JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xi Wang,Guiquan Liu,Xueyu Pu,Tangjun Ren,Fan Zhang,MengJie Shen,Yan Zhu,Alexander Kros,Jian Yang
Drug resistance to chemotherapy in treating cancers becomes an increasingly serious challenge, which leads to treatment failure and poor patient survival. Drug-resistant cancer cells normally reduce intracellular accumulation of drugs by controlling drug uptake and promoting drug efflux, which severely limits the efficacy of chemotherapy. To overcome this problem, a membrane fused drug delivery system (MF-DDS) was constructed to treat cisplatin (DDP)-resistant lung cancer (A549-DDP) by delivering DDP via membrane fusion using a complementary coiled-coil forming peptides (CP 8 K 4 /CP 8 E 4 ). The lipopeptide CP 8 K 4 was pre-incubated firstly and decorated on the surface of A549-DDP cells, and then the cells interacted with the lipopeptide CP 8 E 4 modified on the lipid bilayer (LB) coated PLGA nanoparticles loading DDP (PLGA-DDP@LB-CP 8 E 4 ), leaded to the direct cytosolic DDP delivery and cancer cell death. Compared with free DDP, this MF-DDS achieved a 13.42-folds reduced IC 50 value of A549-DDP cells in vitro , and tumor size was down-regulated, showing only 1/5.26 of the original weight in vivo . Meanwhile, the anti-drug resistant mechanism was explored, where the MF-DDS inhibited the expression of efflux protein genes, including MRP1, MRP2, and ABCG2, leading to increased intracellular drug accumulations. Altogether, this MF-DDS effectively delivered DDP into DDP-resistant cancer cells, making it a promising and improved pharmacological therapeutic approach for drug-resistant tumor treatment.
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高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Yanjuan Huang,Meng Xia,Congjun Xu,Zijun Lin,Meixu Chen,Xianmin Shi,Yaqing Ding,Yan Xiao,Chunshun Zhao
Drug resistance and off-target toxicity of cisplatin (CDDP) pose significant challenges in effectively treating non-small cell lung cancer (NSCLC). Recently, chemodynamic therapy (CDT), an emerging reactive oxygen species (ROS)-mediated tumor-specific therapeutic modality, has shown great potential in sensitizing multidrug resistance tumor cells. Herein, a glutathione (GSH)-responsive Pt(IV) prodrug-based oxidative stress nanoamplifier (CuBSO@Pt C16 ) was developed for effective chemo/chemodynamic therapy to reverse CDDP resistance in NSCLC. CuBSO@Pt C16 , a lipid-coated nanoagent, was constructed by coordinating Cu 2+ with L-buthioninesulfoximine (BSO) as the core framework, and Pt(IV) prodrug (Pt C16 ) was concurrently loaded on the outer lipid bilayer. With appropriate particle size (∼35 nm) and good physiological stability, CuBSO@Pt C16 efficiently accumulated at tumor tissue. Under high intracellular GSH levels, Pt C16 was reduced to generate cytotoxic CDDP that induced cell-killing and boosted intracellular H 2 O 2 levels, and the CuBSO core was disassembled to release Cu ions and BSO simultaneously. The released BSO could efficiently reduce the intracellular GSH content to weaken its detoxification effect on CDDP, leading to more Pt-DNA adduct formation and more severe DNA damage. Meanwhile, Cu ions catalyzed the intracellular elevated H 2 O 2 into highly lethal •OH through Fenton-like reactions, and the reduction of GSH weakened the •OH elimination, which jointly amplified the intracellular oxidative stress levels, finally achieving enhanced chemo/chemodynamic therapeutic effect and reversing CDDP resistance in NSCLC. Therefore, this work offers an inspirational idea for effectively treating drug-resistant cancers. Statement of significance Cisplatin (CDDP) faces challenges in treating non-small cell lung cancer (NSCLC) due to drug resistance and off-target toxicity. Herein, a GSH-responsive nanoreactor (CuBSO@Pt C16 ) was developed for effective chemo/chemodynamic therapy to address CDDP resistance. CuBSO@Pt C16 could efficiently traffic to tumor site and response to high GSH levels in tumor cells to release CDDP, Cu ions and buthioninesulfoximine (BSO) simultaneously. CDDP could induce DNA damage and boost intracellular H 2 O 2 levels, which then served as the substrate of Cu to induce •OH generation through Fenton-like reactions. Meanwhile, the released BSO efficiently reduced the intracellular GSH content to weaken its detoxification effect on CDDP and the elimination of the •OH, leading to amplified intracellular oxidative stress and more severe damage to induce cell death.
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高影响因子
Oncotarget
·
2017
·
IF 5.168
Jianfa Wu,Lingjie Bao,Zhenbo Zhang,Xiaofang Yi
Induction of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) has been demonstrated to be involved in cisplatin resistance in ovarian cancer. Solute carrier family 40 member 1 (SLC40A1) is an iron exporter, which possesses many putative Nrf2 binding sites. Here we hypothesize that it may be a possible downstream gene of Nrf2. Elevated level of Nrf2 and reduced level of SLC40A1 were found in cisplatin–resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. Exogenous knockdown of Nrf2 leaded to increased expression of SLC40A1. While overexpression of Nrf2 resulted in decreased expression of SLC40A1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay revealed that Nrf2 inhibited the transcription of SLC40A1. Overexpression of SLC40A1 was able to reverse cisplatin resistance induced by Nrf2, while knockdown of SLC40A1 restored cisplatin resistance and increased iron concentration. Desferal, an iron chelator, was found to overcome cisplatin resistance through iron deprivation. Its function was boosted when combined with brusatol, an Nrf2 inhibitor. Taken together, this study first demonstrated that Nrf2 could transcriptionally suppress the expression of SLC40A1. Iron overload induced by SLC40A1 resulted in cisplatin resistance in ovarian cancer. Targeting iron metabolism may be a new therapeutic strategy to reverse drug resistance in ovarian cancer treatment.
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高影响因子
Oncotarget
·
2016
·
IF 5.008
Lian Chen,Hengmin Cui,Jing Fang,Huidan Deng,Ping Kuang,Hongrui Guo,Xun Wang,Ling Zhao
Glutamine provides cancer cells with the energy required to synthesize macromolecules. Methods which block glutamine metabolism in treatment of breast cancer inhibit oncogenic transformation and tumor growth. We investigated whether inhibiting glutamine metabolism produces effects that are synergistic with those produced by drugs which damage DNA in triple-negative breast cancer cells. HCC1937 and BT-549 breast cancer cells were co-treated with either cisplatin or etoposide in combination with BPTES (a specific inhibitor of glutaminase 1) or exposure to a glutamine-free medium, and the cell proliferation and cell apoptosis were measured by flow cytometry, immunoblotting studies, and CCK-8 assays. The results showed that both glutamine deprivation and BPTES pretreatments increased the toxic effects of cisplatin and etoposide on HCC1937 cells, as demonstrated by their reduced proliferation, increased expression of apoptosis-related proteins (cleaved-PARP, cleaved-caspase 9, and cleaved-caspase 3) and decreased Bcl-2/BAX ratio. However, in BT-549 cells, glutamine deprivation and BPTES treatment increased etoposide-induced apoptosis only when used with higher concentrations of etoposide, and the effect on cisplatin-induced apoptosis was minimal. These results suggest that the anti-cancer effects produced by a combined approach of inhibiting glutamine metabolism and administering common chemotherapeutic agents correlate with the tumor cell type and specific drugs being administered.
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高影响因子
RSC Advances
·
2016
·Vol. 6
·期 90
·87258-87269
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IF 3.289
Qian Zhang,Huirong Chi,Mingzhi Tang,Jiabin Chen,Guolin Li,Yushi Liu,Bing Liu
The non-covalent functionalization of graphene oxide (GO) with hydroxyethyl cellulose (HEC, nonionic surfactant) and polyanionic cellulose (PAC, anionic surfactant) was developed for anti-cancer drug delivery applications based on a nonideal mixed micelle theory of surfactants. In order to maintain the stability of GO in aqueous electrolytes, the optimal component of the mixed surfactant modified nanocarriers (GO–PAC/HEC) was determined via a multi-factors orthogonal method. Benefiting from the enormous specific surface area of GO and π–π stacking interactions, doxorubicin hydrochloride (DOX), a model anticancer drug, was loaded onto the GO–PAC/HEC surface with high drug loading. The most appropriate loading content of DOX on GO–PAC/HEC was obtained by zeta potential evaluation and a stability time test. The in vitro DOX release profiles from DOX-loaded nanocarriers (GO–PAC/HEC–DOX) exhibited a significant pH-responsive feature and satisfactory performance of drug controlled release. Moreover, in vitro investigation showed that DOX-loaded nanoparticles entered into and treated cancer cells effectively and enhanced the accumulation of DOX in SKOV3/DDP cells (cisplatin-resistant human ovarian carcinoma cell line) exhibiting higher cytotoxicity than free DOX, suggesting that DOX-loaded nanoparticles may overcome DOX resistance of SKOV3/DDP cells to some extent. Based on the results obtained in this study, GO–PAC/HEC shows considerable potential as a drug delivery vehicle.
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APPLIED SURFACE SCIENCE
·
2017
·
IF 3.387
Long Huang,Meiying Liu,Liucheng Mao,Qiang Huang,Hongye Huang,Guangjian Zeng,Jianwen Tian,Yuanqing Wen,Xiaoyong Zhang,Yen Wei
Mesoporous silica nanoparticles (MSNs) should be one of the most important materials for biomedical application owing to their high specific surface area, regular porous structure, adjustable pore size and chemical inert. However, the biomedical applications of unmodified MSNs are largely impeded for their poor hydrophilicity and lack of functional groups. In this work, a novel photo-initiated atom transfer radical polymerization (ATRP) strategy has been reported for modified mesoporous silica nanoparticles (MSNs) with hydrophilicility copolymers using FeBr 3 as the novel photocatalyst and itaconic acid (IA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) as monomers. Because of the hydrophilicity and anticancer agent cis -dichlorodiamineplatinum(II) (CDDP) loading capacity of poly(MPC- co -IA), the controlled drug delivery applications MSNs-NH 2 -poly(MPC- co -IA) composites toward CDDP were further investigated. A series of characterization results demonstrated that MSNs-NH 2 -poly(MPC- co -IA) composites can be successfully fabricated through the novel photo-initiated ATRP. MSNs-NH 2 -poly(MPC- co -IA) composites showed obvious enhancement of water dispersibility, desirable biocompatibility, high drug loading capability, making them great potential for controlled drug delivery of CDDP. Moreover, as compared with the traditional ATRP, that using the transition metal ions and organic ligands as the catalysis systems in elevated temperature, our method provides a more facile, benign and cost-effective route for fabrication of multifunctional MSNs with great potential for biomedical applications. Finally, this FeBr 3 based photoATRP strategy should be further extended for the fabrication of many other polymeric composites owing to its good monomer adoptability.
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高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Rui Zhang,Xuejiao Song,Chao Liang,Xuan Yi,Guosheng Song,Yu Chao,Yu Yang,Kai Yang,Liangzhu Feng,Zhuang Liu
Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme , is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid , forming [email protected] (IV)-liposome for enhanced chemo-radiotherapy of cancer. After being loaded inside liposomes, CAT within [email protected] (IV)-liposome shows retained and well-protected enzyme activity , and is able to trigger decomposition of H 2 O 2 produced by tumor cells, so as to produce additional oxygen for hypoxia relief. As the result, treatment of [email protected] (IV)-liposome induces the highest level of DNA damage in cancer cells after X-ray radiation compared to the control groups. In vivo tumor treatment further demonstrates a remarkably improved therapeutic outcome in chemo-radiotherapy with such [email protected] (IV)-liposome nanoparticles . Hence, an exquisite type of liposome-based nanoparticles is developed in this work by integrating cisplatin-based chemotherapy and catalase-induced tumor hypoxia relief together for combined chemo-radiotherapy with great synergistic efficacy, promising for clinical translation in cancer treatment.
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高影响因子
Discover Nano
·
2024
·Vol. 19
·期 1
·1-16
·
IF 0
Sun Yunhao,Ying Kaijun,Sun Jian,Qiu Limin,Wang Yao,Ji Mingming,Zhou Lulu,Chen Jinjin
Cisplatin (CDDP) is the primary drug used in the initial treatment of esophageal cancer (EC). However, its side effects and resistance can limit its effectiveness in clinical therapy. Curcumin (Cur)-mediated glutathione (GSH) depletion can reverse resistance, enhance the chemosensitivity of CDDP, and further improve the efficacy of platinum-containing chemotherapy in the treatment of esophageal cancer. However, it is also faced with problems of poor water solubility and low bioavailability in vivo, which severely hinders cancer treatments. In order to address these issues, we developed a novel nanotherapeutic system called CDCZA, combining Cur/CDDP/Cu/ZIF8@Au to enhance chemotherapy through GSH depletion and chemodynamic therapy through self-produced H 2 O 2 . Cu and CDDP were precisely co-loaded into Cu/ZIF8 nanoparticles using a one-pot method, then ultra-small gold nanoparticles mimicking glucose oxidase (Au nanoparticles) were embedded in the outer shell to create the CDCZA nano system. The released Cur could notably decrease intracellular GSH content and thus improve the chemosensitivity of CDDP, resulting in severe cellular apoptosis. And the Au nanoparticles effectively enabled chemodynamic therapy enhancement by accelerating the depletion of β-D-glucose into H 2 O 2 . As a result, the CDCZA nanoparticles showed increased tumor accumulation and improved antitumor effectiveness in a model of EC. Taken together, this work provides a new idea for the clinical design of efficient treatment reagents for EC.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yonglong Jin,Nina Dong,Shosei Shimizu,Yinuo Li,Yuan Yao,Hong Qiao,Xiguang Liu,Shuai Liu,Chuanlong Guo,Lijie Wang
The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The in vitro results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The in vivo studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). In vivo mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.
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高影响因子
AAPS PHARMSCITECH
·
2024
·Vol. 25
·期 8
·1-12
·
IF 3.4
Li Bo,Zhao Qianhui,Yang Hanyu,Wang Xueyuying,Zhang Zhijun,Gong Yanling,Wan Xu
Osteosarcoma (OS) is one of the most common primary bone sarcoma with high malignant degree and poor prognosis, for which there is an urgent need to develop novel therapeutic approaches. Recent research has revealed that mifamurtide significantly improved the outcome of OS patients when combined with adjuvant chemotherapy drugs including cisplatin (DDP). The present study aimed to construct a drug delivery system co-loading DDP and mifamurtide. Long-circulating targeted liposomes co-loading DDP and mifamurtide were constructed with Soy lecithin (SPC), cholesterol (Chol) and 1,2-distearoylglycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)] (DSPE-PEG), modified with MMP14 targeting peptide BCY-B in the surface of liposomes. In addition to characterization, the cellular uptake, endocytosis pathway and inhibition on cell viability, migration, invasion and cell apoptosis of MG-63 cells were explored. The constructed liposomal delivery possessed the basic characteristics of liposomes and showed high affinity to MG-63 cells, resulting in high uptake efficiency in MG-63 cells. The endocytosis might be involved in multiple pathways including caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis, dependently on energy. The constructed long-circulating targeted liposomes co-loading DDP and mifamurtide significantly inhibited the cell viability, migration, invasion and cell apoptosis of MG-63 cells, improving the antitumor effect of DDP and mifamurtide in vitro . The constructed liposomal delivery system is suitable for co-loading DDP and mifamurtide to achieve active tumor targeting, supplying a new strategy for the treatment of OS. Graphical Abstract
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高影响因子
JOURNAL OF PHYSICS D-APPLIED PHYSICS
·
2025
·Vol. 58
·期 13
·135207
·
IF 3.2
Liu Jinren,Wang Xiangni,Cui Yixin,Xu Guimin,Lu Jiajia,He Zhirou,Xu Yulin,Li Rongrong,Gao Lingge,Wang Hong,Gao Junhong,Wu Xili,Shi Xingmin,Zhang Guanjun
Cisplatin resistance coupled with adverse effects presents substantial hurdles in the treatment of ovarian cancer. Both cold atmospheric plasma and plasma-activated liquid (PAL) hold the ability to induce DNA damage, which is a primary target of cisplatin. In this study, we investigate the potential of PAL in augmenting cisplatin sensitivity or diminishing the necessary drug dosage by impairing the DNA of cisplatin-resistant cancer cells. We found that plasma irradiated medium exceeding 40 s could decrease the viability, induce DNA damage, trigger cell cycle arrest, and augment apoptosis and autophagy in two types of cisplatin-resistant ovarian cancer cells (A2780/DDP and SKOV3/DDP) after a 24 h incubation period. Notably, pre-treatment with 40 s plasma-activated medium (PAM) for 2 h significantly enhanced the anti-cancer effect of cisplatin administered at lower doses on these cell types. RNA-seq, quantitative real-time PCR and Western blotting analysis revealed that PAM treatment could downregulate the expression of several pivotal proteins involved in nucleotide excision repair (NER) and homologous recombination repair (HRR). The mouse xenograft tumor model demonstrated that plasma-activated saline and cisplatin synergistically inhibited tumor growth and significantly suppressed the expression of proteins related to HRR and NER pathways. We identified plasma-derived peroxide generation in PAM as crucial in these processes. These results pave the way for considering PAM as an adjuvant treatment for cisplatin-resistant ovarian cancer and other abdominal cancers. Additionally, the findings indicate the feasibility of reducing cisplatin dosage to alleviate side effects through sensitization.
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高影响因子
ARCHIVES OF TOXICOLOGY
·
2025
·
IF 6.9
Tang Wei,Zong Shimin,Du Peiyu,Yu Xuan,Li Ting,Liu Bo,Zhong Yu,Lei Wenyang,Yu Wenting,Xiao Hongjun
Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.
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高影响因子
危险品化学品经营许可证（带存储）