attachment. Adsorption of AuNPs onto lipid monolayers was further verified electrochemically at the electrified liquid-liquid interface. Biological studies demonstrated that AuNP decoration significantly enhanced cellular uptake. The effect was most pronounced after 24 h of incubation at a lipid concentration of 40 μg·mL in HeLa cells, where fluorescence intensity increased by approximately 60% compared to nondecorated liposomes. Confocal colocalization analysis indicated a reduced level of trafficking of LipoAuNPs to LysoTracker-positive compartments, suggesting altered intracellular processing. All formulations showed negligible cytotoxicity within the tested concentration range. This study provides mechanistic insight into AuNP-liposome conjugation and demonstrates that dual electrostatic-covalent anchoring improves cellular internalization while maintaining biocompatibility.
Advances in Delta-like Ligand 3-Targeted Diagnosis and Treatment.
Cao C, Nie H, Zhu J … +8 more , Zhang B, Cui Y, Liu Y, Liu Y, Wang M, Yang Z, Zhu H, Li N
Mol Pharm · 2026 May · PMID 41960617 · Publisher ↗
Neuroendocrine neoplasms (NENs) are rare clinical entities that have long posed significant challenges in diagnosis and treatment due to their high histological heterogeneity, a scarcity of effective therapeutic targets,...
Neuroendocrine neoplasms (NENs) are rare clinical entities that have long posed significant challenges in diagnosis and treatment due to their high histological heterogeneity, a scarcity of effective therapeutic targets, and consequently, limited treatment options. Delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch signaling pathway, plays a crucial role in neuroendocrine tumors and is highly expressed in malignancies such as small-cell lung cancer and small-cell neuroendocrine prostate cancer. With the continuous advancement of DLL3-targeted technologies in recent years, an increasing number of novel DLL3-targeted agents have emerged, offering diverse antibody and ligand platforms for both ImmunoPET imaging and targeted radionuclide therapy (TRT) in nuclear medicine. Meanwhile, DLL3 ImmunoPET imaging enables noninvasive molecular imaging-based stratification of patients with high DLL3 expression. The two modalities are mutually reinforcing and hold promise for advancing the precision diagnosis and clinical translation of DLL3-targeted strategies in NENs. This review summarizes recent key advancements in DLL3-targeted nuclear medicine and discusses future directions for DLL3 ImmunoPET imaging and TRT.
Sustained Release of Carvacrol Aldehyde from Hydroxyapatite for Osteosarcoma Inhibition.
Dahiya A, Bose S
Mol Pharm · 2026 May · PMID 41958190 · Full text
The clinical management of bone cancer and infections remains a critical challenge due to limitations in localized drug delivery and rising antibiotic resistance. In our previous studies, we demonstrated carvacrol's (CA)...
The clinical management of bone cancer and infections remains a critical challenge due to limitations in localized drug delivery and rising antibiotic resistance. In our previous studies, we demonstrated carvacrol's (CA) osteogenic and antibacterial potential when loaded onto 3D-printed TCP scaffolds. However, the rapid release and limited retention of CA restricted long-term efficacy. Herein, we develop a hydroxyapatite (HA) substrate to locally deliver CA and its aldehyde derivative (carvacrol aldehyde) (CA-CHO) to enhance its biological properties. CA-CHO is synthesized via SnCl-mediated ortho-formylation, introducing an aldehyde (-CHO) group that modulates drug-substrate interactions. Drug release kinetics exhibit a biphasic pattern, with CA showing 90% release, while CA-CHO demonstrates a controlled 50% release, within 10 days. Cell viability confirms that CA-CHO is not cytotoxic to osteoblast cells. JC-1 staining shows mitochondrial depolarization in osteosarcoma cells, leading to an ∼8-fold reduction in cell viability by day 11 compared to the HA. CA-CHO showed >90% inhibition of () at 72 h, compared to CA. This approach offers a biodegradable, antibiotic-free coating for orthopedic implants that simultaneously prevents infection and suppresses osteosarcoma recurrence.
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