Thiol-modified hyaluronic acid improves the physical stability of curcumin-zein nanoparticles by forming disulfide bonds with zein.

Zein-based nanoparticles have been developed in the food industry. However, their poor pH stability and unfavorable ionic strength stability remain a challenge even with the use of polysaccharides (such as hyaluronic acid) as stabilizers. To address this shortcoming, an improved strategy based on the disulfide bonds between thiol-modified hyaluronic acid (HASH) and zein was proposed. In this study, curcumin-zein nanoparticles (ZNs-HASH) were prepared with HASH as a stabilizer. The ZNs-HASH displayed similar particle sizes and spherical structures with ZNs and ZNs-HA (HA as a stabilizer). The Fourier transform infrared spectroscopy demonstrated the formation of disulfide bonds between zein and HASH. Among the three formulations tested, ZNs-HASH exhibited the highest pH and salt ion stability and the strongest antioxidant capacity. This study provided new insights for the improvement of physical stability of zein nanoparticles and the development of oral bioactive substances by chemical modification of natural polysaccharides.

Comparison of in vivo behaviors of intramuscularly long-acting celecoxib nanosuspensions with different particle sizes for the postoperative pain treatment.

Celecoxib (CXB) has a good analgesic effect on postoperative acute pain, but clinically its compliance is compromised because of frequent administration. Therefore, the development of injectable celecoxib nanosuspensions (CXB-NS) for long-acting analgesic effects is highly desirable. However, how the particle size affects the in vivo behaviors of CXB-NS remains unclear. Herein, CXB-NS with different sizes were prepared by the wet-milling method. Following intramuscular (i.m.) injection in rats (50 mg/kg), all CXB-NS achieved sustained systemic exposure and long-acting analgesic effects. More importantly, CXB-NS showed size-dependent pharmacokinetic profiles and analgesic effects, and the smallest CXB-NS (about 0.5 µm) had the highest Cmax, T1/2, and AUC0-240h and the strongest analgesic effects on incision pain. Therefore, small sizes are preferred for long action by i.m. injection, and the CXB-NS developed in this study were alternative formulations for the treatment of postoperative acute pain.

Preparation and characterization of novel composite nanoparticles using zein and hyaluronic acid for efficient delivery of naringenin.

Hyaluronic acid (HA), a polymer mainly found in animal tissues, plays an important role in food research. In this study, it was used for delivery improvement of naringenin (NAR) by loading it into zein nanoparticles using an anti-solvent precipitation method. The optimal Nar/zein-HA nanoparticles were uniformly spherical with particle sizes of 209.2 ± 1.9 nm, polydispersity indexes of 0.146 ± 0.032 and zeta-potentials of -19.0 ± 0.7 mV. Moreover, the microstructure of Nar/zein-HA nanoparticles was maintained primarily by hydrophobic, electrostatic, and hydrogen-bonding interactions. Furthermore, Nar/zein-HA nanoparticles showed favorable physical stability and enhanced encapsulation efficiency. Additionally, the antioxidant capacity and release in simulated gastrointestinal digestion of Nar were significantly improved. Overall, these findings indicate that the delivery efficiency of Nar was improved by formulation of ternary nanoparticles.

Comparison of in vivo pharmacokinetic behaviors of R- and S-flurbiprofen after intravenous injection of flurbiprofen axetil.

Flurbiprofen axetil (FA) is a prodrug of flurbiprofen (FP), and it is hydrolyzed to the active FP by carboxylesterase in plasma after intravenous injection. The pharmacological action of FP is closely related to its chirality, and S-FP shows better analgesic effects than R-FP. Therefore, it is of great significance to compare the in vivo pharmacokinetic behaviors of R-FP and S-FP. In this study, we designed a sensitive high performance liquid chromatography-tandem mass spectrometry method and used CHIRALPAK-IG3 column for chiral separation to quantify the concentrations of R-FP and S-FP in rat plasma. The results show that this method can accurately and effectively analyze the contents of R-FP and S-FP in plasma. In addition, the systemic exposure was approximately 3.09-folds for the S-FP compared with the R-FP following intravenous administration of the FA to rats at a single dose of 4.5 mg/kg. More importantly, the clearance rate of S-FP is significantly smaller than that of R-FP. Therefore, the development of S-FA injectable emulsion for clinical treatment of postoperative pain is very necessary.

IGFL2-AS1-induced suppression of HIF-1α degradation promotes cell proliferation and invasion in colorectal cancer by upregulating CA9.

PURPOSE: The lncRNA IGFL2-AS1 is a known cancer-promoting factor in colorectal cancer (CRC); nonetheless, the mechanism of its carcinogenic effects has not yet been elucidated. This study elaborated on the role and underlying molecular mechanism of IGFL2-AS1 in promoting CRC cell functions. METHODS: IGLF2-AS1 expression levels in CRC tissue/normal tissue and CRC cell line/normal colon epithelial cell line were detected by quantitative real-time polymerase chain reaction. Cell counting kit-8, colony formation assay, and EdU assay were performed to assess the effect of IGFL2-AS1 knockdown or overexpression on the proliferative capacity of CRC cells. The migration and invasion abilities of LoVo cells were measured using transwell assay. The expression relationship between IGFL2-AS1 and carbonic anhydrase 9 (CA9) and the CA9 expression level in CRC tissues and cells was verified by transcriptome sequencing, western blotting, and immunohistochemical staining. Treatment with MG132 and cycloheximide was utilized to explore the mechanism by which IGFL2-AS1 affects the hypoxia-inducible factor-1α (HIF-1α)/CA9 pathway. A nude mouse xenograft model was constructed to evaluate the effect of IGFL2-AS1 on CRC growth in vivo. RESULTS: We discovered that IGFL2-AS1 was highly upregulated in CRC tumor tissues and cells. IGFL2-AS1 can functionally promote CRC cell proliferation, migration, and invasion in vitro and accelerate CRC occurrence in vivo. Mechanistic studies demonstrated that IGFL2-AS1 upregulated the CA9 level by affecting the degradation pathway of HIF-1α, which elucidates its pro-proliferative effect in CRC. The lncRNA IGFL2-AS1 mediated the inhibition of HIF-1α degradation in CRC and increased CA9 expression, thereby promoting CRC progression. CONCLUSION: Our findings suggested that IGFL2-AS1 is expected to be a promising new diagnostic marker and therapeutic target for CRC.

Hydrophobic ion pairing-based self-emulsifying drug delivery systems: a new strategy for improving the therapeutic efficacy of water-soluble drugs.

INTRODUCTION: Self-emulsifying drug delivery systems (SEDDS) are formulations consisting of oil phase, emulsifiers, and co-emulsifiers, which can be spontaneously emulsified in the body to form O/W microemulsion. Traditionally, SEDDS are used commercially for the improvement of oral absorption and in vivo performances for poorly water-soluble drugs. However, SEDDS formulations were rarely reported for the delivery of water-soluble drugs. Recent studies have found that SEDDS have the potential for water-soluble macromolecular drugs by the application of the hydrophobic ion pairing (HIP) technology. AREAS COVERED: This review summarized the characteristics of HIP complexes in SEDDS and introduced their advantages and discussed the future prospects of HIP-based SEDDS in drug delivery. EXPERT OPINION: Hydrophobic ion pairing (HIP) is a technology that combines lipophilic structures on polar counterions to increase the lipophilicity through electrostatic interaction. Recent studies showed that HIP-based SEDDS offer an effective way to increase the mucosal permeability and improve the chemical stability for antibiotics, proteases, DNA-based drugs, and other water-soluble macromolecular drugs. It is believed that HIP-based SEDDS offer a potential and attractive method capable of delivering hydrophilic macromolecules with ionizable groups for oral administration.

Stabilizer-induced different in vivo behaviors for intramuscularly long-acting celecoxib nanocrystals.

Nanocrystals (NCs) have been widely recognized as an available policy for the formulation of long-acting injections for insoluble drugs. Stabilizers are extremely important for the physical stability of NCs because they can reduce the surface free energy of the system. However, whether stabilizers can affect the in vivo performances of long-acting injectable NCs is unclear. In this study, three celecoxib (CXB) NCs formulated with different stabilizers (PVP K17, TPGS, and F68) were successfully developed by the wet milling method. Among the formulations, CXB-NCs/PVP K17 had a lower dissolution rate. More importantly, CXB-NCs/PVP K17 did not show burst release after intramuscular (i.m.) injection to rats, and it had a strong analgesic effect. These results showed that the stabilizers played a key role in the in vivo behaviors of long-acting injectable NCs. This strongly suggested that the burst release could be avoided by alteration of stabilizers of NCs by i.m. injection.

Ubiquitin-Like Protein UBD Promotes Cell Proliferation in Colorectal Cancer by Facilitating p53 Degradation.

PURPOSE: Ubiquitin D (UBD) is a member of the ubiquitin-like modifier (UBL) family and is highly expressed in a variety of cancers including colorectal cancer (CRC). However, the mechanisms of its regulatory roles in CRC are largely elusive. In this study, we revealed the effect of UBD on the proliferation of CRC. METHODS: The expression of UBD in clinical tissue samples of CRC and seven CRC cell lines was detected using qRT-PCR, immunohistochemistry (IHC) and Western blotting. CCK-8, colony formation, EdU and flow cytometry assays were used to detect the functional changes of CRC cells transfected with UBD stable expression plasmids in vitro. A xenograft model was constructed to assess the effect of UBD on the growth of CRC cells in vivo. The connection between UBD and p53 was analyzed using Western blotting, immunoprecipitation, proteasome inhibition assay and Cycloheximide (CHX) chase assay. RESULTS: UBD was overexpressed in CRC tumor tissues compared with nontumor tissues, and its overexpression was positively associated with the tumor size and TNM stage of CRC patients. Functionally, UBD significantly accelerated CRC cell viability and proliferation in vitro and promoted tumorigenesis in vivo. Mechanistically, UBD interacted with p53 in CRC cells, downregulated the expression of p53 by regulating its degradation, shortened the p53 half-life, thereby further affecting the decrease in p21 and the increase in Cyclin D1, Cyclin E, CDK2, CDK4 and CDK6. Moreover, in vivo experiments showed that UBD-induced tumor growth in nude mice was dependent on a decrease in p53. CONCLUSIONS: Our study proved that UBD mediates the degradation of p53, thereby facilitating the growth of CRC cells and ultimately promoting the progression of CRC. Therefore, UBD may be a potential therapeutic target and a promising prognostic biomarker for CRC.