BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Lixin Niu,Yun He,Xing Zhang,Yanfei Peng,Ding Wang,Tao Wang,Zunting Zhang
A concise and efficient photo-induced rearrangement and oxidation of 2-(3-methylbenzofuran-2-yl)-3-phenyl-1 H -indoles 1 for the synthesis of 5-(2-hydroxyphenyl)-5-methyl-5,7-dihydro-6 H -benzocarbazol-6-ones 2 is described. Irradiation of compounds 1 in anhydrous dichloromethane solution, using 313 nm UV light in an air atmosphere, resulted in the formation of compounds 2 with yields ranging from 55% to 98%. Using the 6π-electrocyclization strategy of compounds 1 containing a methyl, a quaternary carbon stereocenter was introduced in the compounds 2 . The carbonyl group of compounds 2 was formed by the photo-induced oxidation of C-H bond to C-OH and hemiketal-keto tautomerization. Additionally, the antitumor activities of compounds 2 were evaluated and found to demonstrate equivalent or superior activity compared to Cisplatin against various tumor cell lines, including leukemia HL-60, lung cancer A549, liver cancer HepG2, breast cancer MDA-MB-231 and colon cancer SW480. The anticancer activity of compound 2f was particularly significant, with IC 50 values of 2.99, 9.06, 6.81, 9.29, and 14.93 μM respectively, and its IC 50 value of normal cells 11.18 μM. Compound 2k had a relatively high IC 50 values against cancer cells, whereas its IC 50 value greater than 40μM for normal cells.
研究领域:
有机化学
·
药物化学
·
肿瘤学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Hang Yan,Bo Liu,Zilong Chen,Yunni Tu,Yaqin Tu,Xiaoting Zeng,Hongjun Xiao,Lesan Yan
Cisplatin remains a first-line chemotherapeutic for a wide spectrum of solid and metastatic tumors; however, its dose-limiting ototoxicity severely compromises patients' quality of life and causes irreversible deficits in language development and socio-cognitive function in children. To address this challenge, we developed a multifunctional amphiphilic polycarbonate-based nanosponge platform (NPs@AST) loaded with astaxanthin, designed to mitigate cisplatin-induced ototoxicity. This system is synthesized through one-step ring-opening polymerization of a trithioether-containing bicyclic carbonate monomer, resulting in a core-crosslinked nanosponge with densely distributed thioether groups. These groups confer intrinsic ROS scavenging, ROS-triggered drug release, and cisplatin-chelating detoxification in a single, chemically defined platform. Upon transtympanic administration, NPs@AST exhibits prolonged cochlear retention and robust otoprotection via two synergistic mechanisms: (i) thioether groups chelate cisplatin, deactivating it and reducing intracellular accumulation; and (ii) intracellular ROS scavenging, coupled with ROS-triggered astaxanthin release, enhancing antioxidant defense against oxidative stress. In C57BL/6 mice, NPs@AST preserved auditory thresholds at ~35 dB on day 21, compared to ~70 dB in untreated controls, as assessed by auditory brainstem response. Therefore, this ROS-responsive polycarbonate nanoplatform offers a promising strategy to mitigate cisplatin-induced ototoxicity and lays the foundation for developing effective, low-toxicity inner-ear drug delivery systems.
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Weikang Guo,Wanyue Wang,Fei Lei,Ruxin Zheng,Xinyao Zhao,Yuze Gu,Mengdi Yang,Yunshun Tong,Yaoxian Wang
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis , can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
研究领域:
肿瘤学
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药理学
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分子生物学
·
植物科学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Xi Zhang,Wenting Yu,Zilong Chen,Ting Li,Shimin Zong,Jinghang Li,Hongjun Xiao,Lesan Yan
Cisplatin is a first-line chemotherapeutic agent for solid and metastatic tumors, yet its ototoxicity remains a major clinical challenge, causing irreversible, bilateral, dose-dependent sensorineural hearing loss. This toxicity severely impairs patients' quality of life and, in children, disrupts language and socio-cognitive development. Conventional strategies using antioxidants, anti-inflammatory agents, or molecular inhibitors only partially mitigate ototoxicity, while systemic administration compromises cisplatin's antitumor efficacy. Intratympanic delivery reduces systemic interference, but small-molecule drugs suffer from poor solubility, low stability, and short half-lives, necessitating frequent dosing that increases risks of local trauma and infection. Advanced biomaterial-based delivery systems provide promising solutions by protecting therapeutics, enhancing local bioavailability, and minimizing systemic toxicity. Poly(amino acid)s are attractive carriers due to their biocompatibility, biodegradability, and tunable side chains. Here, we developed amphiphilic poly(amino acid)s with intrinsic antioxidant activity and engineered nanoprodrugs via covalent conjugation with antioxidant drugs. Administered intratympanically, these self-assembled micelles exhibited prolonged cochlear retention. Mechanistically, the nanoprodrugs alleviated ototoxicity by reducing intracellular cisplatin accumulation through drug chelation and simultaneously scavenging cisplatin-induced reactive oxygen species within cells. This “dual-function” action significantly preserved hearing, providing both mechanistic insight and a potential therapeutic strategy for cisplatin-induced ototoxicity and other hearing impairments.
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DOI
PubMed
高影响因子
BMC Pulmonary Medicine
·
2024
·Vol. 24
·期 1
·1-14
·
IF 2.6
Wu Yuanlin,Zhang Jiandong,Zhao Junjun,Wang Bin
Cisplatin (DDP) resistance, often leading to first-line chemotherapy failure in non-small cell lung cancer (NSCLC), poses a significant challenge. MiR-219a-5p has been reported to enhance the sensitivity of human NSCLC to DDP. However, free miR-219a-5p is prone to degradation by nucleases in the bloodstream, rendering it unstable. In light of this, our study developed an efficient nanodrug delivery system that achieved targeted delivery of DDP and miR-219a-5p by modifying liposomes with folate (FA). Based on the results of material characterization, we successfully constructed a well-dispersed and uniformly sized (approximately 135.8 nm) Lipo@DDP@miR-219a-5p@FA nanodrug. Agarose gel electrophoresis experiments demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited good stability in serum, effectively protecting miR-219a-5p from degradation. Immunofluorescence and flow cytometry experiments revealed that, due to FA modification, Lipo@DDP@miR-219a-5p@FA could specifically bind to FA receptors on the surface of tumor cells (A549), thus enhancing drug internalization efficiency. Safety evaluations conducted in vitro demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited no significant toxicity to non-cancer cells (BEAS-2B) and displayed excellent blood compatibility. Cellular functional experiments, apoptosis assays, and western blot demonstrated that Lipo@DDP@miR-219a-5p@FA effectively reversed DDP resistance in A549 cells, inhibited cell proliferation and migration, and further promoted apoptosis. In summary, the Lipo@DDP@miR-219a-5p@FA nanodrug, through specific targeting of cancer cells and reducing their resistance to DDP, significantly enhanced the anti-NSCLC effects of DDP in vitro, providing a promising therapeutic option for the clinical treatment of NSCLC.
研究领域:
肿瘤学
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药学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·Vol. 32
·期 33
·7357-7376
·
IF 3.5
Jinna Di,Wei Bo,Chun Wang,Chunying Liu
IntroductionThe effectiveness of therapy is strongly impacted by the resistance of lung cancer cells to cisplatin. The objective of this research is to characterize the impact of ailanthone on cisplatin resistance in non-small cell lung cancer (NSCLC) and examine any potential in vivo and in vitro molecular pathways.MethodsFollowing treatment of A549/DDP cells with ailanthone and cisplatin, cell survival and apoptosis were measured using flow cytometry and Cell Counting Kit-8 (CCK8) assays, respectively. mRFP-GFP-LC3 adenovirus transfection was used to track autophagy, and protein expression levels were analyzed by western blotting. Hematoxylin and eosin (H&E) staining was used after the organs of the mice were removed for in vivo investigations. In A549/DDP cells, ailanthone and cisplatin together induced autophagy and apoptosis in a dose and time-dependent manner (p< 0.05). After receiving combined treatment with ailanthone and cisplatin, the expression levels of cleaved caspase-3, Bcl-2, cleaved PARP, Beclin 1, LC3B-II were considerably elevated by inhibiting the PI3K/AKT/mTOR signaling pathway.ResultsOur findings show that ailanthone, without causing adverse effects in vivo, greatly suppressed the growth of A549/DDP-grafted tumors and improved the anti-tumor efficaciousness of cisplatin.ConclusionAccording to this study, ailanthone may increase sensitivity to cisplatin and promote autophagy and death in NSCLC A549/DDP cells through the signaling pathway of PI3K/AKT/mTOR.
研究领域:
肿瘤学
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分子生物学
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药理学
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转化医学
·
细胞信号转导
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DOI
高影响因子
PHARMAZIE
·
2014
·Vol. 69
·期 4
·281-286
·
IF 1.003
Sun Xiaoyi,Chen Jinliang,Gu Xiaohui,Liang Wenquan,Wang Junbo
The polycation transfection agent, polyethylenimine (PEI) was introduced into cisplatin (CDDP)-encapsulated liposomes by modification with amphiphilic PEI-cholesterol (PEI-Chol) to evaluate its potential application in chemotherapeutic drug delivery. Compared with unmodified neutral
liposomes (CDDP-NL), the remarkable features of PEI-modified cationic liposomes (CDDP-CL) increased cytotoxicity attributed to enhanced cellular uptake and extended cellular retention resulting from endosome escape in vitro. In a H22 hepatoma-bearing mouse model, CDDP-CL reduced the
nephrotoxicity associated with CDDP and had an antitumor activity similar to free drug, without inducing obvious system toxicity. These results confirm that the cationic modification of liposomes with PEI is efficient and safe for antitumor drug delivery.
研究领域:
药学
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肿瘤学
·
生物医学工程
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DOI
高影响因子
ACS Sensors
·
2021
·
IF 7.711
Fubo Ma,Shuanghong Yan,Jinyue Zhang,Yu Wang,Liying Wang,Yuqin Wang,Shanyu Zhang,Xiaoyu Du,Panke Zhang,Hong-Yuan Chen,Shuo Huang
Cisplatin, which selectively binds to N7 atoms of purines to inhibit normal replication and transcription, is a widely applied chemotherapeutic drug in the treatment of cancer. Though direct identification of cisplatin lesions on DNA is of great significance, existing sequencing methods have issues such as complications of preamplification or enrichment-induced false-positive reports. Direct identification of cisplatin lesions by nanopore sequencing (NPS) is in principle feasible. However, relevant investigations have never been reported. By constructing model sequences (83 nucleotides in length) containing a sole cisplatin lesion, identification of corresponding lesions by NPS is achieved with <10 ng of input sequencing library. Moreover, characteristic high-frequency noises caused by cisplatin lesions are consistently observed during NPS, clearly identifiable in corresponding high-pass filtered traces. This feature is, however, never observed in any other combinations of natural DNA bases and could be taken as a reference to identify cisplatin lesions on DNA. Further investigations demonstrate that cisplatin stalls the replication of phi29 DNA polymerase, which appears as a ∼5 pA level fluctuation in the single-molecule resolution. These results have confirmed the feasibility of NPS to identify cisplatin lesions at the genomic level and may provide new insights into understanding the molecular mechanism of platinum-based drugs.
研究领域:
分子生物学
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癌症研究
·
基因组学
·
化学生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2024
·
IF 2.8
Song Zeyu,Li Zhenyuan,Pan Tao,Liu Teng,Gong Baifang,Wang Zhixia,Liu Ke,Fan Huaying
ObjectivesAcute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms.MethodsIn vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins.ResultsPPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system.ConclusionPPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.
研究领域:
药理学
·
肾病学
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 5.6
Shaoqin Cen,Zhenxing Hou,Yuan Zhang,Nan Wang,Zihe Zhao,Ao Li,Guoqiang Wan,Tianhong Zhang,Xia Gao
Cisplatin, a widely used antitumor agent, is limited in clinical application due to its ototoxicity. This study investigates the protective effects of obacunone, an active compound from Phellodendron bark, against cisplatin-induced hearing loss. Obacunone significantly improved the survival of cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, preserved the cochlear explant, and enhanced auditory function in mice upon cisplatin treatment. Mechanistically, obacunone inhibited cisplatin-induced apoptosis by activating autophagy. Transcriptome profiling revealed that the expression of corticotropin-releasing hormone-binding protein (CRHBP) was increased in the cisplatin and obacunone co-treated group compared to the cisplatin-only group. Overexpression of CRHBP significantly enhanced autophagy and inhibited apoptosis, mirroring the effects of obacunone. Our findings demonstrate that obacunone promotes autophagy by upregulating CRHBP, thereby reducing cisplatin-induced hair cell apoptosis. This study provides a novel therapeutic strategy using the natural product obacunone for preventing cisplatin-induced hearing loss and highlights the potential of CRHBP as a target for otoprotective interventions.
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 80
·76905-76914
·
IF 3.289
Liujie Zhang,Ying Kuang,Jia Liu,Zhilan Liu,Shiwen Huang,Renxi Zhuo
In this paper, a receptor-mediated liposomal drug delivery system (DDS) was developed aiming to deliver cisplatin (cis-diaminedichloroplatinum(II); CDDP) targeting the liver. Acetyl glycyrrhetinic acid (AGA) was chosen as the hepatic targeting ligand and acetyl glycyrrhetinic acid-poly(ethylene glycol)-stearate (AGA-PEG-ST) was synthesized. Anionic 5-cholestene-3-beta-ol-3-hemisuccinate (CHO-HS) was also synthesized. The liposomal CDDPs were prepared by employing these functional moieties with phosphatidylcholine (PC) at various ratios. Meanwhile, methoxypolyethylene glycol-stearate (MPEG-ST) with an analogous structure but without AGA was also prepared as a control. The particle sizes of AGA modified liposomes ranged from 120 nm to 180 nm and the zeta potentials were located between −39.7 mV and −3.18 mV. The liposomes had encapsulation percentages of 51.5–61.7% and a loading capacity of 23.2–26.7% for CDDP. The transmission electron microscopy (TEM) observations showed that the liposomes had spherical morphologies with homogeneous distribution. In vitro cytotoxicity of CDDP-loaded liposomes against HepG2 human liver cancer cells and A549 human lung epithelial carcinoma cells were evaluated by MTT assays. The results demonstrated that the introduction of AGA could enhance the cytotoxicity of liposomal CDDP against HepG2 cells but showed less significant impact on A549 cells. CLSM observation and FCM measurement further confirmed that AGA modified liposomes had a stronger affinity to HepG2 cells than that of liposomes without AGA. The tissue distribution of calcein in mice indicated that AGA modified liposomes resulted in higher accumulation in the liver than that of liposomes without the AGA ligand. These results demonstrated the promise of AGA decorated anionic liposomes for hepatic targeted delivery of cisplatin.
研究领域:
药剂学
·
肿瘤学
·
纳米医学
·
药物递送系统
·
肝病学
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DOI
高影响因子
CHINESE JOURNAL OF POLYMER SCIENCE
·
2014
·Vol. 32
·期 10
·1329-1337
·
IF 1.42
Zhang Yan,Wang Xiao-ju,Guo Miao,Yan Hu-sheng,Wang Chen-hong,Liu Ke-liang
Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe 3 O 4 nanoparticles with diblock copolymer folate-poly(ethylene glycol)- b -poly(glycerol monomethacrylate) (FA-PEG- b -PGMA), and triblock copolymer methoxy poly(ethylene glycol)- b -poly(2-(dimethylamino) ethyl methacrylate)- b -poly(glycerol monomethacrylate) (MPEG- b -PDMA- b -PGMA). The PGMA segment was attached to the surfaces of Fe 3 O 4 nanoparticles, and the outer PEG shell imparted biocompatibility. In addition, folate was conjugated onto the surfaces of the nanocarriers. Cisplatin was then loaded into the nanocarrier by coordination between the Pt atom in cisplatin and the amine groups in the inner shell of the multilayer architecture. The loaded cisplatin showed pH-responsive release: slower release at pH 7.4 ( i.e. mimicking the blood environment) and faster release at more acidic pH ( i.e. mimicking endosome/lysosome conditions). All of the cisplatin-loaded nanoparticles showed concentration-dependent cytotoxicity in HeLa cells. However, the folate-conjugated cisplatin-loaded carriers exhibited higher cytotoxicity in HeLa cells than non-folate conjugated cisplatin-loaded carriers.
研究领域:
药学
·
纳米医学
·
肿瘤学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）