Drug Delivery最新文献

Curcumin is renowned for anti-inflammatory, antioxidant and hepatoprotective effects, and has been implicated in the amelioration of obesity and diabetes. Notwithstanding its considerable therapeutic potential, the clinical utility of curcumin is hampered by its suboptimal bioavailability, due to poor aqueous solubility and chemical instability. Consequently, the development of strategies to enhance the aqueous solubility, stability, and ultimately, the bioavailability of curcumin has been a focal point of intense research. This study harnessed tetrahedral framework nucleic acids (tFNAs), a relatively simple DNA nanostructure, to encapsulate curcumin. Meanwhile, novel aptamers for liver-specific targeting were acquired by SELEX (Systematic Evolution of Ligands by Exponential Enrichment) method. By capitalizing on the unique properties of aptamers and tFNAs, an aptamer-mediated liver-targeted curcumin delivery system was constructed, with the goal of providing a more efficacious therapeutic approach for non-alcoholic fatty liver disease (NAFLD). This innovative delivery platform has not only markedly improved the solubility and stability of curcumin but has also significantly bolstered its therapeutic efficacy in the context of NAFLD. This research not only offers a novel approach for the delivery of curcumin but also presents a new therapeutic modality for NAFLD. Moreover, the implications of this research extend beyond curcumin, offering a blueprint for the liver-targeted delivery of other drug molecules.

Myocardial ischemia-reperfusion injury (MIRI), a frequent complication in acute myocardial infarction (AMI) treatment, arises from complex mechanisms including oxidative stress, inflammation, and mitochondrial dysfunction, which impair myocardial repair and recovery. Current therapies for MIRI offer limited efficacy and raise safety concerns, highlighting the need for innovative and precise treatment strategies in cardiovascular research. Ultrasound-targeted microbubble destruction (UTMD) is a promising therapeutic approach that enhances drug delivery precision to the myocardium. By utilizing ultrasound cavitation and nanodrug delivery, UTMD overcomes microvascular barriers, significantly improving drug bioavailability and therapeutic outcomes. It has demonstrated potential in modulating the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway to promote angiogenesis and enhance myocardial perfusion. In addition, it inhibits NOD-like receptor protein 3 (NLRP3) inflammasome activation, thereby reducing inflammatory responses and protecting the myocardium from reperfusion damage. The integration of radiomics and artificial intelligence (AI) further advances MIRI diagnosis and treatment. Real-time monitoring of myocardial blood flow and microcirculatory perfusion, combined with AI-driven image analysis, enables accurate assessment of myocardial injury and therapeutic efficacy, supporting personalized and precise therapy. Moreover, multi-omics technologies-such as single-cell RNA sequencing, proteomics, and metabolomics-combined with UTMD provide deeper insights into its therapeutic mechanisms, laying a robust foundation for clinical translation. This review summarizes recent progress in UTMD-based therapies for MIRI, emphasizing their roles in angiogenesis, immune regulation, precision diagnostics, and multi-omics analysis. It highlights new perspectives for future research and clinical applications in the management of MIRI.

To mitigate risks in central nervous system (CNS) drug development, we established a high-throughput in vitro blood-brain barrier (BBB) model using LLC-PK1-MOCK and LLC-PK1-MDR1 cells in a Transwell system, aiming to replicate in vivo brain distribution and elucidate permeability mechanisms. Model integrity was assessed via transepithelial electrical resistance (TEER) and efflux functionality using control drugs (atenolol, digoxin). Bidirectional transport studies of 41 compounds quantified permeability (P_app), efflux ratios (ER), and recoveries, while in vivo brain distribution parameters (K_p,uu,brain) were derived from literature and rat studies. The model demonstrated critical BBB features: tight junction integrity (TEER > 70 Ω·cm²), P-gp efflux activity (digoxin ER = 5.10 ~ 17.12), and discrimination of passive diffusion (63.41% of drugs) from transporter-mediated mechanisms (19.5% P-gp substrates). A training set of 20 randomly selected drugs revealed a robust correlation between MDR1-derived P_app(A-B) and K_p,uu,brain (R = 0.8886), with the remaining 21 compounds validating predictive accuracy (≤2-fold error). Four alkaloids exhibiting low recovery (<80%) due to lysosomal trapping were corrected using Bafilomycin A1, aligning their permeability with in vivo outcomes. These results position the LLC-PK1-MOCK/MDR1 model as a reliable surrogate tool for early CNS drug screening, enabling rapid prioritization of candidates based on BBB penetration potential. Its integration into preclinical workflows promises to accelerate the development of therapeutics for neurological disorders.

Noise-induced hearing loss (NIHL) involves a biphasic pathophysiology. Intense noise exposure causes immediate cochlear vasoconstriction and ischemia, leading to transient hypoxia. Subsequent reperfusion triggers excess reactive oxygen species (ROS) production, resulting in oxidative stress and hair cell injury. This study therefore developed two oxygenated albumin microbubble (OMB) formulations-ionic-bond metformin-coated (iMet-OMBs) and covalent-bond metformin-encapsulated (cMet-OMBs)-and combined them with transcranial ultrasound (US) to enhance targeted delivery to the cochlea. This approach aims to provide transient oxygen supplementation while simultaneously reducing ROS-mediated injury. Microbubbles were characterized for morphology, oxygen loading, and metformin content. Based on their superior stability and drug-loading profile, cMet-OMBs were selected for in vivo evaluation. In a mouse NIHL model, animals were administered cMet-OMBs systemically via retro-orbital injection, followed by US triggering over the temporal bone. Auditory brainstem response (ABR) thresholds, cochlear oxygen tension, and outer hair cell (OHC) survival were assessed. US-mediated cMet-OMBs rupture transiently increased intracochlear oxygen tension, counteracting early hypoxia after noise exposure. Metformin released from cMet-OMBs attenuated ROS production through mitochondrial complex I inhibition and antioxidant pathway activation. Mice treated with cMet-OMBs + US showed significantly lower ABR threshold shifts and better OHC preservation compared with controls. This dual-action strategy combines transient oxygen supplementation from OMBs with sustained antioxidant protection from metformin. While oxygen delivery raises intracochlear oxygen tension, metformin suppresses ROS generation through mitochondrial complex I inhibition and AMPK/Nrf2 activation. This controlled, US-triggered release achieves net cochlear protection against NIHL without excessive oxidative burden.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that requires innovative therapeutic strategies. This is the first study to evaluate the synergistic effects of LIPUS and CUR-AuNPs in an AD model, which aimed to investigate the effects of these therapies on learning, memory and neuroinflammation in mice with β-amyloid peptide (βA1-42)-induced AD. Sixty mice were divided into five groups: control, βA1-42, βA1-42 + LIPUS, βA1-42 + CUR-AuNPs, and βA1-42 + LIPUS + CUR-AuNPs. Treatments began 24 hours after induction and continued for 17 days using intranasal CUR-AuNPs (25  μg/mL) and transcranial LIPUS (0.8 W/cm², 1 MHz). The results demonstrated that the isolated therapies reversed memory deficits in the Y-maze and radial maze tests. However, the combined therapy group was able to reverse these deficits only in the radial maze. Electron microscopy confirmed the ability of CUR-AuNPs to cross the blood‒brain barrier, especially in the combined group, and no liver toxicity was observed. All the treated groups presented increased BDNF in the hippocampus and cortex. IL-1β and IL-6 levels are reduced in the cortex, while IL-1β and TNF-α levels are decreased in the hippocampus. IL-10 increased only in the hippocampus, while GSH levels increased in both regions. Combination therapy also reduced nitrite concentrations in the hippocampus and cortex and NFκB expression in the hippocampus. APP expression decreased exclusively in the LIPUS group in the hippocampus. These results suggest that although single treatments are effective, their combination enhances neuroprotective responses through the modulation of inflammation, oxidative stress, and neurotrophic signaling, suggesting promising potential for AD treatment.

The fast-growing filed of long-acting depots for subcutaneous (SC) administration holds significant potential to enhance patient adherence to treatment regimens, particularly in the context of chronic diseases. Among them, injectable in situ forming lyotropic liquid crystals (LCCs) consisting of hexagonal mesophases represent an attractive platform due to their remarkable highly ordered microstructure enabling the sustained drug release. These systems are especially relevant for peptide drugs, as their use is limited by their short plasma half-life and inherent poor stability. In this study, we thus aimed to exploit the potential of a liquid crystalline platform for the sustained release of peptide drug thymosin alpha 1 (Tα1), characterized by a short plasma half-life and with that associated twice-weekly SC administration regimen. We initially selected specified ingredients, with ethanol serving to reduce viscosity and stabilize the peptide drug Tα1, lecithin contributing to LCCs formation and stabilization, and glycerol monooleate or glycerol monolinoleate representing the hexagonal LCCs forming matrix material. The selected studied nonaqueous precursor formulations were characterized by suitable rheological properties for SC injection. A convenient and rapid in situ phase transition of precursor formulations to hexagonal LCCs, triggered by water absorption, was successfully accomplished in vitro. Notably, in situ formed LCCs demonstrated sustained release kinetics of the peptide drug Tα1 for up to 2 weeks of in vitro release testing, offering minimized dosing frequency and thus promoting patient adherence. In summary, the newly developed in situ forming liquid crystalline systems represent prospective injectable long-acting depots for SC administration of the peptide drug Tα1.

Objective: Antisense oligonucleotides (ASOs) have reached the clinic; however, they lack tissue specificity. Albumin is a plasma-abundant macromolecule that has been shown to accumulate in inflamed tissues. In this work, we have designed a recombinant human albumin (rHA)-based biomolecular assembly incorporating a DNase-resistant phosphorothioate-based complementary oligonucleotide (cODN) and an anti-ADAMTS5 ASO for potential delivery to inflamed sites. Ultrasound (US) was used to trigger ASO release from the assembly and enhance internalization into articular cartilage.

Methods: A phosphorothioate cODN was conjugated to rHA through a maleimide cross-linker after which, a therapeutic ADAMTS5-specific gapmer ASO was annealed to the cODN. ASO release was assessed after exposing the biomolecular assembly to different US conditions using an US-actuated medical needle operating at 32.2 kHz. Gene silencing efficiency of US-treated anti-ADAMTS5 ASO was assessed in human primary chondrocytes isolated from osteoarthritic patients. US-mediated ASO penetration into articular cartilage was assessed on ex vivo bovine articular cartilage.

Results: ASO release was observed after exposure to US waves in continuous mode conditions that did not compromise ASO gene silencing efficiency in human chondrocytes. Furthermore, US increased ASO internalization into bovine articular cartilage after 30 min of application without detrimental effects on chondrocyte viability.

Conclusion: A medical needle driven by continuous US waves at 32.2 kHz has the capability of disassembling a duplex oligonucleotide and enhancing released ASOs internalization into articular cartilage. This work offers the potential delivery and the local triggered release of ASOs at the surface of articular cartilage providing potential benefits for the treatment of diverse cartilage pathologies.

Drug-loaded liposomes incorporated in nanofibrous scaffolds is a promising approach as a multi-unit nanoscale system, which combines the merits of both liposomes and nanofibers (NFs), eliminating the drawback of liposomes' poor stability on the one hand and offering a higher potential of controlled drug release and enhanced therapeutic efficacy on the other hand. The current systematic review, which underwent a rigorous search process in PubMed, Web of Science, Scopus, Embase, and Central (Cochrane) employing (Liposome AND nanofib* AND electrosp*) as search keywords, aims to present the recent studies on using this synergic system for different therapeutic applications. The search was restricted to original, peer-reviewed studies published in English between 2014 and 2024. Of the 309 identified records, only 29 studies met the inclusion criteria. According to the literature, three different methods were identified to fabricate those nanofibrous liposomal scaffolds. The results consistently demonstrated the superiority of this dual system for numerous therapeutic applications in improving the therapy efficacy, enhancing both liposomes and drug stability, and releasing the encapsulated drug in a proper sustained release without significant initial burst release. Merging drug-loaded liposomes with NFs as liposomal nanofibrous scaffolds are a safe and efficient approach to deliver drug molecules and other substances for various pharmaceutical applications, particularly for wound dressing, tissue engineering, cancer therapy, and drug administration via the buccal and sublingual routes. However, further research is warranted to explore the potential of this system in other therapeutic applications.

Candida albicans is the most prominent conditional fungal pathogen, which can cause systemic candidiasis when an individual becomes immunocompromised. The widespread and long-term use of azoles like fluconazole (FLC) has led to a significant increase in drug resistance, posing substantial challenges to clinical treatment. In our previous study, benzyl isothiocyanate (BITC) was extracted from Carica papaya L. seed, and it exhibited a notable inhibitory effect against C. albicans. However, the application of BITC is restricted by its instability, poor water solubility, volatility, and easy degradation. This study aimed to prepare BITC-loaded nanostructured lipid carrier (BITC-NLC) to address these limitations of BITC and enhance antifungal efficacy in vitro and in vivo against C. albicans. The results of physicochemical properties showed that BITC-NLC had small particle size, good physical stability, and high encapsulation efficiency. In vitro, the antifungal effect of BITC-NLC was better than BITC against both sensitive and resistant C. albicans and better than FLC against resistant C. albicans. Moreover, in the in vivo experiment using systemic candidiasis mice model induced by resistant C. albicans, BITC-NLC was more remarkable than BITC and FLC in the increase of the survival rate and the splenic index, the reduction of the fungal burden, and the alleviation of the pathological damage. These findings may be attributed to the enhanced stability and sustained release of BITC. This study highlights the potential of BITC-NLC as a novel and effective formulation for the clinical treatment of drug-resistant C. albicans infections, thereby expanding the application scope of papaya.

Gene therapy has evolved into a clinically viable strategy, with several approved products demonstrating its therapeutic potential for genetic disorders, cancer, and infectious diseases, and it has ample applications in regenerative medicine. Its success depends on the ability to efficiently and specifically deliver therapeutic nucleic acids (NAs) into target cells. Although viral or chemical carriers have been used in pioneering applications, safety concerns, and variable delivery efficiencies have prompted the search for alternative delivery vehicles. Light-mediated strategies have gained particular interest due to their biocompatibility and ability to improve the intracellular delivery efficiency. In this review, we focus on recent advancements in the development of light-triggered NA delivery carriers and discuss how they can be designed to overcome specific intracellular barriers. Additionally, we discuss notable therapeutic applications and highlight challenges and opportunities for translating this technology to a clinical setting.