Molecular Pharmaceutics最新文献

Polysorbate 80 (PS80) is a commonly used surfactant for stabilizing biotherapeutics by preventing protein adsorption at the air-liquid interface. However, PS80 is susceptible to oxidative degradation during manufacturing and storage. We show here that light exposure combined with the presence of metals can result in byproduct formation and potentially decrease the surfactant's ability to prevent protein adsorption to the air-liquid interface. PS80 formulated in citrate buffer can undergo cis/trans isomerization of unsaturated fatty acids in the presence of disulfides and iron (Prajapati et al., 2022). This work investigates novel surface activity aspects of polysorbate formulations before and after exposure to UV-A light. Polysorbate samples of different grades were formulated in citrate buffer containing iron and glutathione disulfide (GSSG; as a surrogate for peptide and protein disulfides), and a Langmuir trough was used to monitor the surface pressure during adsorption to the air-solution interface. Our results showed significant changes in the polysorbate surface activity after photoirradiation: all-oleate PS80 exhibited a 3-fold increase in the apparent critical micelle concentration (CMC), and the presence of both cis and trans fatty acids was confirmed. Also, the impact of photoirradiation on surface pressure depended on the surfactant concentration during irradiation, suggesting that the presence of micelles can alter the degradation pathway and byproduct formation.

The blood-labyrinth barrier (BLB) is a selective endothelial barrier that maintains the homeostasis of the inner ear and protects it against toxic molecules and pathogens. This highly selective barrier represents a significant challenge for the delivery of therapeutic agents to the inner ear. To overcome this issue, various drug delivery methods have been developed. Among these modalities, microbubble-assisted ultrasound is an innovative and promising method for the noninvasive, targeted and efficient delivery of therapeutic agents through the round window membrane. The safety and the efficacy of this physical modality is strongly dependent on physiological properties of the targeted tissue, the pharmacological properties of the therapeutic molecules, the ultrasound parameters but also microbubble-related properties. The present review focuses on the current state of MB formulations and their use for the acoustically mediated inner ear drug delivery.

The complexity and dynamic nature of the tumor microenvironment (TME) pose significant challenges to effective cancer therapy. Therefore, the development of nanocomposites capable of fully exploiting TME characteristics is crucial for achieving precise and efficient tumor treatment. Herein, the cascade nanoreactor PDA@Mo₂C-MnO₂-Au/Apt-M (PMMAA) was successfully constructed based on Mo₂C MXene and nanozymes. This nanoreactor leveraged the TME to achieve NIR-II-triggered combined photothermal therapy and chemodynamic therapy (PTT/CDT) with active targeting capability. PMMAA exhibited a photothermal conversion efficiency of 41.89% under NIR-II laser irradiation, enabling efficient thermal ablation of tumor tissues. In the acidic TME, the loaded MnO₂ NPs mediated Fenton-like reactions that selectively converted endogenous H₂O₂ into highly cytotoxic ^•OH, realizing intelligent TME-responsive CDT. Notably, the embedded Au NPs in the nanoreactor exhibited glucose oxidase-like activity, catalyzing the conversion of glucose into H₂O₂ and gluconic acid, thereby simultaneously elevating both H₂O₂ levels and local acidity to establish a self-amplifying catalytic cascade. This nanozymes-based cascade amplification effect significantly enhanced CDT efficacy by promoting ^•OH generation. Systematic evaluations demonstrated that the nanoreactor possessed dual enzyme-mimicking activities (POD-like and GOx-like), excellent biosafety, and remarkable tumor suppression effects. This study established a new paradigm for precision cancer therapy through the rational design of multifunctional nanozymes-enhanced CDT capable of dynamically modulating the TME.

Periodontitis represents a persistent inflammatory condition marked by the irreversible destruction of the alveolar bone, eventually leading to tooth loss. The ideal treatment for periodontitis involves three key steps: antibacterial treatment, inflammation control, and periodontal regeneration, ultimately leading to the complete restoration of alveolar bone and the full recovery of periodontal function. However, current periodontitis treatments cannot comprehensively solve these issues. In this study, a ginseng-derived exosomes (GEXs)-loaded injectable hydrogel (GEXs@Gel) was designed. GEXs@Gel was thermosensitive with good fluidity, capable of conforming to the intricate contours of periodontal pockets, while withstanding the persistent wash of gingival crevicular fluid. In vitro studies showed that GEXs and GEXs@Gel can inhibit the growth of periodontal pathogenic bacteria, effectively remove biofilms, promote the polarization of macrophages to the anti-inflammatory (M2) phenotype, and alleviate cellular oxidative stress. In particular, GEXs@Gel had the functions of promoting bone/angiogenesis and regeneration. In vivo studies showed that GEXs@Gel effectively inhibited inflammation, promoted alveolar bone regeneration, and effectively reversed periodontitis. In summary, GEXs@Gel offers a promising strategy for the treatment of periodontitis.

Copper (Cu), as an essential trace element, participates in various physiological processes through strict homeostatic regulation. Abnormal intracellular copper accumulation can cause multiple forms of copper-dependent cell death (including apoptosis, autophagy, ferroptosis, and the recently identified cuproptosis) and disrupt cellular functions, which emphasizes the importance of maintaining copper homeostasis. This review aims to outline the connections between the copper homeostatic regulatory network and different copper-dependent cell death pathways, exploring their potential for understanding disease mechanisms and developing targeted therapies. Therefore, this review systematically discusses copper homeostasis, copper-related diseases, copper-dependent cell death, and the associated mitochondria-dependent mechanisms. Additionally, we highlight the implications of various copper-dependent cell death processes in diseases (such as Menkes disease, Wilson disease, neurodegenerative disorders, and cancer), as well as the potential role of copper-induced cellular proliferation (cuproplasia) in tumor progression. As our understanding of copper metabolism regulation deepens, strategies targeting copper-associated cell death, including copper-based nanobiomaterials and targeted drug delivery, show promise as emerging therapeutic approaches for multiple diseases. Future research should further elucidate the links between copper-dependent cell death and disease, not only to understand the underlying mechanisms but also to develop nanomedicine-based interventions, alongside assessments of the feasibility and safety of restoring copper homeostasis in clinical practice.

Pharmaceutical companies place significant importance on the liver due to its crucial role in numerous biochemical processes, specifically in drug metabolism. This focus has led to significant progress in liver-on-a-chip (LoC) technology, which has proven useful not only in drug development but also in more advanced applications. As a result, elaboration and incorporation of advanced LoC models into preclinical workflows have great potential to decrease R&D expenses and reduce or even replace animal testing, while improving the safety and efficacy of new therapies. To explore this potential, the present review provides an overview of recent academic and commercial LoC models, examines their different designs and cellular compositions, and evaluates the advantages and disadvantages of their complexity. A systematic comparison of these models is then performed, along with a discussion of their current challenges and future perspectives. Ultimately, we hope this review will assist scientists and industry professionals in selecting optimal models and in contributing to future advancements in LoC technology.

Our study aims to develop a novel ¹⁸F-labeled fibroblast activation protein inhibitor (FAPI) probe, ¹⁸F-NOTA-R49, and validate its diagnostic performance across multiple cancers in both preclinical and clinical studies. ¹⁸F-NOTA-R49 was synthesized through chemical methods, and its in vitro affinity, internalization characteristics, and specificity were evaluated in FAP-overexpressing cells HEK-293-hFAP and U-87 MG. Tumor-bearing mouse models were established to assess in vivo targeting and pharmacokinetics via small-animal PET/CT imaging and biodistribution studies. Ten patients with various cancers were enrolled in a clinical study comparing lesion-detection capabilities of ¹⁸F-NOTA-R49 and ¹⁸F-FDG PET/CT. In vivo studies showed significant early uptake in FAP-positive tumors (29.36 ± 1.49%ID/g at 0.5 h), which was effectively blocked by unlabeled NOTA-R49. Clinically, ¹⁸F-NOTA-R49 exhibited superior lesion contrast compared to ¹⁸F-FDG in gastric cancer, mesenchymal tumors, prostate cancer, seminoma, and pancreatic cancer, particularly in peritoneal and lymph node metastases. ¹⁸F-NOTA-R49 demonstrates high affinity and specificity and excellent tumor-targeting properties. It shows better diagnostic efficacy than ¹⁸F-FDG in various malignant tumors, indicating a significant clinical translation potential.

Accurate prediction of the pharmacokinetic (PK) properties of small-molecule drug candidates is a critical aspect of pharmaceutical research. Fast and reliable PK predictions can accelerate compound optimization cycles, reduce animal testing, and enhance the quality of molecules advancing to human studies. Although physiologically based PK (PBPK) models are well-established for compound selection, their application in early discovery faces limitations due to low throughput and the requirement for substantial in vitro data. Recently, high-throughput PBPK (HT-PBPK) methods have become possible, offering scalable, parallel PBPK simulations that can be executed on thousands of compounds within minutes. Additionally, advancements in machine learning (ML) have enabled the substitution of in vitro data by high-quality in silico predictions that are based solely on chemical structures. In this study, the performance of a corporate HT-PBPK application, called SwiftPK, that leverages the HTPK simulation module included in a commercial software package was evaluated for predicting ten primary and secondary PK endpoints for a large (>9000 compounds) set of rodent PK data. Utilizing a corporate ML pipeline, all in vitro parameter inputs were replaced with in silico predictions. This approach is particularly relevant for early stage project phases, such as lead identification, as well as for external collaborations where experimental data are unavailable. The findings demonstrate the highly predictive performance of the HT-PBPK approach, with most endpoints predicted within a three- to four-fold error. Performance improves after filtering for compounds that are predicted, based on structure alone, to be cleared by hepatic metabolism (Extended Clearance Classification System class 2) and when using ML inputs that demonstrate high confidence. The results highlight the key prerequisites for successful application in early phase projects: predicted primary elimination pathway accuracy and prediction quality. This study is expected to inspire more organizations to incorporate HT-PBPK into their discovery pipelines, expediting the development of safe and effective novel medicines for patients.

Renal fibrosis, a central pathological feature in chronic kidney disease progression, is marked by aberrant myofibroblast activation and excessive extracellular matrix deposition. Currently, no effective therapies are available to reverse this condition. Although celastrol (CEL) exhibits potent antifibrotic activity, its clinical application is hindered by poor solubility and significant systemic toxicity. To overcome these limitations, we developed a CD44-targeted and reactive oxygen species (ROS)-responsive nanoparticle (CEL@CB) for targeted renal delivery. The nanoparticle was constructed by conjugating bilirubin (BR) to chondroitin sulfate (CS), creating an amphiphilic CS-BR conjugate that self-assembles into nanoparticles capable of encapsulating CEL. The CS shell enables active targeting of CD44 receptors, which are highly overexpressed on activated renal myofibroblasts, while the BR core responds to elevated ROS levels in fibrotic kidneys, triggering drug release and simultaneously scavenging ROS to alleviate inflammation. Both in vitro and in vivo studies demonstrated that CEL@CB nanoparticles facilitate targeted CEL delivery to activated myofibroblasts, achieving a drug accumulation in fibrotic kidneys more than 2-fold higher than in healthy controls. Treatment with CEL@CB reduced the expression of key fibrotic markers (α-SMA and Col1a1) by approximately 30-70% at both mRNA and protein levels and decreased serum creatinine and blood urea nitrogen (BUN) levels by about 50%, thereby significantly attenuating folic acid-induced renal fibrosis, restoring renal function, and mitigating histological damage. Importantly, this targeted strategy markedly minimized the toxicity to the heart, testis, and hematological systems associated with free CEL. This dual-functional nanoparticle combines CD44-mediated renal targeted delivery with ROS-responsive drug release, offering a novel approach for antifibrotic therapy.