Drug Delivery最新文献

The chemotherapeutic drug doxorubicin (DOX) has been demonstrated to trigger pyroptosis in tumor cells at exceptionally high concentrations. Nevertheless, the administration of DOX at suprapharmacological doses could cause acute off-target cytotoxicity and severe adverse effects. Herein, a biflavonoid derivative, F24, was found to improve the sensitivity of hepatocellular carcinoma (HCC) cells to low-dose DOX and reduce the adverse effects of DOX. We demonstrated that F24 synergized with low-dose DOX to increase pyroptosis and autophagy in HCC cells through dual-target CDK6 inhibition/p53 activation at a proper ratio. To achieve this synergistic effect, nanodiscs with large hydrophobic cavities were selected to codeliver the low-dose hydrophobic drugs DOX and F24 (DOX-F24@Nanodisc, DF@N), which improved the tumor accumulation of the two drugs and ensured precise drug ratio integrity within the tumor cells. DF@N can trigger gasdermin-E (GSDME)-based pyroptosis in tumor cells, accompanied by the cleavage of caspase-3. Strikingly, knocking out GSDME or caspase-3 redirected DF@N-driven cellular death from the pyroptosis pathway to the apoptotic pathway. Furthermore, DF@N administration suppressed tumor growth and activated pyroptosis in a Huh7 mouse xenograft tumor model. Overall, F24 was found to induce autophagy by targeting CDK6 and had a synergistic effect on DOX-induced pyroptosis. These results indicate that the pyroptosis-induced DF@N nanodisc system provides an effective and secure therapeutic strategy for treating HCC.

Photodynamic therapy (PDT) represents a promising noninvasive modality for the selective targeting of tumors. However, its clinical utility is often constrained by the aggregation-induced quenching of photosensitizers and suboptimal reactive oxygen species (ROS) generation. In contrast, gene therapy has exhibited potent antitumor efficacy through the specific silencing of oncogenic targets. In this study, we developed a cationic photosensitizer-based nanocarrier, PEI-PEG-PpIX, designed to deliver the shRNA-BLM plasmid (p-shBLM). The PEI-PEG-PpIX/p-shBLM complex demonstrated a threefold increase in ROS production compared to free PpIX, along with a 57.5% enhancement in transfection efficiency. When this method was combined with photodynamic therapy for the treatment of neuroblastoma, the system significantly suppressed tumor cell proliferation, resulting in an 83.67% tumor growth inhibition rate in murine models. This outcome effectively demonstrates the synergistic integration of gene therapy and photodynamic therapy. Furthermore, the multifunctional nature of this platform enables real-time tumor imaging, thereby facilitating image-guided diagnosis and therapeutic monitoring. Overall, this strategy presents a noninvasive, efficient, and targeted approach to cancer treatment, offering valuable insights for future translational applications.

Ischemic stroke represents one of the leading causes of disability and death worldwide. Neuroprotection aimed at mitigating oxidative stress and inflammation is crucial for improving the prognosis of patients. However, the inadequate accumulation of drugs at the ischemic site significantly restricts their clinical efficacy. We found that platelet membrane (PLTM)-biomimetic nanosystems loaded with curcumin (Cur@PLTM) and tideglusib (Tid@PLTM) actively targeted the ischemic brain and facilitated transcytosis into the ischemic parenchyma via caveolin-dependent transcytosis, mimicking the recruitment of platelets in damaged cerebral vessels. This represented the first application of tideglusib nanoformulations in treating ischemic stroke, further demonstrating that the therapeutic effects were associated with M2 microglia regulation. Additionally, Cur@PLTM and Tid@PLTM synergistically scavenged reactive oxygen species (ROS) and promoted the secretion of neuroprotective cytokines via redox and cellular regulatory mechanisms to mitigate ischemia/reperfusion (I/R) injury. Overall, this platelet membrane-biomimetic nanosystem offers a prospective strategy for targeted brain delivery and combined treatment through antioxidative and anti-inflammatory approaches against ischemic stroke.

Sonodynamic therapy (SDT) has emerged as a promising approach for treating hepatocellular carcinoma (HCC) by combining sonosensitizers with low-intensity ultrasound. However, SDT alone could not achieve satisfactory results. Here, we developed novel nanobubbles loaded with hematoporphyrin monomethyl ether (HMME@NBs) and evaluated its therapeutic potential in combination with the glycolytic inhibitor lonidamine (LND) against HCC. The HMME@NBs was successfully prepared with particle size of 410.58 ± 20.07 nm and zeta potential at -8.38 ± 1.12mV. The encapsulation efficiency and loading efficiency of HMME was 80.6% and 7.12%, respectively. Both in vitro and in vivo studies demonstrated that while SDT and LND monotherapies inhibited the growth of HepG2 cells and xenograft tumors in nude mice, the combination therapy exhibited the most significant inhibitory effect. Multi-omics analysis of tumor tissues revealed substantial alterations in metabolites and gene expression, with key pathways such as glutathione metabolism implicated in the treatment response. Our findings highlight the enhanced antitumor efficacy of HMME@NBs-mediated SDT combined with LND, supported by mechanistic insights from transcriptomic and metabolomic profiling. This synergistic strategy holds great potential for HCC treatment.

Oral delivery is the most preferred route for accessing bioactive peptides and proteins for disease treatment from the patient's viewpoint. However, this is a great challenge because orally administered peptides and proteins are susceptible to the harsh gastrointestinal (GI) environment, various metabolic enzymes, and thiol/disulfide exchange reactions, and they cannot permeate the intestinal mucus and epithelial barriers. The self-emulsifying drug delivery system (SEDDS) has recently gained prominence because of its potential in the oral delivery of peptides and proteins. Stable payloads of hydrophilic proteins can be achieved in SEDDSs using feasible lipidization techniques, especially hydrophobic ion pairing. Upon entrapment in oily droplets derived from SEDDSs, protein drugs can be protected against enzymatic degradation and thiol/disulfide exchange reactions in the GI tract. After optimizing functional excipients and developing an efficient combination strategy, SEDDS droplets exhibit high mucus and membrane permeability and further enhance drug absorption and transport. The desired oral bioavailability and therapeutic effects of peptide and protein drugs could be achieved in vivo. This review presents the progress in the development of multifunctional SEDDSs for oral peptide and protein delivery. However, with the introduction of more novel multifunctional auxiliary agents and complicated structures to new-generation SEDDSs, more work is needed to identify the effects of excipients in the optimized combination and increase our knowledge of the fate of the excipients and the nanocarrier during absorption and transport. This knowledge will facilitate the future development of multifunctional SEDDSs for the oral application of therapeutic peptides and proteins.

To evaluate the comparative effectiveness, safety, and patient acceptance of needle-free injectors and insulin pens through a meta-analysis. A thorough literature search was performed across multiple databases, including CNKI, the Weipu Database, the Wanfang Database, PubMed, Embase, and The Cochrane Library for randomized controlled trials (RCTs) on the use of needle-free injectors and insulin pens in diabetes treatment, with a time frame from database inception until June 2024. Five researchers carefully screened the literature in accordance with the inclusion and exclusion criteria, assessed study quality with validated tools and conducted the meta-analysis using RevMan 5.4. This study included 22 publications encompassing 22 studies, involving a total of 2,580 patients, with 1,290 in the needle-free group and 1,290 in the insulin pen group. The findings suggest that needle-free injectors were superior to insulin pens in improving treatment efficacy, local adverse reactions, and increasing patient acceptability, with statistically significant differences. However, no significant variations were observed in continuous glucose monitoring. Needle-free injectors can improve certain aspects of glycemic control, such as reducing HbA1c, FPG, and 2hPPG; improve local adverse reactions and increase patient acceptability. However, improvements in glycemic variability metrics were not statistically significant, indicating that further research is needed to fully assess their long-term safety and therapeutic effectiveness. In terms of systemic safety, the risk of hypoglycemia in the needle-free group was not significantly different from that in the needle group (P = 0.14). Additionally, our publication bias analysis revealed potential biases in the outcomes related to hypoglycemia and insulin dosage.

The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.

Cell membranes present barriers to the intracellular delivery of therapeutic agents. This impediment is frequently exacerbated by the hydrophobic characteristics of many such molecules, ultimately reducing the efficiency of their cellular uptake and therapeutic effectiveness. Therapeutics are being created that exploit natural bypass mechanisms by forming complexes with cell-penetrating peptides (CPPs) derived from viruses. However, current CPPs lack the ability to selectively target precise cellular macromolecules. As a result, they are distributed broadly and cause off-target side effects. Neurotropic CPPs derived from the rabies virus glycoprotein (RVG) can access the brain by binding to plasma membrane targets, including, but not exclusively, nicotinic acetylcholine receptors (nAChRs). To overcome this barrier of minimal target selectivity, we designed several chimeric peptides composed of regions from the RVG and α-bungarotoxin, an α7 subtype-selective protein. Using human nAChRs expressed in Xenopus laevis oocytes, we screened the selectivity of our peptides using two-electrode voltage clamp electrophysiology. We identified a peptide with improved α7 nAChR subtype selectivity and apparent potency compared to the control RVG peptide. Using mammalian Neuro-2a cells, we demonstrated that our peptide depends on α7 nAChR plasma membrane expression to internalize and carry small-molecule payloads into neuronal-like cells without significant cytotoxic effects. Our novel α7 nAChR subtype-selective CPP may be useful in research applications requiring cargo delivery. Translationally, our α7 nAChR-selective CPP holds potential to be a dual drug delivery system to transport cargo into the brain for the treatment of neurological diseases.

With the advancement of global population aging, the incidence of skeletal diseases (e.g. osteoporosis, fractures, and osteoarthritis) in clinical diagnosis increases and poses a serious threat to human health. Skeletal diseases usually occur as a result of disturbed cellular metabolism in a specific period or environment. The bone microenvironment, as an important physiological environment of bone tissue, consists of various cell types, and cell-cell interactions play a decisive role in the biological behavior and metabolic regulation of bone cells. Disorders of the bone microenvironment can exacerbate bone diseases. Conventional therapeutic for skeletal diseases often suffer from poor efficacy, low targeting, and side effects. Therefore, a new therapeutic strategy should be developed urgently to improve the existing deficiencies. With the continuous advancement of nanomedicine, the application of nanomaterials provides new research perspectives and application value for the treatment of skeletal diseases. With their unique physicochemical properties, nanomaterials can directly or indirectly mediate the bone microenvironment to regulate the bone metabolic process through self-regulation, drug carriers, and in vivo scaffolds. All the above strategies are extensively explored in this study. In this paper, we systematically summarize the nanomaterials currently used in the clinical treatment of bone diseases and discuss the application strategies of nanomaterials to regulate the bone microenvironment and thus bone metabolism. Moreover, we evaluated the challenges faced by nanomaterials in the clinical treatment of bone diseases. We aim to provide basic theories and new perspectives for the design and development of novel nanomaterials for improved clinical applications.

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.