Drug Design Development and Therapy
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2015
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IF 3.028
Ran Liu,Yonglu Wang,Xueming Li,Wen Bao,Guohua Xia,Wei Chen,Jian Cheng,Yuanlong Xu,Liting Guo,Baoan Chen
To increase the encapsulation of hydrophilic antitumor agent daunorubicin (DNR) and multidrug resistance reversal agent tetrandrine (Tet) in the drug delivery system of nano-particles (NPs), a functional copolymer NP composed of poly(lactic-co-glycolic acid) (PLGA), poly-L-lysine (PLL), and polyethylene glycol (PEG) was synthesized and then loaded with DNR and Tet simultaneously to construct DNR/Tet–PLGA–PLL–PEG-NPs using a modified double-emulsion solvent evaporation/diffusion method. And to increase the targeted antitumor effect, DNR/Tet–PLGA–PLL–PEG-NPs were further modified with transferrin (Tf) due to its specific binding to Tf receptors (TfR), which is highly expressed on the surface of tumor cells. In this study, the influence of the diversity of formulation parameters was investigated systematically, such as drug loading, mean particle size, molecular weight, the concentration of PLGA–PLL–PEG–Tf, volume ratio of acetone to dichloromethane, the concentration of polyvinyl alcohol (PVA) in the external aqueous phase, the volume ratio of the internal aqueous phase to the external aqueous phase, and the type of surfactants in the internal aqueous phase. Meanwhile, its possible effect on cell viability was evaluated. Our results showed that the regular spherical DNR/Tet–PLGA–PLL–PEG–Tf-NPs with a smooth surface, a relatively low polydispersity index, and a diameter of 213.0±12.0 nm could be produced. The encapsulation efficiency was 70.23%±1.91% for DNR and 86.5%±0.70% for Tet, the moderate drug loading was 3.63%±0.15% for DNR and 4.27%±0.13% for Tet. Notably, the accumulated release of DNR and Tet could be sustained over 1 week, and the Tf content was 2.18%±0.04%. In cell viability tests, DNR/Tet–PLGA–PLL–PEG–Tf-NPs could inhibit the proliferation of K562/ADR cells in a dose-dependent manner, and the half maximal inhibitory concentration value (total drug) of DNR/Tet–PLGA–PLL–PEG–Tf-NPs was lower than that of DNR, a mixture of DNR and Tet, and DNR/Tet–PLGA–PLL–PEG-NPs. These results clearly indicate that the PLGA–PLL–PEG formulation is a potential drug delivery system for hydrophilic and hydrophobic drugs, and that Tf modification may increase its targeting properties.
研究领域:
药剂学
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肿瘤学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 10
·1178
·
IF 6.6
Qianqian Li,Shaobo Yun,Xiaomin Ren,Sijie Wu,Jia Cheng,Xiaoyong Huang
The rapid emergence and global dissemination of colistin resistance pose a critical threat to public health by limiting therapeutic options against Gram-negative infections. In this study, we report that bakuchiol (BAK), a natural antioxidant meroterpenoid, significantly restores colistin (COL) efficacy against a range of clinically relevant Gram-negative pathogens, including colistin-resistant strains. The combination of BAK and COL reduced the minimum inhibitory concentrations (MICs) of colistin by 8- to 32-fold, indicating strong synergistic antibacterial activity. Mechanistic studies revealed that BAK disrupts bacterial iron homeostasis via chelation-mediated intracellular iron depletion and concurrently compromises membrane integrity through interaction with phospholipids. This dual action induces collapse of the proton motive force and severe metabolic dysfunction. Importantly, the BAK–COL combination exhibited no detectable toxicity and demonstrated potent in vivo efficacy in aGalleria mellonellainfection model. Furthermore, formulation with polyvinylpyrrolidone (PVP) markedly improved the solubility and sustained the synergistic effects of BAK over a broad concentration range. Our findings highlight the potential of bakuchiol as a novel antioxidant adjuvant and provide a promising combinatory strategy for overcoming multidrug-resistant bacterial infections.
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DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2021
·
IF 6.598
Yong Xu,Shi Wang,Longshun Yang,Yuhang Dong,Yafang Zhang,Guoqing Yan,Rupei Tang
TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance (MDR) and as an anticancer agent for synergistic antitumor effects. However, the comparatively high critical micelle concentration (CMC), low drug loading (DL) and poor tumor target limit its further clinical application. To overcome these drawbacks, the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials, ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material. The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin (DOX)-loaded micelles at neutral aqueous solutions. The micelles exhibited the lower CMC (8.2 × 10 −5 mg/ml), higher DL (10.8%) and long-term storage and circulation stability, and showed enhanced cellular uptake, apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH (5.0), MDR reversal of TPGS, and synergistic effect of DOX and TPGS. Therefore, the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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DOI
PubMed
高影响因子
Antibiotics-Basel
·
2025
·Vol. 15
·期 1
·
IF 4.6
Yongqing Liu,Huangwei Song,Muchen Zhang,Junyao Jiang,Yan Zhang,Jian Xu,Xi Xia,Shangshang Qin,Jianzhong Shen,Yang Wang
Background:The reintroduction of colistin has led to the rapid emergence of colistin-resistant strains, significantly diminishing its therapeutic efficacy. This presents a need for effective adjuvants to restore colistin efficacy.Approach: We screened the colistin adjuvants through a high-throughput method and then evaluated their synergistic effects and underlying mechanisms.Results: We identified β,β-dimethylacrylalkannin (β,β-Dim), a naphthoquinone compound derived from Lithospermum erythrorhizon, as a potent colistin adjuvant (fractional inhibitory concentration index (FICI) < 0.5). β,β-Dim enhanced colistin activity against 4 of 6 susceptible strains and all 18 colistin-resistant strains carrying either plasmid-bornemcrgenes (mcr-1,mcr-3,mcr-8, andmcr-9) or chromosomal two-component system (TCS) mutations (pmrA/B,phoP, andmgrB). These strains includedKlebsiella pneumoniae,Escherichia coli,SalmonellaTyphimurium,Pseudomonas aeruginosa, andAcinetobacter baumannii. The combination reduced the minimum inhibitory concentrations (MICs) of colistin by 4–1024-fold (from 512 to ≤2 µg/mL). Mechanistically, colistin-mediated outer membrane permeabilization facilitates β,β-Dim entry. Once internalized, β,β-Dim interacts with cytoplasmic membrane phospholipids and disrupts membrane biofunction. Further analysis showed that LPS transport and efflux pump activity were impaired, leading to LPS accumulation in the cytoplasmic membrane and increased intracellular colistin content. These processes elevated reactive oxygen species (ROS) production and markedly reduced ATP levels. In a murine infection model, β,β-Dim (2 mg/kg) combined with colistin (0.2 mg/kg) markedly increased survival from 20% (colistin alone) to 80%.Conclusions:These findings highlight that β,β-Dim combined with colistin is a promising therapeutic strategy for infections caused by colistin-resistant pathogens.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2015
·
IF 3.65
Lejiao Jia,Zhenyu Li,Jingyi Shen,Dandan Zheng,Xiaona Tian,Hejian Guo,Ping Chang
The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR.
研究领域:
纳米技术
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药物科学
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癌症研究
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）