Nano Research
·
2023
·
IF 9.9
Li Guanting,Xia Fengli,Xiao Hongying,Zheng Shunzhe,Fu Shuwen,Qiao Han,Jin Qianhui,Zhang Xuanbo,Zhou Dun,Tian Chutong,Sun Jin,He Zhonggui,Sun Bingjun
Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems. However, in the case of camptothecins-based prodrug nanoassemblies, linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies, which are highly unfavorable for sterilization through filtration, and may cause capillary blockage upon intravenous injection. The rational design of camptothecins-based prodrug nanoassemblies remains a challenge. Herein, we propose that branched aliphatic alcohol (BAA) functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies. Correspondingly, four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin (SN38) with BAAs of varying lengths via a tumor redox-responsive disulfide bond, which self-assemble into uniform spherical nanoparticles. The length of BAA was found to significant impact the multiple drug delivery process, including colloidal stability, drug release profiles and pharmacokinetics. Overall, SN38-C21 NPs (SN38-11-heneicosanol nanoparticles), featuring the longest BAA, showcased multiple therapeutic advantages, ultimately culminating the optimal antitumor efficacy and tolerance. The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies, and provide valuable insights for developing translational camptothecins-based nanomedicines.
研究领域:
药学
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肿瘤学
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纳米医学
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产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jingjing Yao,Yajuan Guo,Ting Wan,Shaofang Yu,Qinghong Shen,Min Huang,Yu Li,Fuping Xu,Huiyan Zeng,Zhongqiu Liu,Linlin Lu
Ethnopharmacological relevance Aconitum carmichaelii Debx. exhibits overwhelming efficacy against heart failure, inflammation and pain, but its clinical application is limited by concomitant cardiotoxicity and neurotoxicity. Aconitine (AC), the most abundant bioactive alkaloid, has narrow therapeutic window, with well-defined toxic and therapeutic thresholds. However, the overlapping molecular targets mediating dual toxicity and efficacy of AC remain poorly characterized. Aims of the study This study aimed to evaluate dual pharmacological and toxicological roles of AC through integrative pharmacology and transgenic mouse models. Materials and methods The overlapping targets of AC-related toxicity/efficacy were identified based on integrative pharmacology. By generating Cyp3a −/− transgenic mice expressing human CYP3A4 (hCYP3A4), Ugt1, P-gp, Mrp2, BCRP, and Nrf2 knockout mice, the effects of AC on toxicity, pain, inflammation, and heart failure were assessed. Results We identified 143 overlapping targets predominantly enriched in metabolic pathways. Symptom-based toxicity scores were strikingly elevated in AC-exposed hCYP3A4, Mrp2 −/− , P-gp −/− , BCRP −/− , and Nrf2 −/− mice compared to WT mice. Additionally, AC prolonged the latency of response by approximately 18s, 15s, 14s, and 5s, respectively, in hCYP3A4, Mrp2 −/− , P-gp −/− , and Nrf2 −/− mice by hot plate assay. Interestingly, both toxicity score and analgesic latency initially increased and subsequently decreased, peaking at 60 min. AC obviously decreased the acetic acid-induced writhing and permeability by 45.7% and 22.2% in hCYP3A4 mice, whereas these changes were amplified in Mrp2 −/− mice compared to WT mice. Furthermore, AC attenuated DOX induced heart failure in hCYP3A4 mice, with an effective rate of 20.9%, with Septin4 implicated in AC-related metabolism. Conclusions Metabolic targets may elucidate the mechanistic overlap between the toxicity and efficacy of AC. Notably, hCYP3A4 exhibited heightened toxicity, alongside enhanced analgesic, anti-inflammatory, and cardioprotective effects. Our findings position metabolic pathways as critical nodes for AC-related dual effect, and establish Septin4 as a candidate mediator of its metabolic regulation.
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Xiaomeng Lu,Xinyu Zhan,Guozi Xia,Feifei Wang,Mingjia Lv,Renwei Liu,Yuxue Liu,Chen Zi,Guangyong Li,Rui Wang,Jun Li,Fengjiao Yuan,Dianlong Jia
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for anticancer therapeutics due to its efficient pro-apoptotic activity against tumor cells and its well-tolerated safety profile. However, the in vivo antitumor efficacy of TRAIL is often limited by its poor tumor targeting capacity. Nowadays, the B7 homologue 3 (B7–H3) immune checkpoint has emerged as a promising target for tumor immunotherapy and drug delivery. Here, we report the achievement of tumor-targeted delivery of TRAIL by genetically fusing it with a B7H3-antagonistic affibody. The affibody–TRAIL fusion protein, named ACT, was easily expressed in Escherichia coli with a high yield and could form the active trimeric state. In vitro ACT showed significantly increased cellular binding to multiple B7H3-positive tumor cells and improved cytotoxicity by 2–3 times compared to the parent TRAIL. In vivo ACT demonstrated a 2.4-fold higher tumor uptake than TRAIL in mice bearing B7H3-positive A431 tumor grafts. More importantly, ACT exhibited significantly improved antitumor efficacy against tumors in vivo. In addition, ACT treatment did not cause body weight loss or histopathological changes in the major organs of mice, indicating its good safety profile. Overall, our findings demonstrate that targeting B7H3 to enhance TRAIL delivery is a viable approach to improve its therapeutic efficacy, and ACT may be a potential agent for targeted therapy of B7H3-positive tumors.
研究领域:
肿瘤学
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免疫治疗
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nano Research
·
2020
·Vol. 13
·期 10
·2706-2715
·
IF 8.183
Yan Jing,Zhu Rongying,Wu Fan,Zhao Ziyin,Ye Huan,Hou Mengying,Liu Yong,Yin Lichen
Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-( 1 O 2 )PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm 2 ), the generated 1 O 2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (∼5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1 O 2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.
研究领域:
药剂学
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肿瘤学
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生物材料学
✓ 已验证
DOI
高影响因子
Antibiotics-Basel
·
2025
·Vol. 14
·期 5
·499
·
IF 4.6
Liyang Wang,Junying He,Hanzhong Feng,Qian Li,Meirong Song,Haoran Gou,Yongxing He,Kui Zhu
Background:Fungal infections pose an increasingly predominant threat to human and animal health. Modified compounds derived from chemo-diverse natural products offer enhanced therapeutic efficacies and promising approaches to combat life-threatening fungal pathogens.Methods:We performed biosynthetic gene clusters analysis of 2,4-diacetylchloroglucoside (DAPG) in 4292 shotgun metagenomes samples from the healthy and diseased skin. Then, we assessed the antifungal activity of DAPG and the derivative 2,4-diproylphloroglucinol (DPPG) against pathogenic fungi by minimum inhibitory concentrations. The inhibitory effects of DPPG were measured using hyphal growth assay and spore germination assay. Concurrently, the mechanism of DPPG onAspergillus fumigatuswas investigated in membrane permeability and fluidity. The therapeutic efficacy was evaluated in aGalleria mellonellainfection model.Results:We observed a significantly higher abundance of bacteria harboring DAPG biosynthetic clusters on healthy skin compared to diseased skin. Further, we designed and synthesized a series of phloroglucinol derivatives based on DAPG and obtained an antifungal candidate DPPG. DPPG not only exhibited robust antifungal activity againstAspergillusspp. andCandidaspp. but also impaired hyphal growth and spore germination ofA. fumigatusin vitro. A mechanism study showed that DPPG reduced membrane fluidity and increased the leakage of cellular contents, resulting in membrane perturbation and fungal death. Lastly, the therapeutic efficacy of DPPG was confirmed in aG. mellonellainfection model.Conclusions:Our study demonstrates that DPPG is a potent scaffold to combat invasive fungal infections.
研究领域:
微生物学
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药理学
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感染病学
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产品关联
DOI
PubMed
高影响因子
Microbial Drug Resistance
·
2020
·Vol. 26
·期 2
·100-109
·
IF 2.519
Chong-Fa Lai,Wei-Bin Xiao,Hua-Cheng Yan,Hui Yang,Lu-Xia Wang,Hui Guan,Qiu-ju Peng,Zhi-Rong Deng,Jian-Wen Chen,Lin-Kun An,Lei Shi
ZTW-41, an indolizinoquinoline-5,12-dione derivative, was investigated for antibacterial activity against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA). In our study, the MIC90s (minimum inhibitory concentrations) of ZTW-41 against MRSA (MRSA, n = 200), methicillin-sensitive S. aureus (MSSA, n = 100), Enterococcus faecalis (E. faecalis, n = 32), and Enterococcus faecium (E. faecium n = 32) were 0.25, 0.25, 0.125, and 8 μg/mL, respectively, whereas the MBC90s (minimum bactericidal concentrations) were 2, 1, 1, and >32 μg/mL, respectively. ZTW-41 maintained its potency at different pH levels (range 5–9) and in starting inoculum size up to 107 CFU/mL. The presence of human serum (25–75%) increased ZTW-41 MICs by two- to eightfold. Time-kill curves showed that ZTW-41 had bactericidal activity against MRSA, MSSA, and E. faecalis strains within 8 hours, and rebound growth occurred after 8 hours except at higher multiples of the MIC (4 × and 8 × ). In the acute toxicity study, no mortality or signs of toxicity was noted in mice after 14 days of observation at doses <50 mg/kg. ZTW-41 exhibited good selectivity indices (SIs) (SI = IC50/MIC90) ranging from 1.12 to 71.76 against clinical isolates, demonstrating excellent therapeutic selectivity in MRSA, MSSA, and E. faecalis strains. Moreover, the in vivo efficacy (effective dose [ED]50 = 6.59 mg/kg) of ZTW-41 was found comparable with vancomycin. Collectively, our favorable results supported ZTW-41 as a promising investigational candidate for treating drug-resistant bacteria infection.
研究领域:
微生物学
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药理学
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感染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano-Micro Letters
·
2020
·Vol. 12
·期 1
·1-19
·
IF 12.264
Peng Xin,Chen Kun,Liu Wanhua,Cao Xiongfeng,Wang Mengru,Tao Jun,Tian Ying,Bao Lei,Lu Guangming,Teng Zhaogang
Soft mesoporous organosilica nanoplatforms modified with hyaluronic acid and cyanine 5.5 are constructed.
Therapeutic efficacy of the soft nanoplatforms on tumor is higher both in vitro and in vivo after loading photosensitizer chlorin e6 compared to that of stiff counterparts.
研究领域:
纳米技术
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癌症治疗
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药学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Li Chao,Xiong Zhen,Han Jinxin,Nian Weiqi,Wang Zheng,Cai Kailin,Gao Jinbo,Wang Guobin,Tao Kaixiong,Cai Ming
Gastric cancer (GC) is one of the most common and deadliest cancers worldwide. Lipid homeostasis is essential for tumour development because lipid metabolism is one of the most important metabolic reprogramming pathways within tumours. Elucidating the mechanism of lipid homeostasis in GC might significantly improve treatment strategies and patient prognosis. GSE62254 was applied to construct a lipid homeostasis-related gene signature score (HGSscore) by multiple bioinformatic algorithms including weighted gene coexpression network analysis (WGCNA) and LASSO-Cox regression. A nomogram based on HGSscore and relevant clinical characteristics was constructed to predict the survival of patients with GC. TIMER and xCell were used to evaluate immune and stromal cell infiltration in the tumour microenvironment. Correlations between lipid homeostasis-related genes and chemotherapeutic efficacy were analysed in GSCAlite. RT‒qPCR and cell viability assays were applied to verify the findings in this study. HGSscore was constructed based on eighteen lipid homeostasis-related genes that were selected by WGCNA and LASSO-Cox regression. HGSscore was strongly associated with advanced TNM stage and showed satisfactory value in predicting GC prognosis in three independent cohorts. Furthermore, we found that HGSscore was associated with the tumour mutation burden (TMB) and immune/stromal cell infiltration, which are related to GC prognosis, indicating that lipid homeostasis impacts the formation of the tumour microenvironment (TME). With respect to the GSCAlite platform, PLOD2 and TGFB2 were shown to be positively related to chemotherapeutic resistance, while SLC10A7 was a favourable factor for chemotherapy efficacy. Cell viability assays showed that disrupted lipid homeostasis could attenuate GC cell viability. Moreover, RT‒qPCR revealed that lipid homeostasis could influence expression of specific genes. We identified a lipid homeostasis-related gene signature that correlated with survival, clinical characteristics, the TME, and chemotherapeutic efficacy in GC patients. This research provides a new perspective for improving prognosis and guiding individualized chemotherapy for patients with GC.
研究领域:
肿瘤学
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生物信息学
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分子生物学
✓ 已验证
DOI
高影响因子
Nanoscale
·
2021
·Vol. 13
·期 9
·5094-5102
·
IF 7.79
Jing Liu,Can Wu,Guoru Dai,Feng Feng,Yuquan Chi,Keming Xu,Wenying Zhong
Tyroservatide (YSV) belongs to a class of bioactive peptides that have drawn considerable attention in the field of drug discovery, yet it displays limited potency and often requires a millimolar concentration to execute its cellular functions. To enhance the potency of the drug through a self-assembling strategy, we designed and synthesized a series of octapeptides through conjugation of YSV with a pentapeptide sequence bearing alternating hydrophobic and hydrophilic amino acids to promote their self-assembling capabilities. Initial screening for hydrogelation gave a novel octapeptide (denoted as 1-YSV hereafter) that was capable of self-assembling under physiological conditions to afford supramolecular nanofibers with enhanced anti-cancer efficacy compared to YSV itself. Interestingly, 1-YSV formed a robust co-assembly with the anticancer drug hydroxycamptothecin (HCPT) to afford 1-YSV/HCPT hydrogel, which not only greatly improved the viscoelastic properties of hydrogels, but also stabilized HCPT in the hydrogel matrix and avoided the agglomeration of drug molecules. Compared to HCPT solution, the hydrogel formulation of 1-YSV/HCPT demonstrated better efficacy against the proliferation of non-small cell lung cancer A549 cells both in vitro and in vivo. Finally, thanks to the pure amino acid-based composition, the 1-YSV/HCPT formulation exhibited excellent biocompatibility, giving a low hemolytic rate to red blood cells, with mild local tissue reactions and negligible systematic toxicities in mice.
研究领域:
药学
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生物材料学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2021
·Vol. 17
·期 11
·2006877
·
IF 13.281
Yang Wu,Zhiyong Song,Guiyun Deng,Kai Jiang,Huajuan Wang,Xueji Zhang,Heyou Han
Helicobacter pylori ( H. pylori ) infection has ≈75% probability of causing gastric cancer, so it is considered to be the strongest single risk factor for gastric malignancies. However, the harsh gastric acid environment has created obstacles to medical treatment. This work reports a nanomotor with a bottle-shaped container that can be loaded with small molecules of clarithromycin, nano calcium peroxide (CaO 2 ), and Pt nanoparticles (Pt NPs) by ultrasound. Nanomotors can quickly consume gastric acid through the chemical reaction of CaO 2 to temporarily neutralize gastric acid. The product hydrogen peroxide (H 2 O 2 ) is catalytically decomposed into a large amount of oxygen (O 2 ) by Pt NPs. The local concentration gradient of O 2 bubbles causes it to be expelled from the nanobottles through a narrow opening, and then push the nanobottles forward to provide maximum release and prodrug efficacy. Experiments in animal models show that 15 mg nanomotors can safely and quickly neutralize gastric acid in the stomach and simultaneously release prodrugs to achieve good therapeutic effects without causing acute toxicity. H. pylori burden in mice was 2.6 orders of magnitude lower than that in the control group. The stomach returns to normal pH within 1 d after administration.
研究领域:
医学
·
纳米技术
·
生物化学
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Boning Niu,Yuehuang Wu,Min Zhou,Ruimiao Lin,Pengjin Ge,Xiaohui Chen,Hu Zhou,Xiaokun Zhang,Jingjing Xie
Antibody-coated nanoparticles have been reported to have the extremely low delivery efficiency in solid tumors in preclinical trials. Though aptamers were considered to be superior over antibodies in cancer theranostics, whether PEGylated aptamer nanoparticles are better than antibody nanoparticles in improving delivery specificity and penetration efficiency of chemotherapeutics is still unknown. Here, we conjugate celastrol , a natural product with anti-tumor effect, onto PEGylated EpCAM aptamer or antibody dendrimers to obtain two nanoconjugates , and for the first time, conduct a comprehensive study to compare their performance in delivery specificity, intratumoral penetration ability and therapeutic outcomes. Our results showed that compared to antibody counterparts, PEGylated aptamer nanoconjugates exhibited the enhanced accumulation and retention specificities at tumor sites and the stronger intratumoral penetration capabilities by reducing the macrophage reservoir effects in solid tumors . When delivered celastrol to a colorectal xenograft tumor mice model by PEGylated aptamer dendrimers , 20 % of enhanced therapeutic efficiency was achieved compared to that by antibody-modified ones. Moreover, celastrol at 2 mg/kg delivered by PEGylated aptamer dendrimers showed the prominent anticancer efficiency (nearly 92 %) but without obvious side effects. These data firstly provide the proof-of-concept implementation that PEGylated aptamer nanoconjugates will display the great potential in the effective and safe cancer treatment with regard to the superiority over antibody ones in penetration abilities.
研究领域:
药理学
·
肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2022
·
IF 3.915
Nan Jin,Jingwen He,Chenyuan Wu,Zejun Chen,Yuling Li,Jianmin Chen,Jianhu Lin
The aim of this study was to explore the function of glycyrrhizic acid (GA) in an anti-psoriatic dermal delivery, whereby GA is originally designed as the matrix agent, with curcumin (Cur) as the active agent and silica as the drug carrier. Formulations with different GA proportions were prepared and named W-GA (without GA), L-GA (13% w/w GA) and H-GA (26% w/w GA). The results showed that GA had no significant effect on the physical characteristics, such as particle size and amorphous state, as exhibited by scanning electron microscopy and x-ray diffractograms, respectively. Compared with W-GA and L-GA, H-GA resulted in 10% less photodegradation of Cur after storage for one month, 0.45 μg more penetrated Cur in the epidermis, 2-fold higher viscosity, fewer signals of imiquimod-induced psoriasiform skin lesions and less histological morphological changes. The findings showed that H-GA significantly inhibited expression of interleukin 17 A in the dermis, and interleukin IL-23 in the epidermis, compared with Cur raw drug powder (RDP), whereas L-GA had no significant effect on the expression. These results indicated that a high GA proportion results in superior anti-psoriatic efficacy. Therefore, Cur-loaded silicas with approximately 26% GA are recommended as the superior formulation for the treatment of psoriasis.
研究领域:
药剂学
·
皮肤病学
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）