OBJECTIVE: To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain tissueMETHODS: Citicoline, cytidine diphosphocholine, designated as CDP-choline, was purchased as a white powder with the molecular weight of 510.31 g/mol. The triblock copolymers of polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol (PEG-PPG-PEG), branded as Pluronic F127, was used.
RESULTS: When instilled into the nasal cavity, Pluronic F127 for intranasal administration is transformed into a gel that remains retained for 45-55 minutes, which promotes better penetration of drugs into the brain tissue.
CONCLUSIONS: The polymer\'s gelling and adhesive properties performed well, which is crucial for further research at the preclinical stage (Tab. 1, Fig. 5, Ref. 28).

BACKGROUND: The rapid growth and diversification of drug delivery systems have been significantly supported by advancements in micro- and nano-technologies, alongside the adoption of biodegradable polymeric materials like poly(lactic-co-glycolic acid) (PLGA) as microcarriers. These developments aim to reduce toxicity and enhance target specificity in drug delivery. The use of in silico methods, particularly molecular dynamics (MD) simulations, has emerged as a pivotal tool for predicting the dynamics of species within these systems. This approach aids in investigating drug delivery mechanisms, thereby reducing the costs associated with design and prototyping. In this study, we focus on elucidating the diffusion mechanisms in curcumin-loaded PLGA particles, which are critical for optimizing drug release and efficacy in therapeutic applications.
METHODS: We utilized MD to explore the diffusion behavior of curcumin in PLGA drug delivery systems. The simulations, executed with GROMACS, modeled curcumin molecules in a representative volume element of PLGA chains and water, referencing molecular structures from the Protein Data Bank and employing the CHARMM force field. We generated PLGA chains of varying lengths using the Polymer Modeler tool and arranged them in a bulk-like environment with Packmol. The simulation protocol included steps for energy minimization, T and p equilibration, and calculation of the isotropic diffusion coefficient from the mean square displacement. The Taguchi method was applied to assess the effects of hydration level, PLGA chain length, and density on diffusion.
RESULTS: Our results provide insight into the influence of PLGA chain length, hydration level, and polymer density on the diffusion coefficient of curcumin, offering a mechanistic understanding for the design of efficient drug delivery systems. The sensitivity analysis obtained through the Taguchi method identified hydration level and PLGA density as the most significant input parameters affecting curcumin diffusion, while the effect of PLGA chain length was negligible within the simulated range. We provided a regression equation capable to accurately fit MD results. The regression equation suggests that increases in hydration level and PLGA density result in a decrease in the diffusion coefficient.

Bioengineering and drug delivery technologies play an important role in bridging the gap between basic scientific discovery and clinical application of therapeutics. To identify the optimal treatment, the most critical stage is to diagnose the problem. Often these two may occur simultaneously or in parallel, but in this review, we focus on bottom-up approaches in understanding basic immunologic phenomena to develop targeted therapeutics. This can be observed in several fields; here, we will focus on one of the original immunotherapy targets-cancer-and one of the more recent targets-regenerative medicine. By understanding how our immune system responds in processes such as malignancies, wound healing, and medical device implantation, we can isolate therapeutic targets for pharmacologic and bioengineered interventions.

UNASSIGNED: Regadenoson, an agonist of adenosine A2 receptors, enables transient blood-brain barrier (BBB) disruption. The relevance of regadenoson as a pharmacological strategy for brain delivery was investigated using in vivo PET imaging in rats.
UNASSIGNED: Kinetic modeling of brain PET data was performed to estimate the impact of regadenoson (0.05 mg.kg-1, i.v.) on BBB permeation compared with control rats (n = 4-6 per group). Three radiolabeled compounds of different sizes, which do not cross the intact BBB, were tested.
UNASSIGNED: Regadenoson significantly increased the BBB penetration (+116 ± 13%, p < 0.001) of [18F]2-deoxy-2-fluoro-D-sorbitol ([18F]FDS, MW = 183 Da), a small-molecule marker of BBB permeability. The magnitude of the effect was different across brain regions, with a maximum increase in the striatum. Recovery of BBB integrity was observed 30 min after regadenoson injection. Regadenoson also increased the brain penetration (+72 ± 45%, p < 0.05) of a radiolabeled nanoparticle [89Zr]AGuIX (MW = 9 kDa). However, the brain kinetics of a monoclonal antibody ([89Zr]mAb, MW = 150 kDa) remained unchanged (p > 0.05).
UNASSIGNED: PET imaging showed the features and limitations of BBB disruption induced by regadenoson in terms of extent, regional distribution, and reversibility. Nevertheless, regadenoson enables the brain delivery of small molecules or nanoparticles in rats.

Intralesional corticosteroid injections are a first-line treatment for keloids; yet clinical treatment results are highly variable and often suboptimal. Variation in triamcinolone acetonide (TAC) biodistribution may be an important reason for the variable effects of TAC treatment in keloids. In this exploratory study we investigated the biodistribution of TAC in keloids and normal skin using different drug delivery techniques. Fluorescent-labeled TAC suspension was administered into keloids and normal skin with a hypodermic needle and an electronic pneumatic jet injector. TAC biodistribution was represented by the fluorescent TAC volume and 3D biodistribution shape of TAC, using a 3D-Fluorescence-Imaging Cryomicrotome System. Twenty-one keloid and nine normal skin samples were analyzed. With needle injections, the mean fluorescent TAC volumes were 990 µl ± 479 in keloids and 872 µl ± 227 in normal skin. With the jet injector, the mean fluorescent TAC volumes were 401 µl ± 252 in keloids and 249 µl ± 67 in normal skin. 3D biodistribution shapes of TAC were highly variable in keloids and normal skin. In conclusion, TAC biodistribution in keloids is highly variable for both needle and jet injection. This may partly explain the variable treatment effects of intralesional TAC in keloids. Future research is needed to confirm this preliminary finding and to optimize drug delivery in keloids.

This study focused on synthesis of innovative hydrogels with electric field response from modified pineapple peel cellulose and hericium erinaceus chitosan and gelatin based on Schiff base reaction. A series of hydrogels were prepared by oxidized hydroxyethyl cellulose, gelatin and chitosan at different deacetylation degree via mild Schiff base reaction. Subsequently experiments towards the characterization of oxidized hydroxyethyl cellulose/gelatin/chitosan (OHGCS) hydrogel polymers were carried out by FTIR/XRD/XPS, swelling performances and electric response properties. The prepared hydrogels exhibited stable and reversible bending behaviors under repeated on-off switching of electric fields, affected by ionic strength, electric voltage and pH changes. The swelling ratio of OHGCS hydrogels was found reduced as deacetylation degree increasing and reached the maximum ratio ∼ 2250 % for OHGCS-1. In vitro drug releasing study showed the both curcumin loading capacity and release amount of Cur-OHGCS hydrogels arrived about 90 % during 6 h. Antioxidation assessments showed that the curcumin-loaded hydrogels had good antioxidation activities, in which, 10 mg Cur-OHGCS-1 hydrogel could reach to the maximum of about 90 % DPPH scavenging ratio. These results indicate the OHGCS hydrogels have potentials in sensor and drug delivery system.

UNASSIGNED: This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug-device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If \'other differences\' between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested.
UNASSIGNED: The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted.
UNASSIGNED: After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed.
UNASSIGNED: DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug-device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If \'other differences\' are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

OBJECTIVE: Drug inhalation is generally accepted as the preferred administration method for treating respiratory diseases. To achieve effective inhaled drug delivery for an individual, it is necessary to use an interdisciplinary approach that can cope with inter-individual differences. The paper aims to present an individualised pulmonary drug deposition model based on Computational Fluid and Particle Dynamics simulations within a time frame acceptable for clinical use.
METHODS: We propose a model that can analyse the inhaled drug delivery efficiency based on the patient\'s airway geometry as well as breathing pattern, which has the potential to also serve as a tool for a sub-regional diagnosis of respiratory diseases. The particle properties and size distribution are taken for the case of drug inhalation by using nebulisers, as they are independent of the patient\'s breathing pattern. Finally, the inhaled drug doses that reach the deep airways of different lobe regions of the patient are studied.
RESULTS: The numerical accuracy of the proposed model is verified by comparison with experimental results. The difference in total drug deposition fractions between the simulation and experimental results is smaller than 4.44% and 1.43% for flow rates of 60 l/min and 15 l/min, respectively. A case study involving a COVID-19 patient is conducted to illustrate the potential clinical use of the model. The study analyses the drug deposition fractions in relation to the breathing pattern, aerosol size distribution, and different lobe regions.
CONCLUSIONS: The entire process of the proposed model can be completed within 48 h, allowing an evaluation of the deposition of the inhaled drug in an individual patient\'s lung within a time frame acceptable for clinical use. Achieving a 48-hour time window for a single evaluation of patient-specific drug delivery enables the physician to monitor the patient\'s changing conditions and potentially adjust the drug administration accordingly. Furthermore, we show that the proposed methodology also offers a possibility to be extended to a detection approach for some respiratory diseases.

Objective: This study aimed to develop a new delivery strategy that utilized metal organic framework (MOF) loaded with small-interfering RNA (siRNA) targeting ITGAV to overcome tumor matrix barrier, and thus enhance drug penetration and immune accessibility in breast cancer. Methods: MOF@siITGAV particles were constructed and characterized. The uptake of MOF@siITGAV in breast cancer cell line 4T1 was observed by the cellular uptake assay. The toxicity of MOF@siITGAV was detected by cell counting kit 8 (CCK-8). The blank control group, naked siITGAV group and MOF@siITGAV group were set. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect the expressions of ITGAV. The level of transforming growth factor β1 (TGF-β1) in the cell culture medium was detected by enzyme-linked immunosorbent assay (ELISA). The penetration of MOF@siITGAV in 4T1 cells was tested by constructing 3D spheroids. Mouse models of triple negative breast cancer were established. The effect of MOF@siITGAV on the growth of transplanted tumors and main organs was verified. Imminohistochemical (IHC) was used to test the expression of collagen and CD8. Results: MOF@siITGAV particles were constructed with sizes of (198.0±3.3) nm and zeta potential of -(20.2±0.4) mV. MOF@siITGAV could be engulfed by 4T1 cells and triggered to release siRNA. Compared to the blank control group, the expression of ITGAV in the MOF@siITGAV group [(46.5±11.3)%] and the naked siITGAV group [(109.9±19.0)%] was lower. TGF-β1 in the cell culture medium of the blank control group, naked siITGAV group, and MOF@siITGAV group was (474.5±34.4) pg/ml, (437.2±16.5) pg/ml, and (388.4±14.4) pg/ml, respectively. MOF@siITGAV could better penetrate into 4T1 spheroids and exhibit no obvious toxicity. The cell viability was (99.7±3.5)%, (98.2±5.2)%, (97.3±6.6)%, (92.1±8.1)%, and (92.4±4.1)%, respectively, after MOF@siITGAV treatment with the concentration of 0, 10, 20, 40, 80, and 160 μg/ml, respectively, for 24 h. The tumor growth in the MOF@siITGAV group was suppressed significantly. After 15-day treatment, the tumor volume of the MOF@siITGAV group was (135.3±41.9) mm3, smaller than that of the blank control group [(691.1±193.0) mm3] (P=0.025). The expression of collagen and the number of CD8 positive cells of the MOF@siITGAV group were lower than those of the other two groups. No significant abnormalities were observed in the main organs of mice. Conclusions: Targeting the integrinαv on the surface of cancer cells could destroy extracellular matrix, improve drug delivery, and increase immune infiltration.
目的： 开发一种新型递送策略，利用金属有机框架（MOF）负载针对整合素αv（ITGAV）的小干扰RNA siITGAV，以克服基质屏障，进而增强乳腺癌内药物递送及免疫可及性。 方法： 构建MOF@siITGAV颗粒，对其进行材料表征。通过细胞摄取实验观察乳腺癌4T1细胞对MOF@siITGAV的摄取情况，细胞计数试剂盒8法检测MOF@siITGAV的细胞毒性。设空白对照组、游离siITGAV组和MOF@siITGAV组，采用实时荧光定量聚合酶链反应检测各组4T1细胞中ITGAV mRNA的表达，采用Western blot检测ITGAV蛋白的表达，采用酶联免疫吸附试验检测TGF-β1的含量。采用3D球体穿透实验观察MOF@siITGAV穿透4T1细胞球的能力。建立三阴性乳腺癌小鼠模型，观察MOF@siITGAV对移植瘤生长及小鼠心、肝、脾、肺、肾等主要脏器的影响，采用免疫组化染色检测肿瘤组织中Ⅰ型胶原蛋白和CD8的表达。 结果： 成功构建MOF@siITGAV颗粒，粒径为（198.0±3.3）nm，电位为-（20.2±0.4）mV。4T1细胞能有效摄取MOF@siITGAV，并触发siRNA的有效释放，MOF@siITGAV组细胞中ITGAV mRNA和蛋白表达水平、TGF-β1的表达水平均显著下调［相对于空白对照组，游离siITGAV组和MOF@siITGAV组4T1细胞中ITGAV mRNA相对表达水平分别为（109.9±19.0）%和（46.5±11.3）%；空白对照组、MOF@siNC组和MOF@siITGAV组TGF-β1浓度分别为（474.5±34.4）pg/ml、（437.2±16.5）pg/ml和（388.4±14.4）pg/ml］。MOF@siITGAV在4T1细胞球中的穿透能力更强，对4T1细胞无明显杀伤效应，0、10、20、40、80和160 μg/ml MOF@siITGAV分别处理4T1细胞24 h，细胞活性分别为（99.7±3.5）%、（98.2±5.2）%、（97.3±6.6）%、（92.1±8.1）%和（92.4±4.1）%。MOF@siITGAV能有效抑制小鼠乳腺癌移植瘤的生长，给药15 d后，空白对照组、MOF@siNC组和MOF@siITGAV组小鼠的肿瘤体积分别为（691.1±193.0）mm3、（652.7±306.5）mm3和（135.3±41.9）mm3，MOF@siITGAV组小鼠的肿瘤体积小于空白对照组（P=0.025）。与空白对照组和MOF@siNC组相比，MOF@siITGAV组小鼠肿瘤组织中Ⅰ型胶原蛋白的含量明显减少，CD8阳性细胞明显增多，心、肝、脾、肺、肾等主要脏器未见明显异常。 结论： ITGAV可以破坏乳腺癌的ECM，改善药物瘤内递送，促进免疫细胞浸润。.

The potential of using proteins as drugs is held back by their low stability in the human body and challenge of delivering them to the site of function. Extensive research is focused on drug delivery systems that can protect, carry, and release proteins in a controlled manner. Of high potential are cross-linked degradable starch microspheres (DSMs), as production of these is low-cost and environmentally friendly, and the products are degradable by the human body. Here, we demonstrate that DSMs can absorb the model protein lysozyme from an aqueous solution. At low amounts of lysozyme, its concentration in starch microspheres strongly exceeds the bulk concentration in water. However, at higher protein contents, the difference between concentrations in the two phases becomes small. This indicates that, at lower lysozyme contents, the absorption is driven by protein-starch interactions, which are counteracted by protein-protein electrostatic repulsion at high concentrations. By applying small-angle X-ray scattering (SAXS) to the DSM-lysozyme system, we show that lysozyme molecules are largely unaltered by the absorption in DSM. In the same process, the starch network is slightly perturbed, as demonstrated by a decrease in the characteristic chain to chain distance. The SAXS data modeling suggests an uneven distribution of the protein within the DSM particles, which can be dependent on the internal DSM structure and on the physical interactions between the components. The results presented here show that lysozyme can be incorporated into degradable starch microspheres without any dependence on electrostatic or specific interactions, suggesting that similar absorption would be possible for pharmaceutical proteins.