Drug Delivery and Translational Research最新文献

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.

Since the first market authorization of RNA therapies, just eight years ago, the field has witnessed an extraordinary expansion, ranging from hepatic delivery for rare genetic diseases to global-scale vaccination during the COVID-19 pandemic, and now to cutting-edge cancer vaccines and gene editing strategies entering late-stage clinical trials. In parallel, the RNA therapeutics landscape has evolved rapidly, progressing from small interfering RNAs to next-generation and combinatorial RNA modalities. None of these breakthroughs would have been possible without the development of sophisticated RNA delivery technologies capable of navigating complex biological environments, enabling precise cellular targeting, and facilitating efficient intracellular trafficking. In this Editorial Note, we take a step back to reflect on key lessons learned throughout the RNA delivery journey. Featuring insights from leading and experienced voices in the field, this manuscript highlights critical milestones, persistent challenges, and the roles of lipid nanoparticles (LNPs) and polymer nanoparticles (PNPs) as RNA delivery platforms. These experts reflect on the features that have positioned LNPs as the current RNA delivery gold standard, while also exploring the untapped potential and distinctive advantages of polymer-based nanosystems. Collectively, these perspectives underscore a striking truth: we are only beginning to unlock the full therapeutic potential of RNA, and nanomedicine will certainly continue to shape the future clinical translation of RNA-based therapies.

Messenger RNA (mRNA) based therapeutics have emerged as a transformative modality with immense potential for treating infectious diseases, cancer, genetic disorders, and other complex conditions. Despite their promise, clinical translation has been challenged by mRNA's intrinsic instability, rapid degradation, and limited target specificity. The therapeutic value of mRNA lies in its ability to precisely modulate or restore protein expression, offering a versatile platform for personalized medicine. While conventional delivery approaches have yielded modest improvements, the integration of nanotechnology, particularly stimuli-responsive, nanoparticle-mediated systems, represents a breakthrough in overcoming these limitations. These advanced nanocarriers respond to both endogenous physiological triggers (such as pH shifts, redox gradients, reactive oxygen species, enzymatic activity, and hypoxic environments) and exogenous stimuli (including light, ultrasound, magnetic fields, and temperature changes), thereby enabling controlled, site-specific, and temporally regulated mRNA release. This dual responsiveness enhances therapeutic efficacy by improving mRNA stability, bioavailability, and minimizing off-target immune activation. This review highlights the design principles, mechanisms, and therapeutic applications of stimuli-responsive nanocarriers in mRNA delivery. It underscores recent innovations in nanoparticle engineering that address existing challenges and pave the way for next-generation precision medicine. Together, these advancements signal a paradigm shift in targeted mRNA therapy, offering new hope for treating previously intractable diseases.

Injectable hydrogels (IHs) have emerged as versatile biomaterials that enable localized therapy through minimally invasive delivery. Their in situ sol-gel transition supports sustained and targeted release of therapeutics, enhancing patient comfort and reducing dosing frequency. However, clinical translation remains limited due to challenges in achieving controlled degradation, ensuring long-term biocompatibility, scaling production, and meeting regulatory standards. Despite these hurdles, several IH-based formulations are progressing through clinical trials or have reached the market, underscoring their therapeutic potential. This review examines the major translational barriers and highlights recent advances that are accelerating the adoption of IHs in precision and personalized medicine.

Doxycycline (DOXY) is a well-established antibiotic that has recently shown potential in inhibiting matrix metalloproteinase-2 (MMP-2), a key enzyme involved in the progression of abdominal aortic aneurysms (AAA). However, the controlled delivery of DOXY to the aneurysm site, with sustained release and minimal systemic exposure, remains a critical challenge in therapeutic development. To address this, we developed a targeted drug delivery platform based on polymeric nanoparticles (NPs), prepared from water-in-oil-in-water nano-emulsions, encapsulating DOXY and are covalently attached to electrospun ε-poly(caprolactone) (ε-PCL) microfibers. This system was designed to enable local, sustained drug release in the inner wall of aorta while preserving the mechanical properties of the aortic wall. The ε-PCL electrospun microfibers from the patch were first functionalized using oxygen cold plasma treatment, creating free radicals that enabled covalent bonding with chemical groups on the outer layer of DOXY-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. This strategy allowed for robust immobilization of the NPs onto the microfibers surface, forming a composite system capable of localized and controlled drug release over time. Unlike traditional delivery approaches, this method ensures site-specific action of DOXY directly at the aneurysmal tissue, minimizing systemic circulation and reducing off-target toxicity. The platform not only provides a stable drug reservoir but also offers intrinsic biomechanical reinforcement, which is critical in AAA condition. This innovative delivery system represents a significant advance in the localized treatment of vascular disorders. It offers a biocompatible, biodegradable, and precisely targeted therapeutic approach, with potential to reduce the need for surgical intervention and limits the adverse effects associated with systemic drug administration. HIGHLIGHTS: - Novel polymeric Doxycycline loaded PLGA nanoparticles have been developed and result efficacious within hMMP-2 mitigation and collagen degradation in Abdominal Aortic Aneurysm condition. - Doxycycline loaded polymeric nanoparticles were covalently anchored to ε-Poly(caprolactone) electrospun microfibers via cold plasma-induced radical grafting, enabling sustained drug release for over 12 days. - Doxycycline-loaded nanoparticles released from microfibers efficaciously mitigate hMMP-2 in human in vitro models of Abdominal Aortic Aneurysm. - Doxycycline released from drug-coated electrospun ε-Poly(caprolactone) although efficacious does not allows time-control.