搜索结果：Drug delivery

Graphene oxide (GO) has emerged as a versatile nanocarrier owing to its large surface area and rich surface chemistry; however, systematic studies correlating drug physicochemical properties with loading and release behavior remain limited, particularly for central nervous system (CNS) therapeutics. Herein, we present a comparative investigation of pH-responsive loading and release of two structurally distinct CNS drugs, d-cycloserine and riluzole, using graphene oxide as a common nanocarrier under identical experimental conditions. Drug loading efficiency and encapsulation efficiency were systematically evaluated as a function of pH, temperature, and initial drug concentration. GO exhibited a higher affinity for d-cycloserine, which is attributed to its greater polarity and hydrogen-bonding capability, whereas riluzole loading was primarily governed by π-π stacking and hydrophobic interactions. Both GO-drug systems displayed pronounced pH-responsive release behavior, with accelerated release under acidic conditions and sustained release at physiological pH. In vitro cytocompatibility studies using SH-SY5Y neuroblastoma cells demonstrated excellent biocompatibility for all formulations. This comparative study elucidates the critical role of drug chemistry in governing GO-drug interactions and provides design insights for graphene-based nanocarriers tailored for CNS drug delivery.

In a drug product, the major components by mass are the drug inactive ingredients (DIGs), which raises great concerns about their unwanted effects and clinical toxicities. It is demanded to unveil their proteome-wide bioactive landscape using computational methods. However, existing methods are impeded by either incapability to scan human proteome or inaccuracy in DIGs' bioactivity prediction. Here, a cross-attention transformer model, titled TransDIG, leveraging cross-module deep transfer learning was therefore developed to map the bioactive landscape of DIGs using minimal experimental data. First, the generalizability and interpretability of this model was verified by the prediction of zero-shot proteins and identification of key atoms/residues, respectively. Then, the bioactive landscape of hundreds of DIGs was unveiled using TransDIG, and thousands of potential bioactivities were found for the DIGs currently employed in pharmaceutical industry. Finally, the bioactivities of four popular DIGs were identified based on the landscape and experimentally validated by activity assay. As a result, the colorant β-carotene was validated to inhibit a critical drug transporter, and our study presented the first in vitro evidence of the bioactivity of the antioxidant dodecyl gallate that has not previously been reported to regulate any human protein. This study might offer insights for the design of drug formulation and its clinical utilization.

Non-invasive drug delivery for ocular diseases remains a significant challenge in ophthalmology, as conventional eye drops offer less than 5% bioavailability due to pre-corneal barriers and the corneal epithelium. This review explores the intranasal (IN) route as a promising strategy for targeting both the anterior and posterior segments of the eye. The IN route leverages several distinct pathways: the nasolacrimal reflex for remote physiological stimulation; the "neural bridge" through the cribriform plate, allowing direct perineural and vascular transport via the olfactory and trigeminal nerves to bypass the blood-retinal barrier; and systemic absorption that avoids hepatic first-pass metabolism. Pre-clinical evidence indicates that IN administration of agents such as erythropoietin, nerve growth factor, and insulin achieves superior retinal concentrations compared to topical or systemic dosing, offering neuroprotection in models of retinal degeneration and glaucoma. Clinically, varenicline nasal spray is already FDA-approved for dry eye disease, while intranasal steroids demonstrate a favorable ocular safety profile without significantly increasing intraocular pressure. Although limited by mucociliary clearance and small delivery volumes, the IN route offers a painless, non-invasive alternative to intraocular injections, potentially enhancing patient compliance. Future advancements in mucoadhesive nanocarriers are essential to optimize drug residence time and realize the full potential of nose-to-eye delivery in chronic ophthalmic care.

Advances in fetal diagnosis and molecular medicine have opened new opportunities for in utero molecular-targeted drug therapy, shifting fetal treatment from purely procedural interventions toward pharmacologic strategies that address disease mechanisms before irreversible organ damage occurs. In this review, we highlight recent advances in in utero drug therapy, focusing on molecular-targeted approaches with emerging clinical or trial-level evidence. Early clinical experience and ongoing trials have demonstrated the feasibility of achieving therapeutically relevant fetal drug exposure, although the strength of evidence varies considerably across therapeutic classes. However, significant challenges remain, including optimization of fetal drug delivery, characterization of fetal pharmacokinetics and pharmacodynamics, long-term safety assessment, and ethical considerations. The current evidence base ranges from single case reports to ongoing Phase 3 clinical trials, underscoring both the promise of prenatal molecular therapeutics and the need for further prospective evaluation. Continued integration of fetal imaging, genomics, ethics and pharmacology will be essential to advance safe and effective prenatal precision therapies.

Molecular glue degraders (MGDs) have emerged as a transformative modality in the field of targeted protein degradation (TPD), enabling the selective elimination of disease-relevant proteins, including those traditionally considered undruggable. Unlike bifunctional proteolysis-targeting chimeras (PROTACs), MGDs operate through monovalent architectures that induce protein-protein interactions (PPIs) between E3 ligases and neosubstrates, offering advantages in chemical simplicity, cell permeability, and target scope. However, MGD discovery remains serendipitously, and a translational framework that links rational design to predictable selectivity and tissue exposure is still lacking. In this review, we present an integrated framework for advancing next-generation MGDs through three critical dimensions: rational design, specificity optimization, and delivery systems. First, we examined cutting-edge strategies in MGD design, including covalent handle-based reprogramming, PPI-driven stabilization, and multi-site, multi-functional constructs. Second, we explored structure-guided engineering and chemoinformatic models, such as cereblon degron motifs, zone-based design and multiparameter optimization, to improve neosubstrate selectivity while minimizing off-target liabilities. Third, we summarized delivery platforms, including antibody‒drug conjugates, nanoparticle-enabled systems, and folate-mediated targeting, which are primarily intended to improve tissue selectivity and targeted distribution, thereby promoting local tissue accumulation. Finally, we discussed emerging opportunities at the intersection of artificial intelligence, structural biology, and systems pharmacology for accelerating MGD discovery and clinical translation. Collectively, these interdisciplinary insights underscore the therapeutic promise of MGDs and lay the groundwork for their next-generation evolution in precision medicine.

The objective of this study was to develop and optimize a dry powder inhalation formulation of Posaconazole-loaded Chitosan Nanoparticles (POS-CSNPs) using a Quality by Design (QbD) approach. The aim was to enhance pulmonary drug delivery and antifungal efficacy, particularly against Rhizopus oryzae, by improving drug encapsulation, particle dispersion, and lung deposition using leucine as a performance enhancer. A Box-Behnken Design (BBD) was employed to evaluate the effects of Chitosan-to- Tripolyphosphate (CS:TPP) ratio, stirring speed, and polymer concentration on particle size, Polydispersity Index (PDI), and Entrapment Efficiency (EE). Nanoparticles were prepared via ionic gelation and spray-dried with varying concentrations of lactose and leucine. Characterization techniques included FTIR for drug-excipient compatibility, Dynamic Light Scattering (DLS) for size and zeta potential, TEM for morphology, and XRD for crystallinity. In vitro drug release, pulmonary deposition using a twin-stage impinger, antifungal activity, and stability under ICH conditions were assessed. The optimized formulation had a particle size of 248.20 ± 6.82 nm, PDI of 0.225 ± 0.010, zeta potential of 21.92 ± 0.84 mV, and EE of 68.17 ± 1.73%. In vitro release showed sustained drug delivery over 48 hours. The Fine Particle Fraction (FPF) reached 68.9% in leucine-based formulations, and antifungal activity was significantly higher compared to the pure drug, with a zone of inhibition of 21 ± 0.5 mm. The results demonstrated improved particle characteristics, drug release, and antifungal efficacy. Leucine significantly enhanced dispersibility and deposition. However, scale-up and batch consistency remain challenges. Further in vivo studies are needed to confirm clinical applicability. The study successfully developed a stable, effective dry powder POS-CSNP formulation with enhanced pulmonary delivery and antifungal activity, offering potential for improved treatment of pulmonary fungal infections.

Biologic drugs, primarily comprising proteins and nucleic acids, have emerged as powerful therapeutic modalities; however, their discovery and optimization are often hindered by their inherent complexity. The advent of artificial intelligence (AI), particularly deep learning, is catalyzing a paradigm shift in this field, transitioning it from a process reliant on serendipity and laborious experimentation to a data-driven engineering discipline. This review systematically charts the co-evolution of AI methodologies and their transformative applications across the modern biologic drug development pipeline. We first outline AI's methodological progression, from language models deciphering biological sequence grammar to structure prediction models like AlphaFold making macromolecular folds computationally accessible, and finally to generative models enabling de novo molecular creation. We then explore the practical impact of these technologies in two core phases: the de novo design of novel biologics with bespoke functions and the subsequent multi-parameter engineering and optimization of these candidates for clinical viability. While the potential is immense, significant strategic challenges remain, including the need to build a new AI-native experimental ecosystem and bridge the profound complexity gap between molecular-level predictions and systemic in vivo outcomes. Overcoming these obstacles will usher in a new era of AI-driven, automated closed-loop drug discovery.

Somatostatin receptor 2 (SSTR2) is overexpressed in neuroendocrine tumors (NETs) and meningiomas. The objective of this study was to develop an SSTR2-targeted therapy to treat both tumors. We developed a humanized anti-SSTR2 monoclonal antibody demonstrating strong cancer cell binding, internalization in cancer cells, and tumor specificity, as evidenced by flow cytometry, confocal microscopy, and live-animal imaging. Antibody-drug conjugates were generated by conjugating the SSTR2 mAb with potent payloads, including monomethyl auristatin F or mertansine. In vitro assessments revealed high cytotoxicity across NET subtypes and meningioma cell lines. In vivo efficacy was confirmed in two mouse models, i.e. subcutaneous NET xenografts and intracranial meningioma xenografts, where treatment inhibited proliferation, induced apoptosis and cell death, exhibited minimal toxicity, and extended survival. The mechanism of action was further elucidated through bulk RNA sequencing after treatment. These findings highlight the therapeutic potential of our humanized SSTR2 mAb for targeted payload delivery in NETs and meningiomas.

The efficacy of polymer-based nanopesticides (NPs) is strongly governed by carrier concentration and surface charge, which affect shell thickness, drug release kinetics, and photostability. However, the influence of these two factors in pesticide release and delivery performance remains unclear. This study introduces a NIR-II fluorescence dye-tracing strategy to enable high-resolution monitoring of NP behavior in model plants. By systematically varying polymer concentration and copolymer blocks, we investigate their impact on release behavior, photostability, and stem uptake. As the polymer concentration increased, NPs demonstrated a controlled slow release and better photostability, yet a lower pesticide loading capability. In model plants, PISNPs transport quickly and can accumulate at wound sites, effectively offering antifungal properties. This work provides experimental evidence for optimizing polymer carrier design to achieve efficient, controlled release while minimizing photodegradation risks, offering practical guidelines for developing high-performance, low-risk nanopesticide formulations.

Posaconazole prophylaxis is indicated in high-risk patients with haematological malignancies to prevent invasive fungal diseases (IFDs) with guidelines advising steady-state posaconazole plasma concentrations (PPCs) above 0.5-0.7&#x2005;mg/L. Therapeutic drug monitoring (TDM), however, is not routinely recommended for posaconazole delayed-release tablet (DRT) prophylaxis. To describe PPCs in hospitalized high-risk patients with haematological malignancies treated for AML or undergoing allogeneic haematopoietic cell transplantation receiving posaconazole prophylaxis with posaconazole DRT and factors influencing exposure. This prospective, two-centre cohort study measured serial PPCs at Days 7, 14 and 21, and during diarrhoea episodes in adult high-risk patients receiving prophylaxis with posaconazole DRT between August 2019 and May 2023. Patients were followed during hospital admission and for 7&#x2005;days after the last dose of posaconazole or hospital discharge. Ninety-two patients contributed 223 PPCs. Subtherapeutic PPCs (<0.7&#x2005;mg/L) occurred in 77 (34.5%) samples and 49 (53.3%) patients recorded &#x2265;1 subtherapeutic PPC. The median Day 7 PPC was 0.84 (IQR: 0.47-1.16) mg/L, with no significant changes over time. In patients with diarrhoea compared with no diarrhoea, the median PPC was significantly lower [0.74 (IQR: 0.48-1.00) mg/L versus 0.92 (IQR: 0.64-1.40) mg/L, P&#x200a;=&#x200a;0.007]. Multivariate analysis identified older age (>60&#x2005;years) was protective against subtherapeutic PPCs. Six IFDs developed in five patients (5.4%) during follow-up and posaconazole-attributed hepatotoxicity resulted in cessation for one patient (1.1%). Subtherapeutic PPCs are common during posaconazole DRT prophylaxis, suggesting the need for routine TDM to optimize dosing in those receiving this posaconazole formulation.

Introduction: Pain is one of the most common reasons why patients seek medical care, and chronic pain is now recognized as a major health problem worldwide. Better understanding of pain mechanisms has shown the importance of distinguishing nociceptive, neuropathic, and nociplastic pain in order to choose the most effective treatment. In recent years, topical analgesics have gained increasing attention because they can provide pain relief directly at the site of application while reducing systemic exposure and the risk of adverse effects. This is especially important in older adults, patients with multiple diseases, and those exposed to polypharmacy. Methods: This narrative review presents the current knowledge on the pharmacology, efficacy, and safety of topical drugs used in pain treatment. Particular attention is given to topical non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, menthol, and camphor. The review also discusses newer and less established therapies used mainly in neuropathic pain, including topical ketamine, amitriptyline, phenytoin, gabapentin, and clonidine. A structured, non-systematic literature search was conducted using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases to identify studies evaluating the efficacy and safety of topical analgesic therapies. Results: Current evidence supports topical NSAIDs as first-line therapy for localized musculoskeletal pain and osteoarthritis, while lidocaine and high-concentration capsaicin patches are effective options in focal neuropathic pain. Although several newer topical therapies show promising results, more high-quality clinical studies are still needed. Overall, topical analgesia is an important part of multimodal pain management because it combines analgesic efficacy with a better safety profile compared with many systemic therapies. Conclusions: Taking the aspects discussed in this paper into account, it seems justified to search for new drug combinations that would contribute to effective pain therapy with topical agents. It is recognized that a multimodal approach to pain management, which utilizes drugs with different mechanisms of action, can increase efficacy and reduce the systemic adverse events of the drugs used. The effective and safe treatment of patients with pain, especially neuropathic pain, despite emerging new clinical trials, remains a challenge for clinicians.

RNA therapy represents an innovative approach for cancer treatment, with several RNA-based therapeutics having received approval from the US Food and Drug Administration. Circular RNA (circRNA), a closed-loop RNA molecule characterized by its high stability, plays a significant role in regulating biological processes by modulating gene expression and facilitating protein translation. Given its unique structure and diverse functionalities, the delivery of exogenous circRNA has emerged as a novel strategy for cancer therapy. This review examines the mechanism underlying circRNA-mediated tumor therapy, emphasizing its various biological roles, including that of an RNA sponge, aptamer, gene editing tool, and facilitator of protein translation, and explores the therapeutic potential in oncology. The review provides a comprehensive discussion on the synthesis strategies of exogenous circRNA, based on T4 DNA ligase and the permuted introns-exons (PIE) method, as well as elucidating the purification techniques. This article also reviews prominent carriers currently employed for circRNA delivery, such as lipid nanoparticle (LNP), exosomes, and virus-like particle (VLP), with a particular emphasis on their application in cancer-targeted therapies. Finally, the review summarizes key challenges currently in the field along with viable solutions. It highlights the prospective role of artificial intelligence in enhancing circRNA delivery to facilitate precise cancer treatment based on exogenous circRNA.

Urinary tract infections (UTIs), especially complex or recurrent cases, present a significant challenge. Systemic antibiotics often fail to provide adequate local drug concentrations, leading to limited efficacy and relapse. Local delivery is hindered by the bladder's dynamic environment, causing rapid drug clearance. To address this, a hydrogel scaffold, DRIVER (dual release, repair of tissues, immunomodulation, vesical adaptation, elimination of pathogens, and regulation of autophagy), is designed for sustained release in sync with the infection cycle. DRIVER forms a self-regulating 3D network through dynamic bonding and metal ion coordination, ensuring stable release and adaptability. It delivers a biphasic release profile comprising an initial antimicrobial burst that rapidly suppresses acute infection, followed by a 7-day sustained release phase. In vitro, DRIVER retained potent antibacterial and antifungal activity against planktonic, biofilm-embedded, and intracellular pathogens, including drug-resistant strains. Notably, the hydrogel also promoted bladder and kidney repair by modulating mitochondrial activity and autophagy, pathways essential for restoring urothelial integrity. DRIVER achieved >3 log reductions in bacterial and fungal burdens, normalized urinary function, and markedly attenuated systemic and tissue inflammation. Histological analyses confirmed robust architectural recovery in both the bladder and kidney. Together, these findings establish DRIVER as a compelling therapeutic strategy for complex UTIs.

Transdermal delivery of peptides and proteins remains a challenge in the field of drug delivery. In this study, we successfully prepared a series of bio-based ionic liquids by proton exchange reaction adopting green-sourced organic acids and alkaloids as precursors. In addition, we constructed a supramolecular assembly system by taking advantage of self-assembled short peptides (specifically, a custom amphiphilic sequence RRIIIIRR). We also optimized the basic properties of the ionic liquid by a combination of electron microscopy and simulation computation techniques, and the transdermal absorption efficiency of the self-assembled short peptide was successfully increased by 3-fold with the benefit of the pro-permeability properties. Furthermore, cell-level experiments demonstrate that the supramolecular assembly system not only maintains the activity of the self-assembled short peptide but also brings unexpected synergistic amplification effects. In conclusion, this creative system is simple, green, and safe, which can contribute to the application of peptides as well as the interdisciplinary crossover cooperations.

Targeted drug delivery in the gastrointestinal tract remains challenging because therapeutics must overcome multiple hierarchical barriers before reaching diseased tissue. Here, we present a multistage delivery platform that integrates magnetic microrobots, a pH-responsive protective coating, and platelet membrane-coated nanoparticles (PNPs) in one platform. A fillable design enables the formation of an internal magnetic layer for microrobot actuation, while the pH-responsive coating protects the cargo during transit and selectively degrades upon pH change, releasing cancer cell-targeting PNPs. In an in vitro colon cancer model that reproduces key gastrointestinal features, including flow, pH variation, and villi-like structures, this strategy increased nanoparticle retention and enhanced cancer cell cytotoxicity compared to nanoparticles administered alone. Ex vivo studies in porcine stomach and intestine further demonstrated robust locomotion on compliant and folded tissue surfaces. These results establish an environment-responsive hierarchical delivery strategy for more precise oral delivery in complex gastrointestinal settings.