International Journal of Nanomedicine最新文献

Purpose: The clinical use of paclitaxel (PTX) in cancer treatment is limited by its poor water solubility, significant toxicity, and adverse effects. This study aimed to propose a straightforward and efficient approach to enhance PTX loading and stability, thereby offering insights for targeted therapy against tumors.

Patients and methods: We synthesized a paclitaxel palmitate (PTX-PA) prodrug by conjugating palmitic acid (PA) to PTX and encapsulating it into liposomal vehicles using a nano delivery system. Subsequently, we investigated the in vitro and in vivo performance as well as the underlying mechanisms of PTX-PA liposomes (PTX-PA-L).

Results: PTX had a remarkable antitumor effect in vivo and significantly decreased the myelosuppressive toxicity of PTX. Moreover, the introduction of PA increased the lipid solubility of PTX, forming a phospholipid bilayer as a membrane stabilizer, prolonging the circulation time of the drug and indirectly increasing the accumulation of liposomes at the tumor site. Our in vivo imaging experiments demonstrated that PTX-PA-L labeled with DiR has greater stability in vivo than blank liposomes and that PTX-PA-L can target drugs to the tumor site and efficiently release PTX to exert antitumor effects. In a mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was approximately twofold greater than that of Taxol. However, in a nude mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was only approximately 0.8-fold greater than that of Taxol. Furthermore, the originally observed favorable pharmacodynamics in normal mice were reversed following immunosuppression. This may be caused by differences in esterase distribution and immunity.

Conclusion: This prodrug technology combined with liposomes is a simple and effective therapeutic strategy with promising developmental prospects in tumor-targeted therapy owing to its ability to convert PTX into a long-circulating nano drug with low toxicity, high pharmacodynamics, and good stability in vivo.

Purpose: To evaluate the therapeutic effect of oral administration of Lactiplantibacillus plantarum P101 (P101) on skeletal injury in young rats exposed to titanium dioxide nanoparticles (TiO₂ NPs), and explore the potential mechanism.

Methods: Four-week-old male rats were orally administration to TiO₂ NPs and supplemented with P101 2 hours later for 4 weeks. The growth and development, food intake, bone metabolism and serum inflammatory markers of the rats were evaluated. Their tibias were observed and evaluated using microcomputed tomography (micro-CT), tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemistry (IHC) and real-time quantitative PCR (RT-qPCR). We observed the tibia growth plate using safranin and fast green staining. 16S rDNA sequence analysis of fecal samples was performed to observe changes in the gut microbiota.

Results: Our results showed that TiO₂ NPs can lead to bone growth inhibition and osteoporosis, induce intestinal flora imbalance, and induce inflammation in young rats. Further mechanistic studies suggested that TiO₂ NPs disrupts intestinal flora and increases serum IL-1β levels, which increased the expression of RANKL in bone, thereby enhancing osteoclast differentiation and function, leading to bone loss. Through a P101 supplementation experiment, we found that P101 ameliorated the inflammation and osteoporosis on bone caused by TiO₂ NPs.

Conclusion: This study showed that the mechanism by which P101 alleviates bone damage caused by TiO₂ NPs may be through restoring intestinal microbial homeostasis and inhibiting inflammatory response.

Purpose: Based on nanomedicine strategies, this study employed cucurbit[7]uril (Q[7]) as the macromolecular carrier to synthesize nanocomplex drug delivery system for chlorogenic acid (CGA). The nanocomplex drug delivery system is intended to overcome the unsatisfactory biocompatibility and bioavailability of CGA and realizing its potential role in long-term osteoporosis (OP) medication.

Methods: The nanocomplex was synthesized by the reflux stirring method. The chemical structure of the nanocomplex was characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction analysis (XRD), UV-visible spectrophotometry (UV-vis), zeta potential analysis and transmission electronic microscope (TEM). The Cell Counting Kit-8 (CCK-8) assay, Live/Dead staining assay, and cytoskeleton staining were conducted to testify the biocompatibility of the nanocomplex. The release assay, Ferric Reducing Ability of Plasma (Frap) assay and Reactive oxygen species (ROS) staining were implemented to evaluate the release profile of CGA as well as its remaining antioxidative levels.

Results: CGA and Q[7] formed hydrogen bonding through an exclusion interaction, with the binding ratio more than 1:1. The nanocomplex had a crystalline and spherical-like structure and improved thermal stability. The nanocomplex demonstrated better biocompatibility than free CGA. The release profile of CGA from the nanocomplex was much steadier, and 70% of CGA was released in 5 days. The CGA released from the nanocomplex maintained its antioxidative properties at high levels and effectively eliminated the accumulated ROS in MC3T3-E1 cells under oxidative stress.

Conclusion: Q[7] has been demonstrated to be an ideal nanocarrier for CGA and the nanocomplex delivery system holds the potential for the long-term medication strategy of OP.

Background: Lung metastasis is a leading cause of cancer-related death. mRNA-based cancer vaccines have been demonstrated to be effective at inhibiting tumor growth. Intranasal immunization has emerged as a more effective method of inducing local immune responses against cancer cells in the lungs.

Methods: An innovative layered double hydroxide- and 5-OP-RU-based mRNA nanovaccine (Mg/Al LDH-5-OP-RU/mRNA) was synthesized via coprecipitation. The particle size distribution and zeta potential were measured, and the nanovaccine was observed by transmission electron microscopy. The functions and properties of the nanovaccine were evaluated via an mRNA-targeted delivery assay and measurement of dendritic cell (DC) and mucosa-associated invariant T (MAIT) cell maturation and activation. In addition, the cytotoxicity, antigen-specific T cell activation, cytokines, protective ability, and therapeutic ability of the nanovaccine were assessed in a mouse tumor model. Further, the immune cell composition was evaluated in tumors.

Results: The Mg/Al LDH-5-OP-RU/mRNA nanovaccine was efficiently delivered into lung-draining mediastinal lymph nodes (MLNs), and it activated dendritic cells (DCs) and mucosa-associated invariant T (MAIT) cells after intranasal administration. Moreover, the optimized dual-activating mRNA nanovaccine efficiently transfected DC cells and expressed antigen proteins in DC cells. An HPV-associated tumor model revealed that the intranasal delivery of the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine significantly prevented the lung metastasis of tumors and had a therapeutic effect on established metastatic tumor nodules in the lungs. Mechanistically, the enhanced activation of DC and MAIT cells induced by the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine increased the production of immune-stimulating cytokines and decreased the secretion of immunosuppressive cytokines, which led to the expansion and activation of memory T cells targeting the E7 antigen, a reduction in the population of neutrophils, and differentiation of tumor -associated macrophages to the M1 phenotype in the lungs.

Conclusion: These results highlight the potential of the innovative nasal mRNA nanovaccine for both preventing and treating tumor metastasis in the lungs.

Introduction: The photo-activated thermo/gas antimicrobial nanocomposite hydrogel, Gel/PDA@BNN6, is composed of the nitric oxide (NO) carrier N, N'-di-sec-butyl-N, N'-dinitroso-p-phenylenediamine (BNN6), photothermal (PTT) material polydopamine nanoparticles (PDA NPs), and methacrylate gelatin (GelMA). This hydrogel can release NO gas in a stable and controlled manner, generating a localized photothermal effect when exposed to near-infrared laser light. This dual action promotes the healing of full-thickness skin wounds that are infected.

Methods: Gel/PDA@BNN6 was developed, and both in vitro and in vivo experiments were carried out to evaluate its structure, physicochemical properties, antibacterial effects, effectiveness in promoting infected wound healing, and biocompatibility.

Results: Gel/PDA@BNN6 was successfully synthesized, exhibiting a porous three-dimensional lattice structure and excellent mechanical properties. It demonstrated highly efficient photothermal conversion, controllable nitric oxide delivery, strong bactericidal effects, and minimal cytotoxicity in vitro. In vivo, Gel/PDA@BNN6, when used with NIR therapy, showed significant anti-inflammatory effects, promoted collagen deposition, and stimulated vascular neoangiogenesis, which accelerated wound closure. Additionally, it displayed superior biocompatibility.

Discussion: Gel/PDA@BNN6 has shown an explicit curative effect for infected wound healing, suggesting it has a good chance of being an antimicrobial dressing in the future.

Introduction: Squamous non-small cell lung carcinoma (sqNSCLC) is associated with a poorer prognosis and limited treatment options. Sintilizumab combined with chemotherapy is used as first-line treatment for advanced sqNSCLC. However, the efficacy and safety of sintilimab combined with nanoparticle albumin-bound paclitaxel-based chemotherapy for severe squamous NSCLC remain to be unknown in clinical studies.

Methods: Patients with confirmed unresectable stage III/IV sqNSCLC were retrospectively collected between July 1^st, 2019, and December 31^st. According to performance status (PS) scores, these patients received first-line sintilimab plus nab-PTX-based chemotherapy were divided into severe (PS=2) and non-severe groups (PS=0-1). The treatment regimen was repeated every 3 weeks for a maximum of six cycles, or until unacceptable toxicity occurred. The primary endpoint of this study was to assess progression free survival (PFS), with secondary endpoints including the objective response rate (ORR), adverse events (AEs) and disease control rate (DCR).

Results: Among 367 patients with unresectable stage III/IV sqNSCLC, 28 male patients, with a median age of 65.5 years, received first-line sintilimab plus nab-PTX-based chemotherapy. These patients were divided into a severe group (11 patients) and a non-severe group (17 patients). The severe group had a significantly higher incidence of chronic obstructive pulmonary disease (COPD) compared to the non-severe group (54.5% vs 11.8%, p = 0.03). The two groups had a similar median number of treatment cycles and safety profiles. Although the severe group showed higher ORR (63.6% vs 47.1%) and DCR (100% vs 76.5%) than the non-severe group, these differences were not statistically significant. Median PFS and Kaplan-Meier curves were also comparable between the groups.

Conclusion: Sintilimab combined with nab-PTX-based chemotherapy was effective and well tolerated in a small sample of severe lung squamous cell carcinoma population. This combination may offer a potential treatment option for these patients.

Introduction: Atorvastatin (ATV), a medication used to reduce cholesterol levels, possesses properties that can counteract the damaging effects of free radicals and reduce inflammation. However, the administration of ATV orally is associated with low systemic bioavailability due to its limited capacity to dissolve in water and significant first-pass effect. This study aimed to assess the appropriateness of employing nano-vesicles for transdermal administration of ATV in order to enhance its anti-inflammatory effects.

Methods: ATV-loaded transethosomes (ATV-TEs) were optimized using the 3³ Box-Behnken design. The ATV-TEs that were created were evaluated for their vesicle size, encapsulation efficiency (% EE), and percent release of drug. The optimum formulation was integrated into a hydroxypropyl methylcellulose (HPMC) emulsion-based gel (ATV-TEs emulgel) using jojoba oil. ATV-TEs emulgel was examined for its physical characteristics, ex vivo permeability, histological, and anti-inflammatory effect in a rat model of inflamed paw edema.

Results: The optimized transethosomes exhibited a vesicle size of 158.00 nm and an encapsulation efficiency of 80.14 ± 1.42%. Furthermore, the use of transethosomal vesicles effectively prolonged the release of ATV for a duration of 24 hours, in contrast to the pure drug suspension. In addition, the transethosomal emulgel loaded with ATV exhibited a 3.8-fold increase in the transdermal flow of ATV, in comparison to the pure drug suspension. ATV-TEs emulgel demonstrated a strong anti-inflammatory impact in the carrageenan-induced paw edema model.

Discussion: This was evident from the significant reduction in paw edema, which was equivalent to the effect of the standard anti-inflammatory medicine, Diclofenac sodium.

Conclusion: In summary, transethosomes, as a whole, might potentially serve as an effective method for delivering drugs via the skin. This could improve the ability of ATV to reduce inflammation by increasing its absorption through the skin.

Introduction: Deep, second- and third-degree burn injuries may lead to irreversible damage to the traumatized tissue and to coagulation or thrombosis of the microvessels, further compromising wound healing. Engineered, morphologically gradient drug-eluting nanofiber dressings promote wound healing by mimicking tissue structure and providing sustained drug delivery, which is particularly beneficial for wound management.

Methods: This study exploited a resorbable, radially aligned nanofiber dressing that provides the sustained gradient release of metformin at the wound site using a pin-ring electrospinning technique and a differential membrane-thickness approach.

Results: The experimental results suggested that the electrospun nanofibrous dressings exhibited uniform and radially oriented fiber distributions. In vitro, these dressings offered an extended release of metformin for 30 d. The incorporation of water-soluble metformin significantly enhanced the hydrophilicity of the nanofiber membranes. Moreover, the in vivo burn-wound-healing model of rats showed that the radially aligned gradient metformin-eluting poly(lactic-co-glycolic acid) (PLGA) nanofibers exhibited significantly superior healing capability compared to the pristine PLGA, metformin-eluting, and control dressings. Histological images showed that the mesh/nanofibers produced no adverse effects.

Conclusion: The findings in this study emphasize the potential of resorbable, radially aligned nanofiber dressings as advanced wound care solutions, offering broad applicability and meaningful clinical impact.

Purpose: The poor delivery and limited penetration of nanoparticles into breast cancer tumors remain essential challenges for effective anticancer therapy. This study aimed to design a promising nanoplatform with efficient tumor targeting and penetration capability for effective breast cancer therapy.

Methods: A pH-sensitive mitoxantrone (MTO) and copper ion-loaded nanosystem functionalized with cyclic CRGDfK and r9 peptide (TPRN-CM) was rationally designed for chemo-chemodynamic combination therapy. TPRN-CM would be quiescent in blood circulation with the CRGDfK peptide on the surface of the nanoparticle to improve its targeting to the tumor. Then, the structure of TPRN-CM changes in the acidic tumor microenvironment, and the r9 peptide can be exposed to make a surface charge reversal to promote deep penetration in the tumor and facilitate their internalization by cancer cells, which was characterized using transmission electron microscopy, dynamic light scattering, flame atomic absorption, etc. The drug release behavior, anti-tumor effects in vivo and in vitro, and the biosafety of the nanoplatform were evaluated.

Results: TPRN-CM exhibited remarkable capability to load MTO and Cu²⁺ with good stability in serum. It can achieve pH-responsive charge reversal, MTO, and Cu²⁺ release, and can further generate toxic hydroxyl radicals in the presence of glutathione (GSH) and H₂O₂. In vitro experiments demonstrated that this nanoplatform significantly inhibited proliferation, migration, invasion activities and 3D-tumorsphere growth. In vivo experiments suggested that rationally designed TPRN-CM can be effectively delivered to breast cancer tumors with deep tumor penetration, thereby resulting in a notable reduction in tumor growth and suppression of lung metastasis without causing any apparent side effects.

Conclusion: The constructed TPRN-CM nanoplatform integrated tumor targeting, tumor penetration, drug-responsive release, and chemo-chemodynamic combination therapy, thereby providing an intelligent drug delivery strategy to improve the efficacy of breast cancer treatment.

Purpose: The primary goals of endodontic therapy are to eliminate microbes and prevent reinfection. Persistent root canal infections and failure of root canal therapy are primarily attributed to the presence of bacteria, particularly E. faecalis. Chemical irrigants play a crucial role in complementing mechanical instrumentation in ensuring adequate disinfection. However, current techniques and available irrigants are limited in their ability to achieve optimal sterilization of the root canal system. In this study, we developed a novel material called La@PCDs by combining CQD-PVA and lanthanum for root canal irrigation.

Methods: A one-pot hydrothermal method was used to prepare composites of lanthanum and CQD-PVA (La@PCDs). Scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy and the particle size were employed to characterize La@PCDs. ROS generation was evaluated by measuring the fluorescence intensity emitted at 525 nm from 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). In vitro experiments were conducted to assess the effectiveness of the nanoparticles in combating Enterococcus faecalis and eradicating in situ biofilm eradication in root canal. Furthermore, cytotoxicity assessments were carried out to demonstrate the safety of La@PCDs.

Results: SEM and FTIR results showed that La@PCDs were successfully prepared and exhibiting a homogeneous size distribution and irregular morphology. ROS assessment demonstrated that La@PCDs have a synergistic effect, promoting the production of a large number of ROS. This effect only occurred under acidic PH conditions. The inherent acidity in the biofilm microenvironment can act as internal stimulus. In vitro experiments revealed superior antibacterial efficiency under acidic conditions without causing significant cytotoxicity compared to the commonly used NaClO irrigant. The biosafety of La@PCDs was confirmed.

Conclusion: Compared to existing materials, these nanoparticles exhibit favorable antibacterial and anti-biofilm properties, along with improved biocompatibility. These findings emphasize the potential of the integrated La@PCDs as a promising option for enhancing root canal irrigation and disinfection.