Drug Delivery and Translational Research最新文献

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.

Dissolving microneedles (DMNs) are an emerging transdermal drug delivery system that has gained increasing attention as an alternative to traditional oral and injectable methods for treating rheumatoid arthritis (RA). However, these DMNs encounter challenges related to insufficient drug diffusion through passive mechanisms. To address this issue, we developed biocompatible DMNs fabricated from hyaluronic acid (HA) loaded with ultrasound-responsive nanoparticles, aiming at enhancing drug permeation and diffusion through ultrasound (US) assistance. Methotrexate (MTX), a first-line treatment for RA, was encapsulated in poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles containing perfluoro-n-pentane (PFP), referred to as MTX-PFP-NPs. These nanoparticles were then incorporated into DMNs, designated as MTX-PFP-NPs@DMNs. Under the cavitation effect of ultrasound, PFP undergoes a phase transition that facilitates drug release and diffusion. The synergistic effect of the DMNs system and US were demonstrated in both an ex-vivo rat skin model and a collagen-induced arthritis (CIA) mouse model. The MTX-PFP-NPs@DMNs exhibited sufficient mechanical strength to penetrate the stratum corneum and dissolve completely within 20 min, enabling effective drug delivery. The synergistic effect of the DMNs system and US was evidenced by enhanced FITC penetration and diffusion in the ex-vivo rat skin model. Additionally, in vivo studied showed improved therapeutic efficacy in reducing joint swelling, bone erosion, cartilage damage, and pro-inflammatory cytokines level compared to only MTX-PFP-NPs@DMNs. This research underscores the promising integration of DMNs technology and US, offering a high-compliance approach to transdermal drug delivery that could significantly improve treatment outcomes for chronic conditions like RA.

The number of colorectal cancer (CRC) cases is rising among younger people, making it the second most common cancer worldwide. A pH-responsive hydrogel containing chitosan-based microbeads (BHCMB) is proposed for the targeted oral delivery of bevacizumab as a potential treatment for CRC. The structural and functional properties of BHCMB formulations were validated through characterization via FTIR and XPS analyses. Investigations of in vitro drug release by hydrogels have demonstrated their responsiveness to pH variations, facilitating accurate dosing in physiological conditions. The HCT-116 colorectal cancer cell line was utilized to assess the in vitro anti-cancer properties of BHCMB hydrogel formulations. At 50 µg/mL, BHCMB significantly reduced cell growth and caused apoptosis by damaging mitochondrial membranes and generating reactive oxygen species (ROS). The gene expression analysis revealed that BHCMB treatment significantly downregulated COX-2, IL-6, and BCL2 levels, while markedly upregulating p53 and Bax expression. Additionally, protein analysis in HCT-116 cells confirmed increased Bax and cleaved caspase-3 levels alongside reduced BCL2, indicating enhanced pro-apoptotic activity and potential anti-tumor effects in CRC. The in vivo study illustrates the efficacy of the BHCMB hydrogel in inhibiting CRC growth in a mice model. This research proposes an innovative pH-responsive hydrogel system for the oral administration of bevacizumab. The aim was to attain precise drug release at the colorectal tumor site, thereby enhancing apoptosis and effectively hindering CRC progression.

Skin disorders impact nearly one-third of the global population, and represent the fourth most common cause of human diseases. However, delivering drugs into and through the skin is a significant challenge due to its low permeability, which severely limits the efficacy of conventional topical and transdermal formulations. To tackle this issue, liposomes and liposome-derived nanosystems can be of use, which, among other advantages, also have the capacity to encapsulate more than one drug molecule simultaneously, allowing combination therapy. This review provides a comprehensive summary and critical analysis of recent studies regarding dual drug co-encapsulation into liposomes and liposome-derived nanosystems as an improved therapeutic approach for the treatment of several skin diseases, such as acne vulgaris, androgenetic alopecia, cutaneous leishmaniasis, psoriasis, vitiligo, and chronic wounds, and for dermal analgesia and general skin oxidative stress management purposes. Conventional and modified liposomes, niosomes, transfersomes, ethosomes, invasomes, cerosomes, liposomal gels, and niosomal gels were developed, co-encapsulating synthetic and nature-derived substances such as adapalene, amphotericin B, benzoyl peroxide, bicalutamide, bupivacaine, buprenorphine, curcumin, ginger, glycyrrhetinic acid, metformin, methotrexate, microRNA-21, minoxidil, nicotinamide, Nigella sativa seed oil, pentamidine, psoralen, resveratrol, simvastatin, tocopherol acetate, tretinoin, and virgin coconut oil. By co-encapsulating active substances with distinct mechanisms of action, the developed nanosystems provide synergistic therapeutic effects, leading to reduced toxicity and enhanced bioavailability, potentially resulting in improved clinical outcomes, and presenting a promising alternative to conventional treatments. Through addressing clinical and regulatory framework aspects, these innovative therapies might one day transition from bench to market to improve the patient's quality-of-life.

Traditional topical therapies can have considerable side effects, leading to the research for natural and biocompatible alternatives. Ectoine, a natural osmolyte produced by extremophilic microorganisms, possesses an extraordinary ability to bind water molecules and stabilize membranes, with powerful moisturizing and anti-inflammatory properties, which makes it a multifunctional and valuable molecule for topical applications. Pre-clinical and clinical data confirm that ectoine-based creams increase skin moisture, improve the skin's barrier function, and reduce inflammation, effectively alleviating the symptoms of atopic dermatitis. In addition, ectoine can be used in nasal sprays, providing substantial relief from the symptoms of rhinosinusitis, such as nasal congestion and irritation of the mucous membranes, without the adverse effects associated with the usual decongestants. In ophthalmic formulations, ectoine-containing eye drops moisturize, stabilize the tear film, and relieve irritation and itching, making them a viable option for the ocular symptoms of allergic conjunctivitis and the long-term treatment of dry eye disease. Therefore, ectoine is crucial in developing treatments that improve patients' quality of life by offering a safer alternative to conventional therapies.Briefly, this review aims to explore the topical applications, characteristics, and mechanisms of action of ectoine, focusing on its efficacy and safety in the treatment of atopic dermatitis, rhinosinusitis, rhinitis sicca, dry eye disease, and allergic conjunctivitis. Moreover, biotechnological methods for producing ectoine are outlined, highlighting advances in microbial synthesis and process optimization for more sustainable technology, as well as showing ectoine-containing products and their position on the market.

Oral ulcerative mucositis (OUM) is a common painful disease that affects oral functions, such as eating or speaking leading to a low quality of life. This study aims to develop a novel strategy for relieving pain associated with OUM by using local anesthetics. Here, a hybrid dissolving microneedle patch integrated with lidocaine (Lido)-encapsulated invasomes (modified liposomes containing terpenes as penetration enhancers) depots are introduced for sustained Lido delivery, reduced dosing frequency, and improved patient compliance. Different Lido-loaded invasomes formulations were developed using design expert^® software to study the effects of different type terpenes (Limonene, Cineole, Camphor) and their concentration using a thin-film hydration approach. Dissolving microneedle (MN) patches made of sodium alginate (SA), Glycerol and polyvinyl alcohol (PVA) via the casting method. Optimized invasomes formulations containing cineole exhibited excellent stability, a high entrapment efficiency of 83.5%, and a nanoscale size of approximately 295 nm. The incorporation of SA/PVA with 1% glycerin MNs resulted in effective mucosal penetration, rapid dissolution within 10 min, and significant mechanical strength. Research conducted in-vitro and ex-vivo demonstrated enhanced permeation and a significant increase in lidocaine release, achieving 95% within 24 h. In-vivo evaluations demonstrated substantial pain relief, reduced inflammation (evidenced by decreased TNF-α and NF-κB levels), enhanced anti-inflammatory IL-10 expression, and modulation of angiogenesis via VEGF downregulation, leading to accelerated mouth healing with complete epithelial restoration. This hybrid system significantly improves drug delivery and patient comfort by aiding in biocompatibility, Mucoadhesion, and healing. This innovative system transcends traditional anesthetic administration, providing a painless and targeted therapeutic platform that improves OUM management.