Drug Delivery and Translational Research最新文献

Nanostructured lipid carriers (NLCs) decorated with sulfhydryl-modified surfactants have recently gained attention for delivering BCS Class IV drugs. However, the impact of the chain-length of these surfactants on the permeation and bioavailability properties of NLCs is still unknown. Therefore, this study investigates the effect of surfactant chain-length on the mucoadhesive, permeation, and bioavailability properties of NLCs. For this purpose, short- and long-chain sulfhydryl-modified polyethoxylated surfactants were generated to develop mucoadhesive NLCs and loaded with the model drug aprepitant (APT). NLCs were characterized and assessed for comprehensive physicochemical and biological evaluations. Moreover, in-vivo studies were performed for proof-of-concept to show enhanced oral drug bioavailability. NLCs showed particle size under 200 nm with 6.9 and 6.7% drug loading and 85 and 84% drug entrapment for short- and long-chain surfactants, respectively. The drug-loaded NLCs were safe and stable, and short- and long-chain surfactants containing NLCs exhibited 11.6- and 9.6-fold enhanced mucoadhesion, respectively. Moreover, in comparison to long-chain sulfhydryl-modified surfactant, short-chain surfactant is transported into deeper segments of mucus due to less interaction with the mucus. Similarly, short-chain sulfhydryl-modified surfactants showed significantly enhanced cellular permeation across Caco-2 cell lines. Furthermore, the long-chain sulfhydryl-modified surfactants showed 4.38-fold enhanced C_max, whereas due to better diffusion and mucoadhesion properties, the short-chain surfactants exhibited 5.38-fold enhanced C_max. Similarly, 34.8% relative bioavailability was attained for short-chain surfactants and 24.8% for long-chain surfactants. These results suggest short-chain sulfhydryl surfactants are promising candidates for improving the oral delivery of poorly soluble drugs and warrant further investigation for clinical translation.

Inflammatory bowel diseases (IBD) affect millions of people worldwide. The use of anti-TNF-α for the treatment of moderate-to-severe IBD faces primary non-response, loss of response during treatment or intolerance issues. As an alternative, a strategy consisting of oral administration of TNF-α siRNA was evaluated in the present study for the local treatment of IBD. TNF-α siRNA entrapped in lipid nanoparticles (LNPs) was microencapsulated in gastroresistant alginate particles using an original process. The encapsulation yield of both siRNA and LNPs in microparticles (MPs) was at least 90%. Oral administration of MPs significantly reduced both clinical score and therapeutic index in a TNBS-induced colitis model in mice. Near complete removal of tissue damage, including edema, ulceration and necrosis, was observed in colon sections from treated mice. Reduced variation in gene sets involved in the global inflammatory response and the TNF-α/NF-κB signaling pathway was detected in the colon compared to untreated mice, demonstrating the anti-inflammatory activity of MPs. Finally, biodistribution studies showed the targeting of the inflamed colon by MPs and the colocalization of LNPs and MPs at the site of action. These MPs may represent a promising siRNA delivery platform for the oral treatment of IBD.

Glaucoma, a leading cause of irreversible blindness, is marked by elevated intraocular pressure (IOP) and retinal ganglion cell death. Traditional IOP-lowering eye drops often fail to penetrate the ocular barrier, leading to suboptimal outcomes. Microneedles (MN), offer a promising minimally invasive and localized alternative. Our study aimed to formulate a naturally-derived nanodelivery system using Luteolin-loaded colostrum-derived exosomes (LUT-EX) and propolis in MN arrays for better ocular delivery. The isolated exosomes were uniform, averaging 50.83 nm in size, with a zeta potential of -21.89 mV. LUT-EX showed a 48-h sustained release and high safety with an IC50 of 356.3 µg/mL. Integrating LUT-EX and propolis into MN arrays achieved optimal dissolution in over one minute and maintained mechanical strength under 30 N compression. LUT-EX@MN increased LUT permeation through scleral tissues 2.6-fold compared to gel matrix formulations. It also showed a sustained IOP-lowering effect reaching the normal IOP level in the first 3h and sustained over 7 days. The integrated system significantly reversed glaucoma-induced changes in TNF-α, IL-8, MYOC, NRF2, TIMP1, and IL-1β levels, resembling those of the healthy group. It also boosted antioxidant activity, increasing glutathione peroxidase by 1.6-fold compared to glaucomatous rabbits. Thus, our study highlighted that the integration of LUT-EX into microneedle arrays presents a groundbreaking dropless approach for localized glaucoma treatment, offering enhanced therapeutic efficacy. This platform could revolutionize glaucoma management, paving the way for more effective and targeted ocular therapies.

Autoinjectors with dual-chamber cartridges (AIDCs) are single-use, self-administrable injection devices that facilitate automated reconstitution and injection of lyophilized products. We report the development and application of a physics-based model to understand and optimize AIDC behavior, predicting its response as a function of formulation properties and injection device parameters. Our model is based on the equations of motion for the AIDC's dual stoppers, as well as the ideal gas law and an experimentally derived stopper friction vs. glide speed relationship. Our model provides estimates for some of the key essential performance requirements that yield good device performance, including injection time, stopper trajectories, and the maximum diluent volume. We validated our model using experimental injection time data demonstrating good agreement for a range of diluent volumes, reconstituted solution viscosities, and stopper positions. The model allows different device and formulation configurations to be tested virtually without requiring the physical device and formulation, reducing the need for extensive experimental testing and ensuring the robustness of the injector performance for successful drug delivery. The modeling framework applies to a broad class of spring-driven AIDCs for lyophilized drug and vaccine delivery and enables informed device selection through simulation-led technical due diligence.

The global coenzyme Q10 (CoQ10) market is expanding, driven by the increasing prevalence of chronic diseases, particularly cardiovascular disorders. Forecasts project a compound annual growth rate of 9.68% from 2025 to 2034. Despite its critical role in cellular energy metabolism and antioxidant defense, CoQ10's clinical potential is constrained by poor water solubility and low oral bioavailability. This review delivers a critical and translational comparison of lipid-based and water-based encapsulation strategies, offering novel insights into their mechanistic advantages, formulation challenges, and clinical applicability for enhanced CoQ10 delivery. Lipid-based systems, such as self-emulsifying drug delivery systems (SEDDS), liposomes, and nanoemulsions, improve solubility and gastrointestinal absorption, protect CoQ10 from degradation, and promote lymphatic transport. However, they often require high excipient content and exhibit stability concerns, such as susceptibility to oxidation. Water-based approaches, including β-cyclodextrin complexation, polymeric nanoparticles, solid dispersions, and CoQ10-nicotinamide cocrystals, enhance aqueous solubility and absorption while offering better chemical stability and lower formulation cost. This review highlights the mechanistic differences, benefits, and limitations of each strategy, providing critical insights for the rational design of CoQ10 delivery systems. The findings support formulation optimization to improve therapeutic efficacy and inform manufacturing decisions for clinical and commercial applications. Looking ahead, future directions may include nano-enabled personalized medicine strategies based on individual metabolic profiles and the development of intranasal CoQ10 delivery platforms that leverage nanoscale lipid or water-based carriers for direct nose-to-brain transport in neurological disease therapy.

Glioblastoma Multiforme (GBM) is the most common primary malignancy of the central nervous system with an average survival time of 15 months following standard therapy. Furthermore, since its clinical introduction in 1999, temozolomide (TMZ) remains the chief therapeutic agent for GBM to date. However, because TMZ is administered orally, the blood-brain barrier (BBB) poses a significant challenge in GBM treatment, with efforts to overcome it complicated by unsustainable immunosuppression side effects. In this clinical context, there is a pressing need to develop more effective methods of delivering TMZ to GBM. We used temozolomide attached to superparamagnetic iron oxide nanoparticles (TMZ-SPION). First, its efficacy was compared to unconjugated temozolomide in vitro against U87 and U373 glioblastoma cell lines. Second, it was administered intranasally to U87 xenograft mice models and then guided to the brain parenchyma using transcranial magnetic stimulation (TMS), bypassing BBB. The efficacy was evaluated through a survival experiment. We found that TMZ-SPION was as effective as TMZ against glioblastoma cell lines. In the survival experiment, we found that TMZ-SPION + TMS treated mice survived twice longer than the untreated control group while requiring less than one-tenth of the conventional dose. TMZ-SPION guided by a magnetic field is a promising candidate for precise drug delivery to CNS tumor sites. Additionally, the intranasal route has been demonstrated as a reliable method for bypassing the BBB.

Immunotherapy has transformed cancer treatment by harnessing the immune system to target tumor cells, with PD-L1 inhibition emerging as a promising strategy. Exosomes, which naturally function as nanocarriers, offer significant potential for delivering therapeutic payloads, while genetic engineering allows for improved cargo specificity and efficacy. Here, for the first time, we genetically engineered exosomes to express anti-PD-L1 (PDL E) on their surface, enabling targeted drug delivery and immunotherapeutic activity. These engineered exosomes were then loaded with STAT3 siRNA (PDL ESi) and evaluated against doxorubicin-resistant MDA-MB-231 cells in combination with paclitaxel. Both in vitro and in vivo studies demonstrated a pronounced reduction in tumor burden (P < 0.001) and progression. Mechanistic investigations revealed that these exosomes activated apoptotic pathways, including the PI3K/AKT/mTOR axis, while inhibiting survival signals such as BCL-2, thereby enhancing tumor cell apoptosis. Notably, PD-L1 expression was downregulated in tandem with modulation of the STAT3/Nrf2 signaling axis, further augmenting the anti-tumor immune response. Toxicity studies in MCF-10 A cells showed that PDL ESi was well-tolerated, with no off-target effects. Imaging analyses in both 3D spheroids and tumor xenograft models confirmed the efficient tumor targeting of PDL E, demonstrating their time-dependent accumulation at the tumor site. Collectively, these findings highlight the promise of PD-L1-targeted, genetically engineered exosomes as a versatile platform for combination cancer therapy, providing a multifaceted strategy to overcome therapeutic resistance in TNBC.

Dimethyl fumarate (DMF) is a first-line oral medication for the treatment of multiple sclerosis (MS), unfortunately associated with several adverse events, mainly affecting the gastrointestinal tract. Intranasal drug delivery could potentially alleviate these adverse events enhancing the therapeutic efficacy. This study aims to formulate an oil-in-water (o/w) nanoemulsion (NE) encapsulating DMF solubilized in carvacrol (CV), a neuroprotective essential oil component, for a possibly synergistic therapeutic effect. Chitosan oleate as amphiphilic polymer has been selected as a surfactant, owing to its mucoadhesive and permeation enhancement properties. Spectrophotometric (FT-IR) and thermogravimetric analyses used to characterize the DMF-CV combination, revealed an increased stability of DMF due to the presence of CV. Response surface methodology was used for the optimization of NE formulations by applying the Central Composite Design model. The final optimized formulation showed a mean size of around 200 nm, a polydispersity index of about 0.3, a positive zeta potential (about + 30 mV) as attended and a drug content of about 70%. Moreover, NEs demonstrated good cell viability and permeability on RPMI 2650 nasal cell lines. DMF-CV NEs are a promising tool to further studies to verify nose-to-brain efficacy of DMF and therapeutic synergism with CV, in the perspective to reduce the adverse events related to DMF, enhancing therapeutic efficacy as well as patient compliance and medication adherence.

Ulcerative colitis (UC), an inflammatory bowel disease, poses a severe threat to human health. Paeonol has demonstrated potential for the treatment of UC, particularly because of its remarkable anti-inflammatory properties. However, the high volatility and low oral bioavailability of paeonol hinder its application in the treatment of UC. To address this challenge, a paeonol emulsion (PEM)-based oral delivery system was developed for the treatment of UC. In this study, we investigated the colonic-targeting efficacy of PEM and the mechanisms underlying its ability to alleviate colitis. The results revealed that the negatively charged PEM specifically adhered to the positively charged inflamed colonic tissues via electrostatic interactions, enabling effective targeted delivery. Additionally, the PEM maintained the balance between M1 and M2 macrophages, exhibiting excellent efficacy in alleviating UC. Mechanistic studies have shown that PEM significantly inhibits the expression of inflammatory cytokines and repairs the intestinal barrier. Furthermore, PEM modulates the composition of the gut microbiota by inhibiting the growth of harmful bacteria and promoting the growth of beneficial bacteria. In conclusion, the negatively charged emulsion delivery system constructed provides new insights into the development of an oral colon-targeted drug delivery system.