Drug Delivery and Translational Research最新文献

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.

Healthcare-related pain associated with hypodermic needles is prevalent and undertreated in pediatric patients. Currently available topical anesthetics provide insufficient pain relief due to poor drug skin permeability, especially when rapid onset is desired. Herein, our goal was to assess the speed and efficacy of local lidocaine/epinephrine/tetracaine (LET) gel enabled by STAR particles in a first-in-humans clinical trial. Twenty-two children (10 - 15 yr) were randomized in a placebo-controlled, cross-over trial to receive topical treatment of LET gel applied to the antecubital fossa for 10 or 20 min either with or without STAR particle pretreatment. STAR particle pretreatment decreased skin barrier function, demonstrated by increased trans-epidermal water loss compared to placebo (25.0 ± 8.7 g/m²h vs. 14.8 ± 4.3 g/m²h, P < 0.0001). STAR particle pretreatment followed by LET gel (STAR-LET group) resulted in decreased sharp sensations from needle probing after 10 min (51.6 ± 29.2% vs 82.0 ± 18.6%, P = 0.014) and 20 min (55.7 ± 21.8% vs 89.0 ± 15.6%, P = 0.006) compared to LET gel without STAR particle pretreatment (LET group). After hypodermic needle insertion, pain decreased at 10 min (3.1 ± 1.8 vs. 4.1 ± 1.9, P = 0.11) and 20 min (4.2 ± 1.0 vs. 5.3 ± 1.5, P = 0.02) in the STAR-LET group compared to the LET group. STAR particle pretreatment was described as comfortable and without pain by most participants. No adverse skin reactions were observed immediately after STAR-LET application or during the 7-day follow-up period. STAR particle skin treatment in combination with LET gel in children was safe, well-tolerated, and effective to rapidly reduce painful sensations associated with hypodermic needles. Trial Registration: Lidocaine Administration Using STAR Particles, NCT06034340, https://classic.clinicaltrials.gov/ct2/show/NCT06034340.

This study evaluates dissolving microneedle (MN) patches for naloxone (NAL) delivery via the transnasal route, addressing limitations seen with transdermal application of same and the limitations of conventional NAL intranasal sprays, which often require frequent redosing, particularly for long-acting opioids like fentanyl. MN patches composed of polyvinylpyrrolidone (PVP) and PVP/Chitosan were tested on porcine nasal mucosa. PVP patches achieved significantly higher 1-h cumulative permeation (7295.12 ± 2585.17 µg/cm²) compared to transdermal application (103 ± 15.18 µg/cm², p < 0.05). Over 24 h, cumulative permeation reached 13,113.20 ± 597.39 µg/cm² transnasally versus 4112.89 ± 773.40 µg/cm² transdermally (p < 0.05). Chitosan-PVP MN patches improved bioadhesion and demonstrated high 1-h cumulative permeation (3800.19 ± 940.51 µg/cm²). PVP MN patches with drug-loaded tips (MN/TO, where TO implies "tip only") delivered 933.90 ± 161.60 µg/cm² in 1 h that was also a remarkable increase over transdermal permeation (p < 0.05) but had lower 24 h permeation. Similar observation was seen with the PVP/Chitosan variant with drug loaded in just MN tips indicating that sustained delivery requires drug in both the tips and base. To further refine patch designs, a mathematical modeling framework was employed to simulate drug dissolution, permeation dynamics, and plasma concentration kinetics. Simulations demonstrated that optimized patches could achieve plasma profiles comparable to intranasal and intramuscular administration, while minimizing drug dose and patch size. Increasing drug concentration from 50 to 60 mg/ml decreased permeation, likely due to drug crystallization. Overall, MN patches showed consistent, sustained NAL delivery, providing an alternative option for efficient opioid overdose treatment.

This study aimed to utilize the mRNA-lipid nanoparticle (mRNA-LNP) platform to achieve in situ hepatic expression of an interferon-α (IFN-α)/anti-glypican-3 (anti-GPC3) fusion protein (GPA01), enhancing IFN-α targeting and antitumor activity to provide a precision therapy strategy for GPC3-positive hepatocellular carcinoma (HCC). mRNA encoding a GPC-3/IFN-α bispecific fusion protein was designed and synthesized, encapsulated in lipid nanoparticles, and transfected into HCC cell lines (HepG2) for in vitro characterization of protein expression, binding activity, and gene induction. Orthotopic HCC models (HepG2-luc) and subcutaneous tumor model (Hepa 1-6/hGPC3-hi) were established in mice to evaluate tumor growth, survival, and immune cell infiltration following treatment with mRNA-LNP or control agents. Safety was assessed in human IFNAR transgenic mice. In vitro experiments demonstrated successful transfection and bioactive fusion protein expression by mRNA-LNP, with transfected supernatants showing specific GPC3 binding and interferon-stimulated gene (ISG) induction. In vivo studies revealed that GPC-3/IFN-α mRNA-LNP significantly inhibited tumor growth, prolonged median survival, and increased intratumoral CD8⁺ T cell and NK cell infiltration compared to controls, with favorable safety profiles. Combination therapy with PD-1 antibody (PD-1 Ab) exerted synergistic antitumor effects, primarily dependent on CD8⁺ T cell infiltration. Safety evaluations in human IFNAR transgenic mice showed good tolerability at single doses of 1-10 mpk, with transient changes in select biomarkers. Repeated dosing (6 or 10 mpk) identified a maximum tolerated dose (MTD) of 6 mpk, at least 40-fold higher than the minimal effective dose (MED, 0.15 mpk). mRNA-LNP-mediated delivery of IFN-α-anti-GPC3 fusion protein achieves targeted in situ hepatic expression, significantly enhancing antitumor activity with a broad therapeutic window. This strategy offers a novel approach for precision immunotherapy in HCC, holding substantial potential for clinical translation.

Nanovesicular systems hold a significant promise for drug delivery, yet their clinical translation is hindered by challenges in scalability and reproducibility. This study introduces in-line homogenization as a continuous, organic solvent-free approach for scalable fabrication of bilayered unilamellar vesicles, NioTherms (Niosome-like) and ThermoSomes (Liposome-like), loaded with model hydrophobic (Posaconazole, PCZ) and hydrophilic (Dexamethasone Sodium Phosphate, DEX) drugs. Using a heat-mixing method as the baseline, formulations were scaled from 10 mL (1x) to 1 L (100x) via a rotor-stator-based in-line homogenizer. Process parameters including pump speed, homogenizer speed, cycle number, phase ratio and output rate were optimized. The resulting vesicles exhibited uniform particle size and entrapment efficiencies comparable to the lab-scale batches. The formation of vesicles, morphology, internal structure, and integrity of the formed particles was confirmed by TEM and SANS analysis. The system enabled rapid batch processing (< 5 min for 1 L) with substantial product yields up to 80%. The process demonstrated excellent reproducibility and eliminated the need for post-processing. This study establishes in-line homogenization as a robust, scalable platform for faster production of nanovesicular drug delivery systems, effectively bridging the gap between bench-scale development and continuous manufacturing.