Molecular Pharmaceutics最新文献

Glioblastoma multiforme (GBM) is considered to be one of the most devastating brain tumors with a shorter life expectancy. Several factors contribute to the dismal prognosis of GBM patients including the complicated nature of GBM, the ability of tumor cells to resist treatment, and the difficulty of delivering drugs to the brain because of barriers like the blood-brain barrier (BBB) and blood-tumor barrier (BTB). The unique challenges posed by the BBB in delivering therapeutic agents to the brain have led to the development of innovative nanotechnology-based approaches. By exploiting the olfactory/trigeminal pathway, nanosystems offer a promising strategy for targeted drug delivery to the brain, glioblastoma tumors in particular. This review contemplates varied nanocarriers, including polymeric nanoparticles, lipid-based nanosystems, in situ gel formulations, peptide, and stem cell-based nanoformulations, signifying their utility in brain targeting with minimal systemic side effects. Emerging trends in gene therapy and immunotherapy in the context of GBM treatment have also been discussed. Since safety is a paramount aspect for any drug product to get approved, this review also delves into toxicological considerations associated with intranasal delivery of nanosystems. Regulatory aspects and critical factors for the successful development of intranasal products are also explored in this review. Overall, this review underscores the significant advancements in nanotechnology for nose-to-brain delivery and its potential impact on GBM management.

Developing low-toxicity, high-efficacy, and fast-acting strategies to manage acute liver injury (ALI) is critical due to its rapid progression and potential for severe outcomes. Curcumin (CUR) has shown promise in ALI therapy due to its ability to modulate the inflammatory microenvironment by scavenging reactive oxygen species (ROS). Nevertheless, CUR is highly hydrophobic limiting its bioavailability and effective in vivo transport, which hinders its further application. In this study, we developed an inflammatory microenvironment-targeted drug delivery system by covalently coupling human serum albumin (HSA) with ROS-sensitive thioketal linkers and loading it with CUR to form nanoparticles (HSA-TK/CUR). These nanoparticles were then coated with a macrophage membrane (CM@HSA-TK/CUR), resulting in negatively charged spherical particles (≈ -23.26 mV) with an average particle size of around 165 nm. ROS responsiveness was confirmed through drug release assays and enhanced ROS depletion was further demonstrated by Diacetyldichlorofluorescein (DCFH-DA) ROS detection experiments. CM@HSA-TK/CUR treatment resulted in a 94.7% reduction in ROS levels in inflammatory cells. In addition, cellular uptake and in vivo distribution experiments demonstrated that camouflaging HSA-TK/CUR with macrophage membranes significantly enhanced its targeting of the inflammatory microenvironment. The findings revealed that CM@HSA-TK/CUR rapidly accumulated in the injured liver within 6 h, inhibited the production of pro-inflammatory factors (IL-1β, IL-6, and TNF-α), shifted macrophage polarization from M1 to M2 in vivo, and protected hepatocytes from oxidative stress-associated cell death, significantly attenuating the inflammatory response in ALI mice. In conclusion, CM@HSA-TK/CUR has excellent potential in treating mice with ALI.

The morbidity and mortality rates of hepatocellular carcinoma (HCC) are high and continue to increase. The antitumor effects of single therapies are limited because of tumor heterogeneity and drug resistance, and the lack of real-time monitoring of tumor progression during the treatment process leads to poor therapeutic outcomes. Therefore, novel nanodelivery platforms combining tumor therapy and diagnosis have garnered extensive attention. In this study, we developed a multifunctional nanodelivery vector, LPSD-DOX/siRNA, which was loaded with oleic acid-modified superparamagnetic iron oxide nanoparticles (OA-SPION) and the antitumor drug doxorubicin (DOX), further modified by DOTAP to carry small interfering RNA targeting phosphatidylinositol proteoglycan-3 (Glypican-3, GPC3) (siRNA-GPC3). These components were utilized for the combined treatment of HCC and tumor monitoring with magnetic resonance imaging. LPSD-DOX/siRNA exhibited high drug loading, high gene transfection efficiency, and low toxicity. Pharmacokinetic and in vivo distribution experiments showed that LPSD-DOX/siRNA significantly prolonged the circulation time of DOX and enhanced drug accumulation at the tumor site. Magnetic resonance imaging demonstrated that LPSD-DOX/siRNA can serve as a T2 imaging contrast agent to enhance the imaging contrast between the tumor site and other tissues and facilitate the imaging monitoring of tumor tissues. Antitumor experiments revealed that the effects of DOX were promoted by inhibiting the expression of GPC3 protein in HepG2 cell-transplanted tumors, with increased tumor apoptosis. In conclusion, LPSD-DOX/siRNA serves as a promising strategy for combination therapy and monitoring of HCC, with significant potential in antitumor therapy.

This investigation aimed to enhance transdermal methotrexate delivery through human skin by employing Dr. Pen microneedles and poly(d,l-lactide-co-glycolide) acid microparticles formulated from eight polymer grades (Expansorb DLG 95-4A, DLG 75-5A, DLG 50-2A, DLG 50-5A, DLG 50-8A, DLG 50-6P, DLG 50-7P, and DLL 10-15A). A comprehensive characterization of the microparticles was performed, encompassing various parameters such as size, charge, morphology, microencapsulation efficiency, yield, release kinetics, and chemical composition. The efficacy of microneedles in disrupting skin integrity was demonstrated by scanning electron microscopy, dye binding, histological examination, confocal laser microscopy, and pore size analysis. Microneedle-mediated skin microporation led to a substantial reduction in skin electrical resistance and a concomitant increase in transepidermal water loss. In vitro permeation experiments using human skin delivered microparticles into microporated skin and demonstrated a considerable difference in methotrexate delivery among the polymer groups. Microneedle treatment significantly amplified cumulative drug delivery, steady-state flux, diffusion coefficient, permeability coefficient, and drug concentration within skin layers while concurrently diminishing lag time (p < 0.05). Furthermore, a robust correlation was established between microparticle properties (cumulative release, release rate, encapsulation efficiency) and drug deposition in the skin. In conclusion, the synergistic combination of Dr. Pen microneedles and PLGA microparticles facilitated enhanced and regulated transdermal methotrexate delivery.

Dendrimers are a wide range of nanoparticles with desirable properties that can be used in many areas of medicine. However, little is known about their potential use in wound healing. This study examined the properties of phosphorus dendrimers that were built on a cyclotriphosphazene core and pyrrolidinium (DPP) or piperidinium (DPH) terminated groups, to be used as potential factors that support wound healing (in vitro). Therefore, the degree of toxicity of the tested compounds for human erythrocytes and the human fibroblast cell line (BJ) was determined, and it was found that at low concentrations, the tested compounds are compatible with blood. The influence of phosphorus dendrimers on plasma proteins (human serum albumin (HSA) and fibrinogen) was examined, with a lack of conformational changes in the structure of these proteins, suggesting that their physiological function was not disturbed. The effects on plasma coagulation cascade and fibrinolysis were also assessed, and it was found that phosphorus dendrimers in low concentrations are blood compatible and interfere neither with coagulation processes nor in clot breakdown. Skin injuries, especially chronic wounds, are also susceptible to infection; therefore, the antimicrobial potential of dendrimers was tested, and it was found that these dendrimers had antibacterial activity against both Gram-negative and Gram-positive bacteria. The highest activity of the tested compounds was found for higher applied concentrations.

In vitro release testing (IVRT) serves as a crucial tool to assess the quality, physicochemical behavior, and performance of semisolid formulations already available on the market. In vitro skin permeation studies (IVPT) are widely used to evaluate the safety and efficacy profiles of topical drugs, utilizing biological membranes prepared from ex vivo human and porcine skin tissues. This study aimed to develop and validate a discriminative IVRT method to evaluate various marketed topical benzoyl peroxide formulations. Additionally, IVPT was employed to assess skin permeation and retention profiles of these formulations, comparing porcine skin results with those obtained by using ex vivo human skin tissues. Physicochemical differences among the evaluated benzoyl peroxide formulations were identified, with the poloxamer-based formulation exhibiting a higher release rate. IVPT using both porcine and human skin differentiated retention and skin permeation profiles, with the poloxamer-based formulation demonstrating greater skin retention capacity compared to the other formulations evaluated. Similar conclusions on benzoyl peroxide retention and cutaneous permeation were drawn from both porcine and human skin IVPT tests, confirming the correlation between the two models.

Chondrocyte-derived exosomes have shown efficacy in differentiating osteoarthritis-affected cartilage. Intervertebral disc degeneration (IVDD) and osteoarthritis often affect facet joints of the spine and show common epidemiological and pathophysiological characteristics. However, the potential of chondrocyte-derived exosomes for treating IVDD remains unclear. The present study aimed to confirm the effect of end plate chondrocyte-derived exosomes (EPC-Exo) on IVDD and elucidate the underlying mechanism. EPC-Exos were isolated and identified by ultracentrifugation, Western blotting, electron microscopy, and nanoparticle tracking analysis. In the in vitro, EPC-Exo uptake by nucleus pulposus (NP) cells reduced cell death by blocking the nuclear factor-κB (NF-κB) signaling pathway. In the in vivo study, EPC-Exos injected into rat intervertebral discs mitigated lipopolysaccharide-induced IVDD, as revealed by a decreased loss of disc height and improved magnetic resonance imaging findings and histological scores. Bioinformatics and sequencing analyses indicated that EPC-Exos alleviated IVDD through the miR-133a-3p/MAML1 axis. The present study suggests that EPC-Exos reduced IVDD incidence via the miR-133a-3p/MAML1 axis-mediated suppression of NF-κB signaling, which prevented the pyroptosis of NP cells.

Although glycine is the simplest of the amino acids, its solution and solid-state properties are far from straightforward. The aqueous solubility of glycine plays an important role in various applications, including nutrition, food products, biodegradable plastics, and drug development. There is evidence that glycine in subsaturated pH 3-8 solutions forms a dimer, as suggested by several techniques. However, what takes place below pH 3 and above pH 8 in saturated solutions has been sparsely explored and is thought to exhibit complex properties. Although the solubility measurements in the pH 0-13 range have been reported by several groups, the interlaboratory variance between the data below pH 3 and above pH 8 has been high. In a couple of cases, there appears to be no pH dependence on solubility across the wide pH range, even though the reported glycine pK_a values are 2.34 and 9.61. The solubility of the salt forms of glycine is largely uncharacterized. The solubility products of the simplest salts, glycine hydrochloride and sodium glycinate, appear not to have been published. In this study, five series of precision solubility measurements of glycine and its salts were performed at 25 °C, covering the range of pH -0.4 to 12.4, where in each case, just enough glycine was added to reach saturation. We have developed an equilibrium model to rationalize the complicated salt regions. Elemental analysis of isolated solids from saturated solutions supports the speciation model. At least three different salt forms have been indicated in acidic solutions and one salt form in alkaline solutions. Solubility products are reported here. The presence of a water-soluble cationic dimer is also proposed. Data analysis was performed with the aid of the pDISOL-X computer program. Activity corrections based on the Stokes-Robinson hydration theory have been implemented in saturated solutions with ionic strength in some cases exceeding 5 M. Although salt solubility is not a constant, since it depends on two independently controlled reactant concentrations, the salt solubility product is commonly expected to be a constant. However, in the glycine salt region below pH 3, our solubility measurements demonstrate that the solubility products depend on the total amount of added glycine in a saturated solution. We view this as an "uncommon" common-ion effect.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB). Tuberculous granuloma is the central and key pathological structure of tuberculosis and is characterized by tissue hypoxia and ineffective drug delivery. To address these issues, this study fabricated a composite nanoparticle loaded with catalase (CAT) and levofloxacin (LEV) (CAT@LEV-NPs) and then combined it with ultrasound (US) to investigate the bactericidal effect and underlying mechanisms using TB spheroids. The TB spheroids were constructed using attenuated Bacillus Calmette-Guérin (BCG) instead of MTB to facilitate operation under general experimental conditions. This study examined the physical properties and oxygen production efficiency of CAT@LEV-NPs. Subsequently, we treated TB spheroids with nanoparticles alone or in combination with US and found that ultrasound significantly increased drug permeability and activated CAT@LEV-NPs to produce a large number of reactive oxygen species (ROS). The combined treatment showed excellent antibacterial effects, resulting in more severe damage to the bacterial structure than other treatments. Additionally, the combined treatment induced a higher M1 polarization of macrophages, increased the apoptosis rate, and improved the anoxic microenvironment in TB spheroids. These factors may be closely related to the enhanced bactericidal effects of combined treatment. In conclusion, our study suggests that US combined with CAT@LEV-NPs could serve as a novel, noninvasive, safe, and effective treatment modality for intractable MTB infections.

Gallium, a trace metal not found in its elemental form in nature, has garnered significant interest as a biocide, given its ability to interfere with iron metabolism in bacteria. Consequently, several gallium compounds have been developed and studied for their antimicrobial properties but face challenges of poor solubility and formulation for delivery. Organizing the metal into three-dimensional, hybrid scaffolds, termed metal-organic frameworks (MOFs), is an emerging platform with potential to address many of these limitations. Gallium MOFs show improved solubility and antibacterial potency relative to the free metal due to their ability to coload antibiotics and functional biomolecules. Synthetic strategies are equally versatile, with several rapid, cost-effective, and scalable methods available. In this review, we present the advantages and disadvantages of these various synthetic strategies with respect to their antibacterial efficiency, product purity, and reaction control. The activity of gallium-based MOFs against Gram-positive and Gram-negative pathogens in mono- and combinatorial therapeutic settings is discussed in the context of their mechanisms of action and structure-function-performance relationships collated from recent studies. While gallium MOF development as antibacterials is still in its nascent stages, the examples discussed here highlight their potential as a novel class of therapeutics poised to impact the fight against pan-drug-resistant bacterial pathogens.