Drug Delivery and Translational Research最新文献

Agomelatine is an atypical antidepressant with a long half-life and the mechanism of action similar to melatonin. Agomelatine is a strong antioxidant and its anti-inflammatory effect has been reported in many studies. The current study aimed to evaluate the anti-inflammatory effect of agomelatine loaded in targeted nanoparticles (NPs) in an experimental colitis model induced by trinitrobenzene sulfonic acid (TNBS). Poly(1-vinylpyrrolidone)-graft-(1-triacontene) (PVP-TA) and Eudragit^®-FS30D polymers were used alone and in combination as time, pH and time/pH dependent formulations respectively. The optimal formula was selected according to their physicochemical properties such as particle size, morphology, and drug release pattern. Six separate groups of rats were induced with 0.5 ml of TNBS. The designed groups were: normal, untreated, agomelatine (25 mg/kg/d), agomelatine/ Eudragit^®-FS30D NPs, agomelatine/ Eudragit-FS30D/PVP-TA NPs, and dexamethasone (Dex., 1 mg/kg/d). Twenty-four hours after the last administration, colonic tissue was analyzed for macroscopic and histopathological evaluations, along with quantification of malondialdehyde (MDA) and myeloperoxidase (MPO) levels. The results showed that the PVP-TA NPs alone was not suitable regarding to release profile and particle size distribution. However, Eudragit-FS30D NPs alone and Eudragit-FS30D + PVP-TA NPs passed physicochemical evaluations and were both effective in reducing the symptoms and indices of experimental colitis. Taken together, targeted NPs of agomelatine are potentially effective in treatment of ulcerative colitis.

The eyes are easily stimulated by external factors, which can cause inflammation. Anti-inflammatory drugs are usually used to inhibit the production of inflammatory factors. Many nonsteroidal anti-inflammatory drugs have been used for the eye, but due to the poor solubility of meloxicam, there are currently no marketed meloxicam preparations for the treatment of eye diseases. This article uses hydroxypropyl-β-CD (HP-β-CD) to encapsulate meloxicam and combined with thermosensitive gel to prepare an HP-β-CD/meloxicam inclusion complex eye thermosensitive gel, which can improved the water solubility of meloxicam and extend the retention time of the drug in the cornea, and achieve the goal of slow release through continuous dissolution. It not only has the advantages of convenient administration and accurate dosage of eye drops, but also overcomes the disadvantage of easy loss of eye drops, showing the advantages of long retention time and fewer administration times, and provides a basis for the development of other dosage forms of meloxicam.

Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Extracellular vesicles (EVs) are heterogeneously sized, cell-derived nanoparticles operating as proficient mediators of intercellular communication. They are produced by normal as well as diseased cells and carry a variety of cargo. While the molecular details of EV biology have been worked out over the past two decades, one question that continues to intrigue many is how are EVs able to evade the phagocytic immune cells while also being effectively internalized by the target cell or tissue. While some of the components that facilitate this process have started to be identified, many mechanisms are yet to be dissected. This review summarises some of the key mechanisms that cancer cell-derived and viral infected cell-derived EVs utilize to evade the immune system. It will discuss the diverse cloaking mechanisms, in the form of membrane proteins and cargo content that these EVs utilize to enhance pathogenesis. Further, it will highlight the different strategies that have been used to design EVs to escape the immune system, thereby increasing their circulation time with no major toxic effects in vivo. An understanding of the potential EV components that allow better immune evasion can be used to bioengineer EVs with better circulation times for therapeutic purposes.

TXA9, a cardiac glycoside isolated from the root of Streptocaulon juventas (Lour.) Merr., with better therapeutic effect in vitro on non-small cell lung cancer (NSCLC) than cisplatin and has no toxic side effects on the body. However, poor water solubility and rapid metabolism limited its clinical application. Multi-arm star PEG have many advantages over linear PEG, such as high drug loading due to more terminals and better anti-hemodilution ability, which have become popular carriers for drug delivery. In this study, to improve the efficacy of TXA9, 6/8armPEG_n-Glycine Carbamate (Gly) (n = 10, 20, and 40 kDa) were used as carriers to prepare star PEG-TXA9 conjugates. The particle size and zeta potential of six prodrug NPs for effective tumor targeting, with suitable drug loading, and good water solubility. Compared with free TXA9, 6/8APG_n-T NPs had more significant anti-tumor effects in vitro. Since the multi-arm star PEG formed an "umbrella" structure on the surface of NPs, the 8APG_40k-T NPs with the best pharmacokinetic properties increased half-life of TXA9 about 60 times in vivo. In addition, the arm numbers and molecular weight of multi-arm star PEGs significantly influenced the in vivo destiny of prodrugs. In vivo experiments showed that the same dose of 8APG_40k-T NPs increased the tumor inhibition rate about 3.56 or 1.22 times compared with TXA9 or cisplatin, and had good biocompatibility. This study provides a simple but effective strategy to solve the challenges caused by the poor water solubility and short half-life of TXA9 for developing the TXA9 as a safe and effective drug against NSCLC.

Cardiovascular diseases as myocardial infarction (MI) represent a major cause for morbidity and mortality worldwide. Even though, patients who survive MI are susceptible to high risk of heart failure. This is mainly attributed to the major loss of cardiomyocytes and limited regenerative potential of myocardium. Despite the availability of various cardiovascular drugs, they fail to address the main cause of MI. The optimum therapeutic goal should therefore focus on enhancing cardiac regeneration through cellular and cell-free therapeutic approaches. This review focused on different mechanisms of cardiac regeneration that can be achieved via non-cellular therapeutic modalities. Passive and active targeting of the infarcted myocardium using various nanoparticles that can be loaded with growth factors, drugs or affordable natural products can reduce negative ventricular remodeling, infarct size and the apoptotic rate of cardiomyocytes. In addition, injectable biomaterials-based nanocomposite can be used as a scaffold to support infarcted heart and recruit cells. Innovative affordable and less invasive cell-free approaches can be implemented to enhance cardiac regeneration post MI.

Using the knowledge from decades of research into RNA-based therapies, the COVID-19 pandemic response saw the rapid design, testing and production of the first ever mRNA vaccines approved for human use in the clinic. This breakthrough has been a significant milestone for RNA therapeutics and vaccines, driving an exponential growth of research into the field. The development of novel RNA therapeutics targeting high-threat pathogens, that pose a substantial risk to global health, could transform the future of health delivery. In this review, we provide a detailed overview of the two RNA interference (RNAi) pathways and how antiviral RNAi therapies can be used to treat acute or chronic diseases caused by the pandemic viruses SARS-CoV-2 and HIV, respectively. We also provide insights into short-interfering RNA (siRNA) delivery systems, with a focus on how lipid nanoparticles can be functionalized to achieve targeted delivery to specific sites of disease. This review will provide the current developments of SARS-CoV-2 and HIV targeted siRNAs, highlighting strategies to advance the progression of antiviral siRNA along the clinical development pathway.

Small interfering RNA (siRNA) and messenger RNA (mRNA) have drawn considerable attention in recent years due to their ability to modulate the expression of specific disease-related proteins. However, it is difficult to find safe, robust, and effective RNA delivery systems suitable for pulmonary delivery to treat lung diseases. In this study, two cationic peptides, namely LAH4-L1 and PEG₁₂KL4, were employed as non-viral vectors for siRNA and mRNA delivery. Four formulations (i.e. LAH4-L1/siRNA; PEG₁₂KL4/siRNA; LAH4-L1/mRNA and PEG₁₂KL4/mRNA) were investigated. Microfluidic mixing method was utilised to fabricate RNA complexes in a controllable and reproducible manner. Upon optimisation of the microfluidic mixing protocol, a vibrating mesh nebuliser was employed to aerosolise the RNA complexes, and their transfection efficiency was evaluated on A549 and BEAS-2B cells. Following nebulisation, inhalable mist was generated for all RNA formulations with mass median aerodynamic diameter below 5 μm. Although the hydrodynamic particle sizes of the RNA complexes were significantly reduced to around 100 nm after nebulisation regardless of the original size of the complexes prior to nebulisation, the RNA binding efficiency and the in vitro RNA transfection ability of all the peptide formulations were successfully preserved with no significant differences compared to the same system before nebulisation. The current result indicates that both LAH4-L1 and PEG₁₂KL4 hold significant potential for future clinical application for pulmonary siRNA and mRNA delivery through nebulisation.

This study reports the preparation of hydrogels (HG) made with xanthan gum (XG) and ƙ-carrageenan (KC) polysaccharides containing ketoprofen (KET)-loaded nanoemulsions (NK) and their evaluation in a rheumatoid arthritis (RA) model. The nano-based HGs exhibited nanometric-sized droplets (~ 100 nm), an acidic pH (5.10-6.83), drug content above 85%, a suitable spreadability factor, and pseudoplastic flow behavior. The most promising blend (HGCX 2:1) demonstrated sustained KET release, reaching 81.44 ± 6.11% after 5 h, and superior drug concentration in the skin layers (237.91 ± 41.0 µg/g). The formulation was selected due to its enhanced bioadhesiveness, with the HG-NK formulation showing the highest bioadhesion force and occlusion factor. RA was induced by complete Freund's adjuvant (CFA) intraplantar injection into the left hind paw of male and female Swiss mice. Treatments with HGs were applied to the animals' dorsal region for 7 days. Notably, HG-NK demonstrated remarkable efficacy, reversing mechanical sensitivity in male mice and significantly reducing thermal sensitivity in both genders. Moreover, HG-NK provided a significant reduction in paw edema (52-fold in males, 27-fold in females) and inflammatory markers, such as myeloperoxidase activity (32-fold in males, 14-fold in females) and lipid peroxidation (2.5-fold in males, twofold in females). The formulation also promoted greater permeation of KET across the skin. These findings underscore the significant reduction in inflammatory markers by the HG-NK formulation, highlighting its potent anti-inflammatory effects and potential as a promising therapeutic strategy for managing RA.

Aim: It was the aim of this study to compare two different dry reverse micelle (RM) preparation methods for the incorporation of hydrophilic drugs into oral self-emulsifying drug delivery systems (SEDDS).

Methods: Cationic ethacridine lactate, anionic fluorescein sodium salt and the antibiotic peptide bacitracin were solubilized in RM containing sodium docusate, soy phosphatidylcholine and sorbitan monooleate in highly lipophilic oils such as squalane. In the dry addition (DA) method, drugs were directly added to empty RM in their powder form. In the organic solvent-aided (OS) method, drugs were pre-dissolved in ethanol or 2-propanol, which were then evaporated to form loaded dry RM.

Results: RM with sorbitan monooleate prepared via the DA method yielded up to 2.7-fold higher solubility only for bacitracin compared to the OS method. In contrast, OS-RM with sodium docusate and soy phosphatidylcholine exhibited significantly higher drug solubilities, achieving up to 109-fold, 44-fold and 97-fold increase for ethacridine, fluorescein and bacitracin, respectively. For all model drugs, the logD_{lipophilic phase/water} was highest for RM comprising sorbitan monooleate, with a slight increase for OS-RM. This was consistent with the release profiles from SEDDS, showing an enhanced retention when loaded with OS-RM. While DA-RM showed no significant difference in cellular uptake, it was 1.6-fold higher in OS-RM loaded squalane-based SEDDS.

Conclusion: The DA method is an easier approach for incorporating hydrophilic drugs into dry RM. However, the OS method presents a more promising alternative as it significantly enhanced the solubility and retention of these drugs in highly lipophilic formulations.