Drug Delivery and Translational Research最新文献

There is a poor response of prostate cancer to immunotherapies because of dysfunctions in the tumor microenvironment (TME) characteristics, like abnormal vasculature structure, stiffened stroma, increased interstitial fluid pressure (IFP), and regions of hypoxia. However, the existing computational modelings are unable to tackle this issue, as they are based on two-dimensional (2D) geometry that ignores TME properties (like TME biphasic composition) and interaction between cancer and immune cells. To address this knowledge gap, this paper offers a patient-specific multiphysics model for prostate cancer. The proposed model is based on three-dimensional (3D) geometry obtained from magnetic resonance imaging (MRI) and combines three complementary approaches to normalizing the tumor microenvironment: vascular normalization via anti-angiogenic therapy, stromal normalization via extracellular matrix softening, and immune checkpoint blockade. One important new aspect of this work is that new nanoparticle delivery models have been developed for 20-100 nm nanoparticles (NP) delivering immunotherapy agents. These equations explicitly incorporate interactions between the components of the TME and directly account for mechanical stress induced by tumor growth, enabling mathematical modeling of physical TME changes and their subsequent impact on the dynamics of immune cells (such as cytotoxic T cells (CD8 + T cells), regulatory T cells (Treg), and pro-inflammatory macrophages (M1-like)/anti-inflammatory macrophages (M2-like) and cancer cells. This capability is absent in previous models. The other important novelty is that for the first time in a prostate cancer model, factors for vascular and stromal normalization and immunotherapy have been incorporated in a 3D geometry. The parameters of this model have been optimized based on literature and preclinical trial data related to immunology and tumors. The sensitivity analysis has confirmed that all therapeutic factors, optimized vascular function (functional vessel density increases from 43 to 112 cm²/cm³), reduced stromal solid stress (decrease in shear modulus from 10.4 to 6.1 kPa), as well as a 70% reduction in IFP (from 1471 to 441 Pa), in combination contribute to a 30% increase in accumulation of nanoparticles in the tumor, 60% increase in the ratio of CD8 + /Tregs, a 45% decrease in the ratio of M1/M2 macrophages, a 15% reduction in the tumor hypoxia gradient, and a 40% decrease in the size of the tumor within 50 days. This model can thus provide a clinically applicable tool for predicting the efficacy of nano-immunotherapy in prostate cancer. Experimental confirmation is required to better evaluate NP toxicity.

Glaucoma is a leading cause of irreversible blindness, with current treatment strategies focusing on reducing the intraocular pressure (IOP). The Durysta^® (bimatoprost) intracameral implant offers a sustained-release alternative to conventional eye drops by continuously delivering medication directly into the anterior chamber (AC). This study employs advanced computational modeling using ANSYS Fluent to investigate the interaction between aqueous humor (AH) flow and drug distribution following Durysta^® implantation. Drug transport is modeled using the unsteady convection diffusion equation, and concentration profiles are analyzed at different times: 10 min, 30 min, 1 h, 1 day, 15 days, 30 days, and 60 days. The results show that AH circulation significantly influences by Durysta^® implant, with flow-driven mixing facilitating its distribution across ocular tissues. In the early phase, high concentration zones appear near the implant, while long-term simulations demonstrate sustained and uniform drug distribution throughout the AC. These findings advance the understanding of sustained intraocular drug delivery and establish a computational framework to guide the optimization of future implant designs, aiming to improve therapeutic outcomes in glaucoma management.

Retinitis pigmentosa (RP) is a chronic genetic condition that leads to progressive loss of photoreceptor cells and vision. While gene therapy is available for a small subset of patients with specific mutations, developing a therapeutic that broadly targets the cellular stresses that lead to cell death could address a major unmet need. One such option would be utilizing antioxidant therapies to neutralize reaction oxygen species (ROS) in the retina that underlie RP progression. Here, we describe an approach for delivering the antioxidants N-acetyl cysteine (NAC) or N-acetyl cysteine ethyl ester (NACET) with a gel-forming eye drop previously demonstrated to provide therapeutic drug delivery in the posterior segment in animals. We demonstrated therapeutic protection of photoreceptor structure and function in a chemically-induced rat model of RP (48% increase in photopic b-wave amplitude), as well as some limited protection in an aggressive genetic mouse model (rd10) of retinal degeneration (~ 31% increase in photopic b-wave amplitude) with once daily application. However, antioxidants have inherent stability issues when stored in solution, so we investigated the use of additional excipients to improve stability and retain potency. While a promising approach, future work to address product stability and efficacy in larger eyes is needed for further development.

In the current study, polysaccharides (APS) extracted from the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao were demonstrated to promote hair regeneration. However, with an average molecular weight of 20,000, they exhibit poor transdermal absorption. To enhance local efficacy, we synthesized chemically crosslinked hyaluronic acid (cHA) and prepared γ-cyclodextrin-modified potassium metal-organic frameworks (MOFs) loaded with minoxidil (MDX) (MDX@MOF).The aforementioned materials were mixed with APS to form soluble microneedles (MDX@MOF-APS/cHA-MNs). Their oblique spike structure facilitates local fixation after skin penetration. MOF-based drug loading increased MDX water solubility by ninefold, while cHA provided significant sustained-release effects.Furthermore, APS enhances the mechanical properties of hydrogel microneedles and optimizes drug delivery. Notably, APS promotes human hair follicular papilla cell proliferation in a dose-dependent manner and exhibits synergistic effects with MDX. Concurrently, MDX@MOF-APS/cHA-MNs significantly prolong drug retention time in the skin, effectively improving hair coverage and growth rate in androgenetic alopecia mice. In summary, APS emerges as a clinical candidate for treating androgenetic alopecia, while novel microneedles with unique composition and structure enrich topical delivery strategies.

Interest in drug repurposing has increased significantly in recent decades owing to its potential to accelerate the development of new medicinal products, provide new therapeutic options for patients, and generate business opportunities for pharmaceutical companies. Idiopathic pulmonary fibrosis (IPF) is defined as a chronic disease that causes an irreversible loss of lung function and premature death. Recent studies have highlighted the key role of mitochondria in lung homeostasis and the ability of thyroid hormones to promote mitochondrial activity, suggesting their potential involvment in IPF pathogenesis. In this work, we translate the findings derived from the above-mentioned researches into a dry powder drug delivery system intended to target epithelial lung cells with levothyroxine. To this end we developed nano-embedded respirable microparticles by spray drying a nanosuspension composed of levothyroxine and a hydrophilic polymer. The powder was characterized in terms of physico-chemical, toxicological and aerodynamic performance, as well as for its ability to be internalized by A549 cells and modulate their metabolic activity. The nano-embedded microparticulate drug delivery system proved to be potentially able not only to reach the deep lung but also to promote levothyroxine internalisation and mitochondria activation.

Current drug delivery devices can't deliver drugs toward targeted intestinal lesions non-invasively. A novel magnetically controlled delivery capsule endoscopy (MDCE) system was developed to accurately deliver topical therapy toward intestinal lesions under real-time optical visualization. We aimed to evaluate the feasibility and efficacy of this MDCE system in precisely targeted delivery of topical therapy. The delivery feasibility of the MDCE were first evaluated using an ex vivo swine intestinal model. In this model, simulated lesions (n = 27) were created and marked with a pre-selected dye (0.1% methylene blue). The MDCE delivery processes for small intestine lesions were conducted in four Bama miniature pigs. The feasibility of MDCE was defined as successful drug delivery to specific simulated small bowel lesion under optical surveillance. Efficacy was evaluated using parameters including image quality, maneuverability of the MDCE, and the time required for aiming and drug delivery taken by MDCE. The MDCE system demonstrated robust feasibility in an ex vivo intestinal model, achieving over 80% targeting success rate across 27 lesions at various orientations. This precision was successfully translated in vivo, with 91.7% (22/24) of target lesions precisely stained. Except for two raised lesions, 22 of them were precisely stained. The image quality and the maneuverability of the MDCE system were both graded as the best. Further analysis of procedural efficiency revealed that while the time for aiming lesions (16 s to 191 s) was longer in the small intestine than in the colon, especially when aiming at flat lesions (p = 0.0304), the rapid dye delivery time (4 s to 11 s) remained consistent across all locations and lesion types (p > 0.05). This study confirmed the feasibility and efficacy of the MDCE system for delivering targeted drug to specific intestinal lesions with real-time, vision-based monitoring in swine models.

Additive manufacturing offers unprecedented opportunities for personalized medicine, but most pharmaceutical printing platforms are optimized for milligram-range doses, limiting their suitability for microdosing. This work introduces a novel liquid deposition approach using a modified technical pen integrated into a pharmaceutical printer. The gravity-driven mechanism enabled precise microscale dispensing without external thermal, pneumatic, or electrical inputs, which have been associated with molecular stress in other printing technologies. Desmopressin, a potent synthetic hormone indicated for diabetes insipidus and requiring ultra-low doses, was selected as a model compound. Oral films (2 × 4 cm) containing therapeutically relevant doses (33-134 µg) were produced by depositing up to four layers of pharmaceutical ink. A custom-developed software interface allowed precise control of key process parameters, supporting reproducibility and automated workflows. The system achieved ~ 100% dose accuracy, with a strong correlation between drug content and layer number. Films exhibited rapid disintegration and immediate release. Stability testing showed no drug degradation over one month. Unlike more complex printing platforms, the technical printhead architecture offered straightforward manipulation and rapid setup. Given the constant ink flow rate and low, consistent, deposition volumes, only 1 mL of formulation is sufficient to produce up to 238 single-layer 2 × 4 cm films. These findings position the technical pen-based printhead as a promising, precise, and cost-effective addition to the additive manufacturing landscape, with strong potential for low-dose personalized pharmaceutical applications, including biologics. Moreover, its performance underscores the potential for further optimization and broader application.

Glioblastoma recurrence after surgery is a major contributor to its high mortality, primarily occurring near the original tumour margin. Various hydrogels have been developed to fill the post-surgical cavity and deliver drugs to the surrounding brain tissue to eliminate residual cells. However, the impact of tissue, hydrogel, and drug properties on delivery outcomes remains unclear. Here, a parametric study is conducted to investigate these effects using mathematical modelling. The results show that post-surgical oedema strongly influences delivery: longer duration or delayed onset of oedema can homogenise drug distribution, with delayed onset yielding a larger and more sustained therapeutic drug volume. Hydrogels with higher permeability or lower drug affinity enhance early concentration and distribution but decline faster over time. Drugs with lower intracellular partitioning improve early efficacy, whereas those with stronger binding to cellular or extracellular components sustain delivery longer. Lower transvascular permeability and slower elimination further enhance outcomes, while extracellular diffusivity must be optimised to maximise drug concentration and distribution. These findings provide guidance for optimising hydrogel-based drug delivery systems to prevent glioblastoma recurrence.

Three-dimensional printing of medicines is moving from feasibility to practice across hospital point-of-care manufacture, community-pharmacy compounding and industrial production. Recent signals include a point-of-care printed oral solid dosage form that met bioequivalence in healthy adults, automated capsule preparation with embedded checks in pharmacies and the first approved industrial product. These advances suggest that 3D printing can deliver clinically acceptable quality when responsibilities, verification and documentation are in place. This review integrates evidence across all three settings and offers a critical appraisal of what is required for safe adoption. We examine how regulatory responsibilities should be allocated across distributed sites, how non-destructive testing and chemometric models can be validated for small batches and which digital systems are essential for traceability and oversight. We analyse where economics break even compared with conventional compounding and identify use cases where 3D printing is comparatively advantaged, including low-dose titration, paediatric formats and rapid design iteration. We also outline risks that must be managed, including training and competency, cleaning validation, cross-contamination control and pharmacovigilance across networks. Finally, we propose a near-term agenda that includes standardised conduct of point-of-care trials, multi-site cost and quality benchmarking, explicit guidance on recalls and labelling and deeper industrial-clinical partnerships to turn pilots into routine practice.

Inclusion of physiologically relevant clearance mechanisms into organ-on-a-chip models is essential to reproduce tissue exposure and predict therapeutic efficacy, especially for local therapies and drug delivery applications that are already common in the clinic for ocular and cancer treatments. There remains a need for clearance-enabled organ-on-a-chips amenable to high throughput screening, especially with the emerging trend to expedite formulation and drug delivery vehicle (DDV) design with machine learning. To address this gap, we developed a microfluidic platform that incorporates continuous, pressure-driven clearance through interconnected microchannels and three-dimensional (3D) systems, enabling translational evaluation of local therapies and DDVs, such as injectable hydrogels, that aim to reduce systemic toxicity and enhance efficacy by prolonging drug residence at disease sites. In this study, fluorescent 4 and 65 kDa dextrans were used to confirm that pressure gradients across the platform promote efficient clearance versus passive diffusion. The pressure gradients were then applied to breast cancer spheroids co-cultured with macrophages in a fibrin hydrogel to evaluate the therapeutic efficacy of an interferon gamma (IFN-γ)-releasing agarose hydrogel in combination with anti-human epidermal growth factor receptor 2 (anti-HER2). Fluorescent imaging of spheroid area revealed increased cancer cell viability, lower drug efficacy, when continuous clearance was present, highlighting the impact of drug clearance. This study establishes the clearance-enabled microfluidic platform as a translationally relevant in vitro model for evaluating local therapies under continuous clearance, thereby bridging the gap between traditional static platforms and in vivo models for evaluating local pharmacokinetics and pharmacodynamics.