Drug Delivery and Translational Research最新文献

Despite being the most widely prescribed formulation, oral formulations possess several limitations such as low adherence, low bioavailability, high toxicity (in the case of anticancer drugs), and multiple-time administration requirements. All these limitations can be overcome by long-acting injectables. Improved adherence, patient compliance, and reduced relapse have been observed with long-acting formulation which has increased the demand for long-acting injectables. Drugs or peptide molecules with oral bioavailability issues can be easily delivered by long-acting systems. This review comprehensively addresses the various technologies used to develop long-acting injections with a particular focus on hydrophilic drugs and large molecules as well as the factors affecting the choice of formulation strategy. This is the first review that discusses the possible technologies that can be used for developing long-acting formulations for hydrophilic molecules along with factors which will affect the choice of the technology. Furthermore, the mechanism of drug release as well as summaries of marketed formulations will be presented. This review also discusses the challenges associated with the manufacturing and scale-up of the long-acting injectables.

We demonstrated for the first time that a marine-derived antimicrobial peptide (AMP), Sph_12-38, exhibit high antimicrobial activity against P. acnes with a minimum bactericidal concentration (MBC) value of 7 μM. Meanwhile, Sph_12-38 has no significant cytotoxicity to human keratinocytes (HKs) at its high concentration (33.5 μM). The topical application of sponge Haliclona sp. spicules (SHS) dramatically enhanced the skin penetration of Sph_12-38 up to 40.9 ± 5.9% (p < 0.01), which was 6.1 ± 0.9-fold higher than that of Sph_12-38 alone. Further, SHS resulted in the accumulation of most Sph_12-38 in viable epidermis and dermis. Further, the combined use of Sph_12-38 and SHS resulted in a cure rate of 100% for rabbit ear acne treatment in vivo for two weeks, while the one induced by other groups was 40%, 0% and 0% for SHS alone, Sph_12-38 alone and control group, respectively. The strategy of combined using AMP and SHS can also be applied in a rational designed topical delivery system for the management of other deep infection of the skin. The effectiveness of SHS by itself on the treatment of acne was also demonstrated by clinical trials. After 14 days of treatment by 1% SHS gel. The number of skin lesions decreased by 51.4%.

Effective strategies against the spread of respiratory viruses are needed, as tragically demonstrated during the COVID-19 pandemic. Apart from vaccines, other preventive or protective measures are necessary: one promising strategy involves the nasal delivery of preventive or protective agents, targeting the site of initial infection. Harnessing the immune system's ability to produce specific antibodies, a hyperimmune serum, collected from an individual vaccinated against SARS-CoV-2, was formulated as a dry powder for nasal administration. The selection of adequate excipients and process are key to maintaining protein stability and modulating the aerodynamic properties of the powders for reaching the desired respiratory regions. To this end, a hyperimmune serum was formulated with trehalose and mannitol as bulking agents during spray drying, then the ability of the redissolved immunoglobulins to bind Spike protein was verified by ELISA; foetal bovine serum was formulated in the same conditions as a reference. Moreover, a seroneutralization assay against SARS-CoV-2 pseudoviruses generated from different variants of concern was performed. The neutralizing ability of the serum was slightly reduced with respect to the starting serum when trehalose was used as a bulking agent. The powders were loaded in hypromellose capsules and aerosolized employing a nasal insufflator in an in vitro model of the nasal cavity connected to a Next Generation Impactor. The analysis of the powder distribution confirmed that all powders were inhalable and could target, at the same time, the upper and the lower airways. This is a preliminary proof-of-concept that this approach can constitute an effective strategy to provide broad coverage and protection against SARS-CoV-2, and in general against viruses affecting the airway. According to blood availability from donors, pools of hyperimmune sera could be rapidly formulated and administered, providing a simultaneous and timely neutralization of emerging viral variants.

Oral diseases rank among the most widespread ailments worldwide posing significant global health and economic challenges affecting around 3.5 billion people, impacting the quality of life for affected individuals. Dental caries, periodontal disease, bacterial and fungal infections, tooth loss and oral malignancies are among the most prevalent global clinical disorders contributing to oral health burden. Traditional treatments for oral diseases often face challenges such as poor drug bioavailability, breakdown of medication in saliva, inconsistent antibiotic levels at the site of periodontal infection as well as higher side effects. However, the emergence of nanoemulgel (NEG) as an innovative drug delivery system offers promising solutions where NEG combines the advantages of both nanoemulsions (NEs) and hydrogels providing improved drug solubility, stability, and targeted delivery. Due to their minuscule size and ability to control drug release, NEGs hold promise for improving treatment of oral diseases, where versatility of these delivery systems makes them suitable for various applications, including topical delivery in dentistry. This review concisely outlines the anatomy of the oral environment and investigates the therapeutic potential of NE-based gels in oral disorder treatment. It thoroughly examines the challenges of drug delivery in the oral cavity and proposes strategies to improve therapeutic efficacy, drawing attention to previous research reports for comparison. Through comprehensive analysis, the review highlights the promising role of NEGs as a novel therapeutic approach for oral health management via research advancements and their clinical translation. Additionally, it provides valuable insights into future research directions and development opportunities in this area.

New wound dressings based on polymeric membranes have been widely exploited for clinical applications to assist in the healing process and prevent additional complications (e.g., bacterial infections). Here we propose the development of a new production method of polymeric membranes based on chitosan, incorporating glycolic extract of Aloe vera with joint synthesis of silver nanoparticles for use as a new bioactive dressing. The membranes were obtained by casting technique, and their morphological, physicochemical characteristics, degree of swelling, degradation profile and antimicrobial activity evaluated. Morphological analyzes confirmed the synthesis and presence of silver nanoparticles in the polymeric membrane. The chemical compatibility between the materials was demonstrated through thermal analysis (TGA and DSC) combined with ATR-FTIR tests, showing the complexation of the membranes (Mb-Ch-Ex.Av-NPs). All membranes were characterized as hydrophilic material (with a contact angle (ө) < 90°); however, the highest degree of swelling was obtained for the chitosan. (Mb-Ch) membrane (69.91 ± 5.75%) and the lowest for Mb-Ch-Ex.Av-NPs (26.62 ± 8.93%). On the other hand, the degradation profile was higher for Mb-Ch-Ex.Av-NPs (77.85 ± 7.51%) and lower for Mb-Ch (57.60 ± 2.29%). The manufactured bioactive dressings showed activity against Escherichia coli and Staphylococcus aureus. Our work confirmed the development of translucent and flexible chitosan-based membranes, incorporating Aloe vera glycolic extract with joint synthesis of silver nanoparticles for use as a new bioactive dressing, with proven antimicrobial activity.

Due to the small capacity of the eye cavity and the rapid drainage of liquid into the nasolacrimal duct, patients must frequently administer the drops. Nanoparticles (NPs) and in situ gel systems have each proven their ability to achieve eye retention independently. In this study, timolol-loaded chitosan-carbomer NPs were prepared using the polyelectrolyte complexation method, and incorporated into a pH-responsive in situ gel system made of carbomer. The rheological behavior of NPs-laden in situ gel was examined at room and physiological conditions. Characteristics such as zeta potential, surface tension, refractive index, mucoadhesive properties, drug release, transcorneal permeability, and intra-ocular pressure (IOP) lowering activity were investigated on NPS and NPs-laden in situ gel formulations. The optimum gained NPs system had an encapsulation efficiency of about 69% with a particle size of 196 nm. The zeta potential of the NP and NPs-laden in situ gel were - 16 and + 11 mV respectively. NPs-laden in situ gel presented enhanced viscosity at physiological pH. All physicochemical properties were acceptable for both formulations. NPs and NPs-laden in situ gel systems proved to sustain drug release. They showed mucoadhesive properties which were greater for NPs-laden in situ gel. IOP reduction by NPs-laden in situ gel was significantly higher and more long-lasting than the timolol solution and NPs. In conclusion, the developed NPs-laden in situ gel is a promising carrier for ocular drug delivery due to the slow release of drug from nanoparticles, its mucoadhesive properties, and high viscosity acquisition in contact with precorneal film, which lead to improved therapeutic efficacy.

The therapeutic potential of natural medicines in treating bone disorders is well-established. Modifications in formulation or molecular structure can enhance their efficacy. Gingerol, an osteogenic active compound derived from ginger roots (Zingiber officinale), can form metal ion complexes. Zinc (Zn), a trace element that combats bacterial infections and promotes osteoblast proliferation, can be complexed with gingerol to form a G-Zn⁺² complex. This study investigates a porous 3D-printed (3DP) calcium phosphate (CaP) scaffold loaded with the G-Zn⁺² complex for drug release and cellular interactions. The scaffold is coated with polycaprolactone (PCL) to control the drug release. Diffusion-mediated kinetics results in 50% release of the G-Zn⁺² complex over 6 weeks. The G-Zn⁺² complex demonstrates cytotoxicity against MG-63 osteosarcoma cells, indicated by the formation of apoptotic bodies and ruptured cell morphology on the scaffolds. G-Zn⁺² PCL-coated scaffolds show a 1.2 ± 0.1-fold increase in osteoblast cell viability, and an 11.6 ± 0.5% increase in  alkaline phosphatase compared to untreated scaffolds. Treated scaffolds also exhibit reduced bacterial colonization against Staphylococcus aureus bacteria, highlighting the antibacterial potential of the G-Zn⁺² complex. The functionalized 3DP CaP scaffold with the G-Zn⁺² complex shows significant potential for enhancing bone regeneration and preventing infections in low-load-bearing applications.

Bacterial resilience within biofilms, rendering them up to 1000 times more resistant to antibiotic drugs, poses a formidable challenge. This study introduces a targeted biofilm eradication strategy, termed "target-penetration-killing-eradication", implemented through magnetic micro-robotic technology. Specifically, we present the development of a magnetic-guided nano-antibacterial platform designed for alternating magnetic field (AMF) controlled vancomycin release in the eradication of Staphylococcus aureus biofilms. To address the issue of premature vancomycin release in physiological conditions, we employed a temperature-sensitive linking agent, 4,4'-azobis(4-cyano valeric acid), facilitating the conjugation of vancomycin onto Fe₃O₄/CS nanocomposites, resulting in the novel construct Fe₃O₄@CS-ACVA-VH. The release mechanism adheres to first-order kinetics and Fickian diffusion, with each 10-min AMF treatment releasing approximately 8.4 ± 1.1% of vancomycin. The potency of vancomycin in the release solution was similar to that of the original drug (MIC: 7.4 ± 3.5 vs. 5.6 μg/mL). Fe₃O₄@CS-ACVA-VH exhibited sustained antibacterial efficacy, inhibiting bacterial growth for four consecutive days and preventing the formation of bacterial biofilms on its surface. Contact-inhibition bacterial activity of Fe₃O₄@CS-ACVA-VH against S. aureus was 0.046875 mg/mL. Conceptually validating our approach, we emphasize Fe₃O₄@CS-ACVA-VH's exceptional ability to penetrate S. aureus biofilms under static magnetic field attraction. Furthermore, the nano-platform offers the unique advantage of on-demand vancomycin release through alternating magnetic field stimulation, effectively clearing a larger biofilm area. This multifunctional nano-platform demonstrates magnetic-guided biofilm penetration followed by controlled vancomycin release, presenting a promising strategy for enhanced biofilm eradication.

Metal-Organic Frameworks (MOFs) have been shown to enhance the activity of encapsulated compounds by facilitating their passage across cell membranes, thereby enabling controlled and selective release. This study investigates the efficacy of BNZ@Zn-MOFs against the acute phase of Trypanosoma cruzi infection in a mouse model. The particles were synthesized by electroelution (EL), doped with BZN via mechanochemistry, and characterized using scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and X-ray diffraction (XRD). BNZ@Zn-MOFs released 80% of the encapsulated BZN within 3 h, demonstrating no cytotoxicity in NIH-3T3 and HeLa cells. Furthermore, in a model of acute experimental T. cruzi-infection in BALB/c mice, the delivery system exhibited antiparasitic activity at a significantly lower BZN concentration compared to free BZN treatment. PCR analysis of treated mice revealed no parasite DNA in their tissues, and hematoxylin-eosin staining showed no apparent damage to tissue architecture. Additionally, serum levels of liver function enzymes remained unchanged, indicating no adverse effects on liver function. This delivery system, utilizing suboptimal BZN doses, enables the preservation of drug activity while potentially facilitating a substantial decrease in side effects associated with Chagas disease treatment.

Mifepristone, a progesterone receptor antagonist, was initially used to terminate early pregnancy. As scientific research advanced, it emerged to be effective in the treatment of various tumors and tumor-like conditions such as endometriosis. Despite the therapeutic potential of mifepristone, its therapeutic effect is still far from ideal because the drug is difficult to dissolve and to accumulate in the target tissue sites. To address this issue, mifepristone-loaded nanostructured lipid carriers (Mif-NLC) were prepared by a simple solvent diffusion method and their anti-endometriosis performance and mechanisms were initially investigated. By optimizing the preparation protocol, we obtained uniform and spheroidal Mif-NLC with an average particle size of 280 nm. The encapsulation rate and drug loading capacity were 64.67% ± 0.15% and 2.7% ± 0.014%, respectively, as measured by UV spectrophotometry. The in vitro release kinetics indicated that mifepristone was released from NLC in a sustained-release manner. Compared with free mifepristone, Mif-NLC exhibited enhanced cellular uptake and inhibition of invasion activity in primary mesenchymal cells of endometriosis. A certain reduction in the size of endometriotic cysts was observed in animals compared to controls. The induction of autophagy via Mif-NLC may serve as the molecular mechanism underlying this effect. Furthermore, observation of uterine structures showed negligible toxic effects. This suggested that mifepristone encapsulated in NLC can improve its bioavailability and anti-endometriosis efficacy, which provided a new strategy for the treatment of endometriosis.