Mol. Pharm. [JOURNAL]
Sun
200 papers
In Vivo Comparison of Site-Specific and Site-Selective Methods for Pretargeted Imaging in a Murine Model of Colorectal Cancer.
Zabrocki M, Delaney S, Hvass L … +3 more , Battisti UM, Kjær A, Herth MM
Mol Pharm · 2026 Mar · PMID 41705578 · Publisher ↗
Pretargeting based on the inverse electron-demand Diels-Alder reaction between a tetrazine and a -cyclooctene-modified (TCO) antibody has emerged as a powerful approach to the imaging and therapy of cancer. However, poor...
Pretargeting based on the inverse electron-demand Diels-Alder reaction between a tetrazine and a -cyclooctene-modified (TCO) antibody has emerged as a powerful approach to the imaging and therapy of cancer. However, poorly constructed immunoconjugates with TCOs in ill-defined places often leads to suboptimal image contrast in pretargeted immune-PET and SPECT. To address these limitations, site-specific and site-selective approaches to antibody bioconjugation may be used for pretargeted imaging. Herein, we present a comparative study between stochastically, site-specifically, and site-selectively modified immunoconjugates for pretargeted SPECT. First, a trio of immunoconjugates─TCO-CC49, TCO-CC49, TCO-CC49─were produced with active TCO moieties sufficient for tetrazine ligation. All immunoconjugates retained high affinity for their target antigen, TAG-72, in enzyme-linked immunosorbent assay experiments and in antigen-expressing tumor tissue. A DOTA-modified tetrazine was labeled with indium-111 in high radiochemical yield and used for in vivo experiments. Then, mice bearing subcutaneous LS 174T xenografts received either TCO-CC49, TCO-CC49, TCO-CC49 followed 72 h later by [In]In-DOTA-Tz (16-20 MBq). SPECT scans were acquired at 1 and 24 h postinjection of radiotracer, and all three constructs produced clear tumor delineation. Ex vivo biodistribution data at 24 h showed [In]In-DOTA-Tz-TCO-CC49 with the highest tumoral uptake (10.4 ± 1.2% ID/g) probably due to the highest TCO loading, but [In]In-DOTA-Tz-TCO-CC49 and [In]In-DOTA-Tz-TCO-CC49 increased tumor-to-blood and tumor-to-lung ratios. Ultimately, this comparative study serves as a critical step toward identifying the optimal bioconjugation strategy that may be used in pretargeted systems.
Investigating the Theranostic Potential of Elementally Matched [Sc]Sc-PSMA-617 and [Sc]Sc-PSMA-617.
Cingoranelli SJ, Putnam E, Houson HA … +4 more , Gimblet GR, Samuel S, Tekin V, Lapi SE
Mol Pharm · 2026 Mar · PMID 41705479 · Full text
UNLABELLED: The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Sc...
UNLABELLED: The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate Sc, the diagnostic nuclide, and Sc, the therapeutic nuclide, as a theranostic pair. METHODS: Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1-9 h. LNCaP tumor-bearing mice injected with [Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [Sc]Sc-PSMA-617. RESULTS: Sc and Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [Sc]Sc-PSMA-617. PET studies showed specificity of [Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [Sc]Sc-PSMA-617 up to 48 h. [Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [Sc]Sc-PSMA-617, showing that Sc PET data can predict therapeutic outcomes in individual animals from Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line. CONCLUSIONS: Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher Sc PET SUV was strongly correlated to therapeutic response from the Sc agent, demonstrating that Sc and Sc can be used as an elementally matched theranostic pair.
Hydrogen Bonding as a Failure Mechanism for Release of Ibuprofen-Copovidone Amorphous Solid Dispersions.
Cousineau ML, Deac A, Purohit HS … +3 more , Zhang GGZ, Gao Y, Taylor LS
Mol Pharm · 2026 Mar · PMID 41702853 · Publisher ↗
Amorphous solid dispersions (ASDs) are often used to increase the bioavailability of poorly water-soluble drugs. However, there are substantial formulation challenges associated with optimizing their performance. The hig...
Amorphous solid dispersions (ASDs) are often used to increase the bioavailability of poorly water-soluble drugs. However, there are substantial formulation challenges associated with optimizing their performance. The high polymer content needed to ensure rapid and extensive release creates a pill burden for patients, leading to lower compliance. To combat this problem, formulations with higher drug loading are desirable, but often have poor release. Previous research suggests that specific interactions between the drug and polymer can have a negative effect on ASD release, but the failure mechanisms are not fully understood. In this study, a model system of the low glass transition temperature drug, ibuprofen, and polyvinylpyrrolidone vinyl acetate (PVPVA) was used to investigate the mechanisms underlying poor release from an ASD with drug-polymer hydrogen bonding at high drug loading. Infrared spectroscopy was used to demonstrate the presence of hydrogen bonds between the carboxylic acid of ibuprofen and the pyrrolidone carbonyl group of PVPVA. ASD phase morphology following exposure to water, either via the vapor phase or following immersion in aqueous media, was studied using confocal fluorescence microscopy. Surface area normalized release studies of ASDs were performed at different drug loadings. Phase separation was readily induced following exposure to water vapor and was also observed following immersion in aqueous media. Furthermore, the resultant phase morphology varied with drug loading, changing from discrete drug-rich regions at low drug loading to continuous drug-rich regions at higher drug loading, explaining why release rate decreased dramatically with increasing drug load. Approximately 40% of PVPVA was present in the insoluble drug-rich phase, indicating a high affinity of the polymer for the drug in an aqueous environment, likely due to drug-polymer hydrogen bonding interactions. The presence of the polymer resulted in an increase in the volume of the insoluble drug-rich phase, underpinning the observed change in phase separation morphology at a relatively low drug loading. This study thus provides mechanistic understanding of the role played by drug-polymer hydrogen bonding in lowering the limit of congruency of PVPVA-based ASDs.
Mechanistic Study on Catechin-Derived Carbon Quantum Dots Promoting Wound Healing via Activating the MAPK/ERK-p38 Signaling Pathway.
E K, Wang X, Liu R … +5 more , Tao H, Zhang J, Han Q, Song Y, Wang G
Mol Pharm · 2026 Mar · PMID 41701903 · Publisher ↗
Nanomaterials have shown great potential in promoting wound healing; however, most studies focus only on describing their apparent functions, lacking an in-depth exploration of their underlying molecular mechanisms. This...
Nanomaterials have shown great potential in promoting wound healing; however, most studies focus only on describing their apparent functions, lacking an in-depth exploration of their underlying molecular mechanisms. This has significantly hindered their clinical translation and application. Herein, this study developed a nanomaterial, carbon quantum dots (Ct-CQDs), using natural catechin as a precursor, with a focus on systematically elucidating the precise molecular mechanism by which Ct-CQDs promote wound healing. Through comprehensive in vitro cell experiments, we confirmed that Ct-CQDs exhibit biosafety and the ability to promote cell migration. Meanwhile, this study is the first to reveal that Ct-CQDs promote wound healing by specifically activating phosphorylation of ERK and p38 in the MAPK signaling pathway. Innovatively, we used specific inhibitors (PD98059 and SB203580) to verify the mechanism both in vitro and in animal models, confirming that once the ERK/p38 pathway is blocked, the wound-healing-promoting effect of Ct-CQDs is significantly inhibited. In conclusion, this study provides a theoretical basis for the development of novel nano wound dressings based on natural products and offers solid theoretical and experimental support for their application as a nanodrug therapeutic strategy with clear mechanisms, high efficiency, and safety.
TRIPODD Enables Single-Cell Quantification of Therapeutic Efficacy.
McMahon NP, Solanki A, Montaño AR … +5 more , Ozdemir ES, Samkoe KS, Tichauer KM, Wang LG, Gibbs SL
Mol Pharm · 2026 Mar · PMID 41701619 · Full text
Targeted, small-molecule therapeutics have improved patient survival across cancer types, with >20 tyrosine kinase inhibitors (TKIs) receiving FDA approval as cancer therapies. While the initial TKI response is often pro...
Targeted, small-molecule therapeutics have improved patient survival across cancer types, with >20 tyrosine kinase inhibitors (TKIs) receiving FDA approval as cancer therapies. While the initial TKI response is often promising, it is typically transient due to tumor evolution and subsequent therapeutic resistance driven by primary or acquired resistance mechanisms. While resistance mechanisms vary, there are currently no spatially resolved methodologies that provide a quantitative, mechanistic understanding of drug delivery and therapeutic response across therapeutic modalities (e.g., chemotherapy, radiotherapy, TKIs, immunotherapy) to enable personalized cancer therapy. Herein, we utilize our previously reported fluorescence imaging platform, herapeutic esponse maging through roteomic and ptical rug istribution (), which is a quantitative protocol capable of interpreting the relationship between drug delivery and therapeutic response within the spatial context of a tumor to evaluate single-cell response and resistance to epidermal growth factor receptor TKI therapy. In this study, we applied TRIPODD to quantify the therapeutic response of EGFR-TKI-sensitive nonsmall cell lung cancer (NSCLC) xenografts to erlotinib, as a proof of concept for the platform. Through these studies, we were able to identify unique signatures of therapeutic response linked to the accumulation and engagement of erlotinib on a single-cell basis, demonstrating the utility of our TRIPODD platform technology in evaluating the treatment response and resistance at the single-cell level in heterogeneous tumors.
Regulation of CAF by α-Mangostin Promotes the Penetration of Nanomedicine and Inhibits the Metastasis of Breast Tumor.
Wang Y, Li X, Wang Q … +5 more , Chen Z, Qi C, Jiang X, Zhang Z, Feng X
Mol Pharm · 2026 Mar · PMID 41701112 · Publisher ↗
In the treatment of breast cancer, loading chemotherapy drugs into nanoparticles can accumulate in tumor tissues by virtue of the enhanced permeability and retention (EPR) effect, thereby reducing the systemic toxicity o...
In the treatment of breast cancer, loading chemotherapy drugs into nanoparticles can accumulate in tumor tissues by virtue of the enhanced permeability and retention (EPR) effect, thereby reducing the systemic toxicity of chemotherapy drugs and improving the therapeutic effect. However, the interior of solid tumors contains a dense extracellular matrix (ECM) composed largely of cancer-associated fibroblasts (CAFs), which severely hinders the deep penetration of drugs and limits their full therapeutic efficacy. Although the antifibrotic effects of α-mangostin (α-M) have been reported, its potential in remodeling the tumor microenvironment (TME) to synergistically enhance nanomedicine penetration and antimetastatic efficacy remains underexplored. For this reason, our study proposes a combined therapeutic strategy that inhibits the activity of CAFs through the antifibrotic drug α-mangostin, in order to promote better penetration of shikonin nanomedicine (NP/SHK) into the tumor tissue and enhance the therapeutic effect of breast cancer. Chitosan thermosensitive hydrogel loaded with α-M (HG@α-M) is designed to transform CAFs from an activated state to a quiescent state and reduce the deposition of ECM. In addition, we designed glutathione (GSH)-responsive nanomedicine (NP/SHK) carrying shikonin (SHK), which solves the problem of poor water solubility of SHK itself. In breast cancer model mice, compared with the single NP/SHK treatment group, the combined treatment down-regulated the expressions of CAF markers α-SMA and FAP-α by 52.70 and 56.77%, respectively, increased the tumor growth inhibition rate by 32.27%, and reduced lung metastatic nodules by 26.06%. This study effectively inhibited the growth and metastasis of tumors, providing a new and efficient combined treatment approach for metastatic breast cancer.
Macrophage Responses to Silica Nanoparticles: Role of Physicochemical Properties and Surface Modification.
Tonbul H, Arunachalam P, Adnan M … +4 more , Saha SK, Tunç CÜ, Khurana N, Ghandehari H
Mol Pharm · 2026 Mar · PMID 41700360 · Publisher ↗
Silica nanoparticles are widely studied nanomaterials for biomedical applications owing to their tunable physicochemical properties, such as size, porosity, geometry, and surface modification. Despite their promising pot...
Silica nanoparticles are widely studied nanomaterials for biomedical applications owing to their tunable physicochemical properties, such as size, porosity, geometry, and surface modification. Despite their promising potential, concerns regarding their safety continue to limit clinical translation. In this study, we systematically investigated how key physicochemical parameters and surface attachment of poly(ethylene glycol) (PEG) affect the cytotoxicity and immune activation profiles of silica nanoparticles in macrophages. A structurally diverse set of silica nanoparticles (rod, spherical, porous, nonporous, and surface-modified) was synthesized and characterized. RAW 264.7 macrophages were used as a model cell line to evaluate nanoparticle internalization, membrane integrity, apoptosis, cell cycle progression, and macrophage activation. While PEGylation and physicochemical variations significantly influenced both cellular uptake and maximum nontoxic dose, none of the tested nanoparticles impaired macrophage viability or baseline functionality at their respective saturation points. Notably, PEGylated silica nanoparticles approximately 100 nm in diameter and rod-shaped nanoparticles elicited pronounced immune activation, highlighting their distinct immunomodulatory potential despite the preserved cellular integrity.
Liposome-Encapsulated Carfilzomib as a Radiosensitizer in Solid Tumors.
Molinaro M, Saha P, Skrodzki D … +2 more , Machtay M, Pan D
Mol Pharm · 2026 Mar · PMID 41699819 · Full text
Chemoradiotherapy is a common treatment option for many cancers. Carfilzomib (CFZ) is an effective chemotherapeutic drug with a multitude of cellular effects. However, CFZ has yet to be studied in the context of chemorad...
Chemoradiotherapy is a common treatment option for many cancers. Carfilzomib (CFZ) is an effective chemotherapeutic drug with a multitude of cellular effects. However, CFZ has yet to be studied in the context of chemoradiotherapy. To study the application of CFZ in chemoradiotherapy, we synthesized CFZ-loaded liposomes. We report a novel liposomal formulation of the proteasome inhibitor CFZ designed to enhance tumor radiosensitivity while improving drug solubility and tolerability. CFZ-loaded PEGylated liposomes were synthesized via thin-film hydration and probe sonication, achieving an average diameter of ∼127 nm and an encapsulation efficiency of 64%. In murine 4T1 breast carcinoma cells, CFZ treatment prior to irradiation significantly reduced clonogenic survival (dose enhancement factor = 1.26) and increased γ-H2AX foci retention, indicating impaired DNA double-strand break repair. In a dual-flank Balb/cJ allograft model, local intratumoral administration of CFZ followed by ionizing radiation (8 Gy × 2) markedly suppressed primary tumor growth compared with monotherapies without inducing systemic toxicity. Although a strong abscopal effect on distant tumors was not observed, the combination treatment reduced the pulmonary metastatic burden relative to controls. Collectively, these results demonstrate that liposomal carfilzomib can act as an effective radiosensitizer, functioning through perturbation of DNA repair and modulation of the tumor response to radiation. This study highlights a translationally relevant nanotherapeutic approach for enhancing chemoradiotherapy outcomes in solid malignancies.
Overcoming Challenges in Dengue Vaccine Development: Advanced Delivery Approaches.
Sengupta A, Bhattacharyya J
Mol Pharm · 2026 Mar · PMID 41693158 · Publisher ↗
Dengue virus (DENV), comprising four antigenically distinct serotypes, remains a major global health problem. Vaccine development is hindered by immunological barriers, including antibody-dependent enhancement (ADE), ori...
Dengue virus (DENV), comprising four antigenically distinct serotypes, remains a major global health problem. Vaccine development is hindered by immunological barriers, including antibody-dependent enhancement (ADE), original antigenic sin, and the requirement for balanced, long-lasting immunity against all serotypes. This review focuses on emerging strategies that improve vaccine-induced immune memory through rational antigen design and advanced delivery systems. Nanoparticles, including lipid-based carriers, polymeric particles, and virus-like particles (VLPs), support antigen stability, promote dendritic cell (DC) uptake, and enhance delivery to the lymph node. Injectable hydrogels and responsive biomaterials provide sustained antigen release, promoting germinal center (GC) formation and memory B and T-cell memory responses. Targeted delivery using ligands for C-type lectins or mannose receptors further increases the antigen presentation efficiency. Potent adjuvants, including toll- like receptor (TLR) agonists (Poly I:C, CpG, and R848) and saponin-based molecules (QS-21, MPL), activate innate immune sensors and guide Th1-type adaptive responses. New vaccine formulations, including multiepitope peptide vaccines, mRNA and DNA constructs, and extracellular vesicle (EV)-based carriers derived from DCs or milk, offer cell-free, scalable, and immune system-activating platforms. Furthermore, approaches facilitate epitope identification, MHC-binding prediction, and immune response simulation. Collectively, these strategies address recent challenges and support the development of dengue vaccines that offer enhanced safety and durable immunity.
Combination with Immunocytokines Enhances the Anticancer Activity of Small Molecule Drug Conjugates and Radioligand Therapeutics Targeting Fibroblast Activation Protein.
Bocci M, Lucaroni L, Ravazza D … +7 more , Rotta G, Prodi E, Principi L, Gilardoni E, Neri D, Cazzamalli S, Galbiati A
Mol Pharm · 2026 Mar · PMID 41686207 · Publisher ↗
The targeted delivery of radionuclides and cytotoxic drugs represents a viable alternative to conventional chemotherapy, aiming to improve therapeutic efficacy and reduce systemic toxicity by selective accumulation of th...
The targeted delivery of radionuclides and cytotoxic drugs represents a viable alternative to conventional chemotherapy, aiming to improve therapeutic efficacy and reduce systemic toxicity by selective accumulation of the active payload at the tumor site. Our group has developed radioligand therapeutics (RLTs) and small molecule-drug conjugates (SMDCs) targeting fibroblast activation protein (FAP), a tumor-associated antigen abundantly and selectively expressed in the majority of solid human malignancies. Among these, Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE showed selective accumulation in FAP-positive tumors in murine models and demonstrated potent anticancer activity. To further enhance the therapeutic efficacy, combining targeted drugs with immunotherapy may provide synergistic benefits by engaging both direct tumor cell killing and immune system activation. In this work, we explored the combination of FAP-targeting cytotoxic and radioactive therapeutics with three different immunocytokines targeting the Extra Domain B (EDB) of fibronectin: L19-hIL2, L19-mIL12, and L19-mTNF. A therapy experiment in immunocompetent mice bearing low FAP-expressing tumors showed that the combination with L19-hIL2 potentiated the antitumoral activity of Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE. These results provided the motivation for the clinical development of these combinations for treating FAP-positive solid tumors.
Intracellular Fate of a Dual-Fluorescent Hydrophobic Ion Pair: Comparison of Lipid-Based Nanocarriers.
Koutná G, Werner L, Truszkowska M … +3 more , Richter LM, Kubová K, Bernkop-Schnürch A
Mol Pharm · 2026 Mar · PMID 41678770 · Full text
Effective intracellular trafficking and delivery of hydrophilic drugs remain challenging due to poor membrane permeability and limited encapsulation in lipid-based nanocarriers. To address this, we developed a dual-fluor...
Effective intracellular trafficking and delivery of hydrophilic drugs remain challenging due to poor membrane permeability and limited encapsulation in lipid-based nanocarriers. To address this, we developed a dual-fluorescent hydrophobic ion pair (HIP) by pairing a model fluorescent hydrophilic drug, Cascade Blue hydrazide, with the lipophilic probe DiA. The HIP was subsequently incorporated into three lipid-based nanocarriers─self-emulsifying drug delivery systems (SEDDS), nanoemulsions, and liposomes─to enable visualization and comparison of how formulation composition influences intracellular uptake and fate of a model hydrophilic drug surrogate delivered as an HIP complex. The complex showed a precipitation efficiency of 95% and an >8130-fold increase in lipophilicity compared to noncomplexed Cascade Blue hydrazide, which enabled incorporation into SEDDS (64.41 ± 0.26 nm), nanoemulsions (92.61 ± 1.27 nm), and liposomes (175.03 ± 3.18 nm). Dissociation studies revealed a strong medium dependence, with <10% release in FaSSGF but ∼60% in phosphate-rich FeSSIF. Cytotoxicity testing demonstrated >90% cell viability at 0.01% for all formulations after 24 h, confirming their biocompatibility under relevant conditions. Hemolysis assays showed negligible membrane disruption for SEDDS, while uptake studies in Caco-2 cells indicated that internalization was mainly energy-dependent, with modest effects observed after inhibition of clathrin- and caveolae-mediated pathways. Confocal laser scanning microscopy highlighted a formulation-dependent intracellular fate: SEDDS confined Cascade Blue to vesicular compartments while redistributing DiA to the plasma membrane, whereas nanoemulsions and liposomes enabled endosomal escape, dispersing Cascade Blue into the cytosol and relocating DiA to perinuclear and plasma membranes. Liposomes also showed residual uptake at 4 °C with membrane colocalization of DiA, supporting fusion as a complementary uptake mechanism.
Histidine as a Bridge: Fabricating pH-Sensitive and Target-Specific Hyaluronic Acid Nanoparticles via ZIF-8 for Drug Delivery.
Yan Y, Shi J, Zheng Z … +2 more , Shi X, Zhao X
Mol Pharm · 2026 Mar · PMID 41678538 · Publisher ↗
The self-assembly of hyaluronic acid (HA) into stable nanoassemblies remains a significant challenge. To address this, we report a novel strategy utilizing l-histidine (His) as a molecular bridge to integrate HA with a z...
The self-assembly of hyaluronic acid (HA) into stable nanoassemblies remains a significant challenge. To address this, we report a novel strategy utilizing l-histidine (His) as a molecular bridge to integrate HA with a zeolitic imidazolate framework-8 (ZIF-8). The key to this approach is the covalent conjugation of His to the HA backbone, which enables Zn from ZIF-8 to coordinate with the imidazole groups of His. This coordination facilitates the ZIF-8-induced assembly of HA into stable hybrid nanoparticles (HA-His/ZIF-8 NPs). The resulting system synergistically combines the CD44-targeting capability of HA with the pH-responsive dissociation of ZIF-8. These NPs demonstrated a high doxorubicin (DOX) loading capacity (0.34 mg/mg) and encapsulation efficiency (76.8%). Importantly, they exhibited controlled drug release with significant pH-dependency, achieving a cumulative release of 50.2% under weakly acidic conditions (pH 5.0) compared to only 12.4% at physiological pH (7.4). In vitro studies confirmed the target-specificity of the DOX-loaded HA-His/ZIF-8 NPs, which were efficiently internalized by CD44-positive MKN-45 gastric cancer cells via receptor-mediated endocytosis, leading to a potent cytotoxic effect (IC = 1.71 μg•mL). In contrast, the efficacy was significantly lower in CD44-negative SNU-216 cells (IC = 5.22 μg•mL). This work highlights the strategic use of His as a bridge to create a synergistic HA-ZIF-8 platform, offering a powerful and promising approach to the targeted therapy of CD44-overexpressing cancers.
Reduced-Resistances Model for Enhanced Drug Permeation via a Solubilizing Receiver Medium: A Mechanistic Study with Hollow Fiber Membranes.
Murray JD, Patel RP, Bennett-Lenane H … +3 more , O'Dwyer PJ, Griffin BT, Polli JE
Mol Pharm · 2026 Mar · PMID 41677118 · Full text
A solubilizing receiver medium has been documented to increase drug flux in vitro, but the mechanisms underlying this effect remain poorly understood. This study investigated these mechanisms and established a mathematic...
A solubilizing receiver medium has been documented to increase drug flux in vitro, but the mechanisms underlying this effect remain poorly understood. This study investigated these mechanisms and established a mathematical model to describe the increase in apparent permeability. Flow rate experiments were performed to quantify the individual boundary layer and membrane resistances associated with diffusion. The impact of nine solubilizing receiver additives, including surfactants, cyclodextrins, and bovine serum albumin, on the flux of griseofulvin was investigated. The increase in apparent permeability followed the rank-order, though not the magnitude, of the solubility enhancement in the receiver (Spearman's ρ = 0.93, < 0.001, = 20). The mechanistic model, termed the reduced-resistances model, demonstrates that a solubilizing receiver reduces diffusional resistance in the membrane and in the receiver-side boundary layer. At high ratios of receiver to donor solubility, a hyperbolic relationship was observed where diffusion through the donor-side boundary layer becomes rate-limiting. Additional drug cocktail permeability studies with antipyrine, phenytoin, and meloxicam confirmed the broader applicability of this model. These findings provide a framework for informed receiver selection in permeability assays and underscore the importance of considering the receiver medium when comparing results across experiments.
Preclinical Study of Carbonic Anhydrase IX and Prostate-Specific Membrane Antigen Bispecific Probe for Synergistic Targeting of Hypoxia and Neovasculature.
Chen Y, Zhang Z, Xiao Y … +6 more , Rao M, Yang Z, Wang Z, Zhang Y, Feng Y, Cai L
Mol Pharm · 2026 Mar · PMID 41676913 · Publisher ↗
The heterogeneous expression of tumor biomarkers limits the diagnostic performance of single-target imaging agents. Carbonic anhydrase IX (CAIX) is highly expressed in hypoxic regions of clear cell renal cell carcinoma (...
The heterogeneous expression of tumor biomarkers limits the diagnostic performance of single-target imaging agents. Carbonic anhydrase IX (CAIX) is highly expressed in hypoxic regions of clear cell renal cell carcinoma (ccRCC) and multiple solid tumors, whereas prostate-specific membrane antigen (PSMA) is specifically upregulated in tumor-associated neovasculature. Both targets have been implicated in tumor metastasis and poor clinical outcomes. This study aimed to design and evaluate a novel bispecific PET tracer, [Ga]Ga-PCA, targeting both CAIX and PSMA, with the goal of achieving improved tumor-specific uptake. Subcutaneous xenograft models were established in nude mice by inoculation with OS-RC-2, PC3-PIP, and HEK-293 cells. PET/CT imaging and biodistribution studies were performed following intravenous administration of [Ga]Ga-PCA. Target specificity was evaluated via competitive blocking assays employing excess unlabeled ligand. Immunohistochemical staining was performed to validate the expression profiles of the targets within the tumors. After being labeled with gallium-68, [Ga]Ga-PCA showed favorable physicochemical properties, such as a high radiolabeling yield (>80%), radiochemical purity over 95%, good stability in vitro, and an albumin-binding rate of 93.44 ± 0.81%. PET/CT imaging revealed pronounced and specific tracer accumulation in both OS-RC-2 and PC3-PIP tumor models. In OS-RC-2 tumors (PSMA/CAIX), the SUVmax (13.10 ± 0.84) was higher than those of the single-target tracers [Ga]Ga-DOTA-NY104 (5.31 ± 0.77) and [Ga]Ga-PSMA (2.31 ± 0.49) at 60 min postinjection. An excess of unlabeled DOTA-NY104, a PSMA-targeted ligand, or a mix of the two ligands can block the uptake of [Ga]Ga-PCA. These results demonstrate that the tracer can bind to both targets at once. In conclusion, [Ga]Ga-PCA is a bispecific PET tracer that targets both hypoxic tumor cells and tumor neovasculature by binding to both CAIX and PSMA. The probe exhibited significant specificity, advantageous imaging contrast, and robust blocking validation, indicating its potential for molecular imaging of malignancies, including clear cell renal cell carcinoma (ccRCC).
Copper-Based Nanoparticle Co-Loaded with Natural PD-L1 Inhibitor and 5-Fluorouracil for Enhanced Immunotherapy of Hepatocellular Carcinoma.
Huang H, Peng B, Zhao X … +2 more , Chen X, He D
Mol Pharm · 2026 Mar · PMID 41676880 · Publisher ↗
Despite the revolutionary breakthroughs in immunotherapy for hepatocellular carcinoma, its efficacy remains limited due to low tumor immunogenicity, insufficient immune cell infiltration, and an immunosuppressive tumor m...
Despite the revolutionary breakthroughs in immunotherapy for hepatocellular carcinoma, its efficacy remains limited due to low tumor immunogenicity, insufficient immune cell infiltration, and an immunosuppressive tumor microenvironment. To address these challenges, we developed a novel copper-based nanoparticle designed for the synergistic delivery of the chemotherapeutic agent 5-fluorouracil (5-FU) and the natural programmed cell death ligand 1 (PD-L1) inhibitor chrysin (Chr). This nanosystem facilitates the targeted accumulation of these drugs at the tumor site and enables the responsive release of 5-FU, copper ions, and Chr in an acidic environment, thereby synergistically activating antitumor immune responses through the induction of cuproptosis, promotion of immunogenic cell death (ICD), and downregulation of PD-L1 expression. In vitro experiments demonstrated that this nanoparticle reduced the half-maximal inhibitory concentration (IC50) for Hepa1-6 cells by approximately 3.0 times compared with the administration of 5-FU alone. In vivo experiments revealed significant tumor suppression effects with an inhibition rate reaching as high as 89.8%. Notably, this nanoparticle successfully activated systemic antitumor immunity, as evidenced by a dendritic cell maturation rate of 32.9% in lymph nodes and a CD8+ T cell infiltration rate of 28.3% within the tumor microenvironment. This study presents an efficient nanomedicine strategy that synergistically induces cuprotosis and ICD and inhibits PD-L1 expression, thereby providing a new direction for enhancing immunotherapy in hepatocellular carcinoma.
Multi-Targeting Effects and Orchestrated Induction of Multiple Cell Death Modalities by Silver-Copper Alloy Nanoparticles Functionalized Drug Nanocrystals in Cancer Cells.
Zhan H, Guo J, Song Q … +4 more , Tian X, Wang Z, Sha X, Liu B
Mol Pharm · 2026 Mar · PMID 41674488 · Publisher ↗
To combat multidrug resistance and cancer stem cell (CSC) persistence, we constructed a tumor-targeted nanoplatform integrating silver/copper alloy nanoparticles (Cu-Ag NPs) and camptothecin (CPT) nanocrystals for synerg...
To combat multidrug resistance and cancer stem cell (CSC) persistence, we constructed a tumor-targeted nanoplatform integrating silver/copper alloy nanoparticles (Cu-Ag NPs) and camptothecin (CPT) nanocrystals for synergistic multimodal therapy. The nanocomposite was fabricated by stepwise assembly of CPT nanocrystals, a polydopamine coating, and functionalization with Cu-Ag NPs plus a tumor-mitochondria dual-targeting peptide. It exhibited a hydrodynamic diameter of ∼152.67 nm, high colloidal stability, favorable photothermal performance, and pH/NIR-responsive drug release. Under NIR irradiation, it showed potent and selective cytotoxicity against triple-negative breast cancer cells (IC = 16.92 ± 0.22 μg/mL), with strong synergy (CI < 0.3) between inorganic Cu-Ag NPs and organic CPT. Actively targeting both cancer cells and mitochondria, it induced severe mitochondrial dysfunction─loss of MMP, ATP depletion, ROS burst, and mtDNA damage. Moreover, it acted as a potent cuproptosis inducer via exogenous copper, evidenced by FDX1 and DLAT downregulation (48.23% and 68.61%) and HSP70 upregulation (61.42%). Additional cell death pathways, including apoptosis, necrosis and pyroptosis, were also activated through nuclear DNA damage and plasma membrane rupture. Importantly, this nanoplatform effectively targeted stubborn breast CSCs, exhibiting an IC as low as 13.70 ± 0.36 μg/mL─attributed to the mitochondrial targeting and subsequent inhibition of robust oxidative phosphorylation within CSCs, which rely more heavily on this pathway than on glycolysis compared to conventional cancer cells. In summary, this work presents a novel "multi-targeting" therapeutic strategy that orchestrates mitochondrial dysfunction, cuproptosis, apoptosis, and pyroptosis via a chemo-photothermal combination, offering a robust and broad-spectrum approach to eradicate both conventional resistant cancer cells and refractory CSCs.
Cholesterolated Rapamycin Prodrug Liposomes Induce Antigen-Specific Tolerance and Enable AAV Redosing.
Li L, Huang W, Zhao Z … +8 more , Gao Y, Zhang R, Liao Z, Hu Y, Ma Q, Yang Y, Wang Y, Liu H
Mol Pharm · 2026 Mar · PMID 41674289 · Publisher ↗
Antidrug antibodies (ADAs) compromise the pharmacokinetics and efficacy of biologics and can trigger adverse reactions. We engineer a tolerogenic liposomal platform in which rapamycin is covalently conjugated to choleste...
Antidrug antibodies (ADAs) compromise the pharmacokinetics and efficacy of biologics and can trigger adverse reactions. We engineer a tolerogenic liposomal platform in which rapamycin is covalently conjugated to cholesterol (RAPA-chol) and formulated as nanoliposomes (RA-c@L) to induce antigen-specific immune tolerance to coadministered proteins. Covalent anchoring enables high drug encapsulation (>95%) and improves colloidal stability. In a three-dose weekly tolerization regimen with uricase, followed by a high-dose challenge, RA-c@L markedly suppresses ADA formation: by day 42, antiuricase IgG titers are reduced by 2.15-fold compared to uricase alone and 2.17-fold compared to free rapamycin. Responses to an irrelevant antigen (KLH) remain unchanged, indicating antigen specificity. Importantly, coadministration of RA-c@L with rAAV8-SEAP enables vector readministration, yielding approximately 2-fold higher sustained serum SEAP expression after the second dose compared to rAAV alone. Mechanistically, intravenously delivered RA-c@L preferentially accumulates in the liver and reshapes systemic immunity, with reduced splenic T follicular helper cells and germinal-center B cells and an expansion of CD4Foxp3 regulatory T cells. Together, these data show that RA-c@L establishes durable, antigen-specific tolerance to therapeutic proteins and facilitates AAV redosing, offering a practical strategy to mitigate ADA-mediated loss of efficacy in repeated biotherapeutic treatments.
Preclinical Evaluation of Ga-Labeled GSK3326595 for PRMT5 Expression with microPET-CT in Pan-Cancer.
Liu X, Sun L, Bai L … +3 more , Huang G, Li J, Song S
Mol Pharm · 2026 Mar · PMID 41672486 · Publisher ↗
PRMT5, a member of the arginine methyltransferase family, is mainly distributed in the nucleus and cytoplasm and is closely involved in tumorigenesis, development, and metastasis. Based on GSK3326595, we first designed a...
PRMT5, a member of the arginine methyltransferase family, is mainly distributed in the nucleus and cytoplasm and is closely involved in tumorigenesis, development, and metastasis. Based on GSK3326595, we first designed and synthesized a PRMT5-targeted precursor (DOTA-FZ-P5R). MOE simulation results indicated a strong binding affinity (KD ≈ 10) of DOTA-FZ-P5R toward PRMT5 (PDB: 4 × 61). The Ga-labeled tracer exhibited high RCP (>98%) and excellent stability. Western blot and cell uptake studies confirmed that PRMT5 was highly expressed in MDA-MB-231 and AsPC1 cells, while expression in A549 cells was comparatively low. Correspondingly, microPET-CT imaging demonstrated a significantly higher uptake of [Ga]Ga-DOTA-FZ-P5R in MDA-MB-231 and AsPC1 tumor-bearing mice compared to A549. At 30 min postinjection, uptake values were 3.47 ± 1.53%ID/g for MDA-MB-231, 3.63 ± 0.81%ID/g for AsPC1, and 1.53 ± 0.25%ID/g for A549. These results were consistent with PRMT5 expression levels confirmed by IHC, further validating the tracer's specificity and potential for imaging PRMT5 expression . [Ga]Ga-DOTA-FZ-P5R can dynamically visualize and quantify PRMT5 expression levels in real time across pan-cancer. This research demonstrates that [Ga]Ga-DOTA-FZ-P5R enables rapid imaging of PRMT5-positive tumors. The probe has significant potential to enable individualized and precise diagnosis in patients with PRMT5-positive tumors, define an optimal treatment window, assess therapeutic efficacy, and serve as a predictive imaging modality for tumor resistance.
Dual-Pathway Sequential Transcytosis Unlocks Enhanced Tumor Penetration and Efficacy of Mitochondria-Targeted Nanodrugs.
Zheng F, Chen Y, Song B … +4 more , Niu X, Liu D, Bai Y, Xu L
Mol Pharm · 2026 Mar · PMID 41671051 · Publisher ↗
The limited penetration of nanomedicines into tumor tissues remains a major obstacle to their therapeutic efficacy. To overcome this barrier, we designed a novel nanodrug that leverages receptor/cation dual pathway-media...
The limited penetration of nanomedicines into tumor tissues remains a major obstacle to their therapeutic efficacy. To overcome this barrier, we designed a novel nanodrug that leverages receptor/cation dual pathway-mediated transcytosis to achieve deep tumor penetration and targeted disruption of mitochondria, resulting in significantly enhanced antitumor outcomes. The multifunctional carrier, P1, was constructed through the synthesis of an amphiphilic block copolymer, terminal conjugation of the CRGDK peptide, and side-chain modification with 7-diethylaminocoumarin (DEAC) for mitochondrial targeting. Dynamic light scattering analyses confirmed the pH/ROS-responsive behavior of P1 micelles, including acid-triggered charge reversal. Drug release kinetics, cellular uptake and endocytic mechanisms, lysosomal escape efficiency, mitochondrial colocalization, induction of ROS generation, mitochondrial membrane potential (ΔΨ) depolarization, apoptosis induction, penetration in multicellular tumor spheroids (MTSs) and in vivo tumors, and antitumor efficacy (in vitro and in vivo) were systematically evaluated. Results indicated that DOX/P1 micelles initially target tumor tissue via CRGDK binding, followed by NRP-1-mediated transcytosis. Subsequent acidity-induced charge reversal activates a secondary cation-mediated transcytosis pathway, synergistically promoting deep tumor infiltration. Upon mitochondrial localization, the carrier undergoes ROS-triggered degradation, leading to concurrent release of doxorubicin (DOX) and cinnamaldehyde (CA) within mitochondria. This dual release acts synergistically to amplify oxidative stress, collapse ΔΨ, and induce mitochondrial DNA damage, collectively precipitating irreversible apoptosis. This study establishes a programmable platform for developing tumor-penetrating nanotherapeutics with precise subcellular organelle-targeting capabilities.
Ultrasmall Iron Oxide as an Imaging Nanoenzyme Loaded Autologous Exosomes for Targeted Imaging and Chemotherapy Promotion of Pancreatic Cancer.
Wu R, Jin L, Zeng A … +6 more , Xu K, Shen W, Ni J, Chen C, Zhu Y, Wang J
Mol Pharm · 2026 Mar · PMID 41665508 · Publisher ↗
Pancreatic cancer presents significant imaging challenges due to its poor vascularization, while the hypoxic tumor microenvironment further contributes to chemoresistance. To address these limitations, we engineered exos...
Pancreatic cancer presents significant imaging challenges due to its poor vascularization, while the hypoxic tumor microenvironment further contributes to chemoresistance. To address these limitations, we engineered exosome-ultrasmall iron oxide (Exo-USIO), a targeted exosomal nanoprobe encapsulating USIO nanoparticles (USIO NPs), designed to enable precise tumor imaging and enhance chemotherapy efficacy in pancreatic cancer. Exosomes derived from Panc-02 pancreatic cancer cells were isolated and loaded with USIO NPs via electroporation to synthesize Exo-USIO. The nanoprobe's targeting specificity, MRI contrast enhancement, and catalase-like activity (converting HO to O) were systematically evaluated. assays assessed cellular uptake, hypoxia modulation, and chemosensitivity, while studies validated tumor-targeted MRI imaging, hypoxia alleviation, and synergistic therapeutic effects with gemcitabine (GEM). Exo-USIO demonstrated a 2.3-fold increase in T-weighted MRI signal intensity compared to free USIO NPs ( < 0.01), alongside efficient enzymatic conversion of HO to O, significantly reducing HIF-1α expression ( < 0.05). Combined with GEM, Exo-USIO reduced tumor cell viability to 39.8% and suppressed tumor growth by 62% ( < 0.001). Biosafety evaluations revealed negligible systemic toxicity or metastatic risk. By leveraging exosome-mediated targeted delivery and the dual enzyme-mimetic activity of USIO NPs, Exo-USIO achieves dual functionality: enhanced MRI-guided tumor localization and catalytic alleviation of hypoxia to reverse chemoresistance. This strategy overcomes key limitations of the pancreatic tumor microenvironment, offering a translatable platform for precision theranostics.
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