Acta Pharmaceutica Sinica B
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2023
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IF 14.5
Yani Xu,Lan Yang,Min Li,Haozhou Shu,Na Jia,Yunzhen Gao,Rongying Shi,Xiaojia Yang,Zhirong Zhang,Ling Zhang
Osteosarcoma is usually resistant to immunotherapy and, thus primarily relies on surgical resection and high-dosage chemotherapy. Unfortunately, less invasive or toxic therapies such as photothermal therapy (PTT) and chemodynamic therapy (CDT) generally failed to show satisfactory outcomes. Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma. Herein, a simple nanocomposite that synergistically combines CDT, PTT, and chemotherapy for osteosarcoma treatment was fabricated. In this composite, small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil (5-FU) with high loading capacity. The nanospheres were then adsorbed onto larger 2D Ti 3 C 2 MXene monolayers and finally shielded by bovine serum albumin (BSA) to form 5-FU@NiFe-LDH/Ti 3 C 2 /BSA nanoplatforms (5NiTiB). Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy, NiFe-LDH driven chemodynamic effects, and MXene-based photothermal killing collectively exhibited a synergistic “all-in-one” anti-tumor effect. 5NiTiB improved tumor suppression rate from <5 % by 5-FU alone to ∼80.1 %. This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose, thereby minimizing side effects. Moreover, the composite is simple to produce, enabling the fine-tuning of dosages to suit different requirements. Thus, the platform is versatile and efficient, with potential for further development.
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JOURNAL OF CONTROLLED RELEASE
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2017
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IF 7.786
Yingying Chi,Xuelei Yin,Kaoxiang Sun,Shuaishuai Feng,Jinhu Liu,Daquan Chen,Chuanyou Guo,Zimei Wu
This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma . Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG 2000 ) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG). Hyaluronic acid (HA, MW 20–40 kDa), a ligand to CD44, was non-covalently coated on the cationic liposomes. Doxorubicin (DOX) was actively loaded in the liposomes as a model drug. The roles of HA and Chol-SS-mPEG on intracellular drug delivery efficiency, and antitumor efficacy were studied. The structure of Chol-SS-mPEG was confirmed with Fourier-transform infrared and nuclear magnetic resonance ( 1 H NMR). The liposomes, Chol-SS-mPEG/HA-L had a mean diameter of 165 nm, zeta potential − 28.9 mV, and destabilized in reducing or acidic (pH 5–6) conditions. In vitro release of DOX was well-controlled at physiological conditions, but a burst release of 60% was observed in the presence of 10 mM glutathione (GSH), in contrast to non-redox sensitive liposomes (Chol-mPEG/HA-L and Chol-mPEG-L). MTT cell viability assay showed that the dual-functional Chol-SS-mPEG/HA-L with a drug loading of 15.0% (w/w) had significantly higher cytotoxicity to MG63 osteosarcoma cells compared with non-reduction sensitive or non-HA coated liposomes (p < 0.01), consistent with the cellular uptake and intracellular trafficking studies using confocal microscopy and flow cytometry. Furthermore, the HA-coated GSH-responsive liposomes preferentially internalized to MG63 over human liver cells LO2. In rats, liposomes stabilized with either Chol-SS-mPEG or Chol-mPEG, with or without HA, increased the half-life of DOX by > 10-fold. In a MG63 xenograft mouse model, Chol-SS-mPEG/HA-L showed the most effective tumor suppression with minimal uptake by the liver compared with other liposomes. All animals treated with liposomal formulations survived, in contrast to those free-DOX treated. In conclusion, the easily prepared Chol-SS-mPEG/HA-L was demonstrated as an excellent CD44-mediated intracellular delivery system capable of long-circulation and GSH-triggered cytoplasmic drug release. Further translational and multidisciplinary research is required to make it real clinical benefits to cancer patients.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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Frontiers in Chemistry
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2023
·
IF 5.5
Jiapeng Deng,Su Liu,Guoqing Li,Yien Zheng,Weifei Zhang,Jianjing Lin,Fei Yu,Jian Weng,Peng Liu,Hui Zeng
Introduction: Chemotherapy is a common strategy for the treatment of osteosarcoma. However, its therapeutic efficacy is not ideal due to the low targeting, lowbioavailability, and high toxicity of chemotherapy drugs. Nanoparticles can improve the residence time of drugs at tumor sites through targeted delivery. This new technology can reduce the risk to patients and improve survival rates. To achieve this goal, we developed a pHsensitive charge-conversion polymeric micelle [mPEG- b -P(C7- co -CA) micelles] for osteosarcoma-targeted delivery of cinnamaldehyde (CA). Methods: First, an amphiphilic cinnamaldehyde polymeric prodrug [mPEG- b -P(C7- co -CA)] was synthesized through Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization and post-modification, and self-assembled into mPEG- b -P(C7- co -CA) micelles in an aqueous solution. The physical properties of mPEG- b -P(C7- co -CA) micelles, such as critical micelle concentration (CMC), size, appearance, and Zeta potential were characterized. The CA release curve of mPEG- b -P(C7- co -CA) micelles at pH 7.4, 6.5 and 4.0 was studied by dialysis method, then the targeting ability of mPEG- b -P(C7- co -CA) micelles to osteosarcoma 143B cells in acidic environment (pH 6.5) was explored by cellular uptakeassay. The antitumor effect of mPEG- b -P(C7- co -CA) micelles on 143B cells in vitro was studied by MTT method, and the level of reactive oxygen species (ROS) in 143B cells after mPEG- b -P(C7- co -CA) micelles treatment was detected. Finally, the effects of mPEG- b -P(C7- co -CA) micelles on the apoptosis of 143B cells were detected by flow cytometry and TUNEL assay. Results: An amphiphilic cinnamaldehyde polymeric prodrug [mPEG- b -P(C7- co -CA)] was successfully synthesized and self-assembled into spheric micelles with a diameter of 227 nm. The CMC value of mPEG- b -P(C7- co -CA) micelles was 25.2 mg/L, and it showed a pH dependent release behavior of CA. mPEG- b -P(C7- co -CA) micelles can achieve chargeconversion from a neutral to a positive charge with decreasing pHs. This charge-conversion property allows mPEG- b -P(C7- co -CA) micelles to achieve 143B cell targeting at pH 6.5. In addition, mPEG- b -P(C7- co -CA) micelles present high antitumor efficacy and intracellular ROS generation at pH 6.5 which can induce 143B cell apoptosis. Discussion: mPEG- b -P(C7- co -CA) micelles can achieve osteosarcoma targeting effectively and enhance the anti-osteosarcoma effect of cinnamaldehyde in vitro . This research provides a promising drug delivery system for clinical application and tumor treatment.
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Journal of Orthopaedic Translation
·
2023
·
IF 6.6
Fengxiang Pang,Shouchang Ding,Nan Li,Zhipeng Li,Nannan Tian,Chuanjian Shi,Fengwei Zhang,Yongxin Mai,Jinfang Zhang,Junyan Wang
Background Osteosarcoma (OS) is the most common primary malignancy in bone tissues, and effective therapeutics remain absent in clinical practice. Traditional Chinese medicines (TCM) have been used for thousands of years, which provide great insights into OS management. Gallic acid (GA) is a natural phenolic acid enriched in various foods and herbs. Several pharmacological activities of GA such as anti-oxidation and anti-inflammation have been well-established. However, its biological function in OS remains not fully understood. Methods The potential anti-cancer properties of GA were evaluated in 143 B, U2OS and MG63 cells. Its effects on cell growth, cell cycle, apoptosis and migration were examined in these OS cells. The lncRNA H19 and Wnt/β-catenin signaling were detected by qPCR, luciferase activity and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using an orthotopic mouse model. Results In the present study, GA was found to suppress the tumor growth in vitro via inducing cell cycle arrest and apoptosis in OS cells, and inhibit the invasion and metastasis as well. Using the orthotopic animal model, GA was also found to suppress tumorigenesis in vivo . Long noncoding RNA (lncRNA) H19 was demonstrated to be down-regulated by GA, and thus disrupted the canonical Wnt/β-catenin signaling in OS cells. Furthermore, the ectopic expression of H19 rescued the GA-induced suppressive effects on tumor growth and metastasis, and partially reversed the inactivation of Wnt/β-catenin signaling. Conclusions Taken together, our results indicated that GA inhibited tumor growth through an H19-mediated Wnt/β-catenin signaling regulatory axis in OS cells. The translational potential of this article The information gained from this study provides a novel underlying mechanism of GA mediated anti-OS activity, suggesting that GA may be a promising drug candidate for OS patients.
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Cell Death & Disease
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2023
·Vol. 14
·期 1
·1-12
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IF 9
Yuan Baoshi,Shi Kexin,Zha Juanmin,Cai Yujia,Gu Yue,Huang Kai,Yue Wenchang,Zhai Qiaocheng,Ding Ning,Ren Wenyan,He Weiqi,Xu Ying,Wang Tao
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.
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Frontiers in Genetics
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2023
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IF 3.7
Huang Hui,Ye Zhifang,Li Zhengzhao,Wang Bo,Li Ke,Zhou Kai,Cao Huiyuan,Zheng Jiaxuan,Wang Guangji
Identifying effective biomarkers in osteosarcoma (OS) is important for predicting prognosis. We investigated the prognostic value of ferroptosis-related genes (FRGs) in OS. Transcriptome and clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. FRGs were obtained from the ferroptosis database. Univariate COX regression and LASSO regression screening were performed and an FRG-based prognostic model was constructed, which was validated using the Gene Expression Omnibus cohort. The predictive power of the model was assessed via a subgroup analysis. A nomogram was constructed using clinical markers with independent prognostic significance and risk score results. The CIBERSORT algorithm was used to detect the correlation between prognostic genes and 22 tumor-infiltrating lymphocytes. The expression of prognostic genes in erastin-treated OS cell lines was verified via real-time PCR. Six prognostic FRGs (ACSL5, ATF4, CBS, CDO1, SCD, and SLC3A2) were obtained and used to construct the risk prognosis model. Subjects were divided into high- and low-risk groups. Prognosis was worse in the high-risk group, and the model had satisfactory prediction performance for patients younger than 18 years, males, females, and those with non-metastatic disease. Univariate COX regression analysis showed that metastasis and risk score were independent risk factors for patients with OS. Nomogram was built on independent prognostic factors with superior predictive power and patient benefit. There was a significant correlation between prognostic genes and tumor immunity. Six prognostic genes were differentially expressed in ferroptosis inducer-treated OS cell lines. The identified prognostic genes can regulate tumor growth and progression by affecting the tumor microenvironment.
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Pharmaceutics
·
2023
·Vol. 15
·期 2
·668
·
IF 5.4
Jie Zhu,Rui Gao,Zhongshi Wang,Zhiming Cheng,Zhonghua Xu,Zaiyang Liu,Yiqun Wu,Min Wang,Yuan Zhang
While chemotherapeutic agents have particularly potent effects in many types of cancer, their clinical applications are still far from satisfactory due to off-target drug exposure, chemotherapy resistance, and adverse effects, especially in osteosarcoma. Therefore, it is clinically promising to construct a novel tumor-targeted drug delivery system to control drug release and alleviate side effects. In this study, a pH-responsive nonapeptide hydrogel was designed and fabricated for the tumor-targeted drug delivery of doxorubicin (DOX). Using a solid-phase synthesis method, a nonapeptide named P1 peptide that is structurally akin to surfactant-like peptides (SLPs) due to its hydrophobic tail and hydrophilic head was synthesized. The physicochemical properties of the P1 hydrogel were characterized via encapsulation capacity, transmission electron microscopy (TEM), circular dichroism (CD), zeta potential, rheological analysis, and drug release studies. We also used in vitro and in vivo experiments to investigate the cytocompatibility and tumor inhibitory efficacy of the drug-loaded peptide hydrogel. The P1 peptide could self-assemble into biodegradable hydrogels under neutral conditions, and the prepared drug-loaded hydrogels exhibited good injectability and biocompatibility. The in vitro drug release studies showed that DOX-P1 hydrogels had high sensitivity to acidic conditions (pH 5.8 versus 7.4, up to 3.6-fold). Furthermore, the in vivo experiments demonstrated that the DOX-P1 hydrogel could not only amplify the therapeutic effect but also increase DOX accumulation at the tumor site. Our study proposes a promising approach to designing a pH-responsive hydrogel with controlled doxorubicin-release action based on self-assembled nonapeptides for targeted chemotherapy.Keywords:peptide hydrogel;pH responsive;tumor targeted;drug delivery;doxorubicin;osteosarcoma
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JOURNAL OF CLINICAL LABORATORY ANALYSIS
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2022
·Vol. 36
·期 11
·e24698
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IF 3.124
Chunfa Chen,Liang Liu
Background Osteosarcoma (OS) is a highly recurrent malignancy occurring among adolescents. The goal of this research was to scrutinize the role and action mechanism of KLF3-AS1 in OS. Methods Western blotting and quantitative reverse transcription real-time PCR were conducted to ascertain the mRNA expressions of miR-338-3p, KLF3-AS1, and MEF2C in OS cell lines and tissue samples. Colony formation and CCK-8 experiments were done to evaluate the proliferative capacity of the cells. Western blotting was also executed to measure the relative expressions of the proteins Bcl-2 and Bax. RNA immunoprecipitation and dual luciferase reporter experiments were carried out to validate the target relationships among MEF2C, KLF3-AS1, and miR-338-3p. Mouse xenograft models were created to assess the influences of KLF3-AS1 on the growth of tumors in vivo. Results Elevated levels of KLF3-AS1 and MEF2C and reduced amounts of miR-338-3p were identified in OS. KLF3-AS1 targeted miR-338-3p, and miR-338-3p further targeted MEF2C. Silencing KLF3-AS1 induced apoptosis and attenuated proliferation in vitro and repressed the tumor growth in vivo. Inhibiting miR-338-3p inverted the cancer-suppressing effects of KLF3-AS1 silencing. Meanwhile, loss of MEF2C partially eliminated the effects brought about by miR-338-3p downregulation, namely the stimulation of cell growth and suppression of apoptosis. Conclusions Silencing of KLF3-AS1 could repress the growth of cells and induce apoptosis by regulating miR-338-3p/MEF2C in OS. This suggests that the regulatory axis KLF3-AS1/miR-338-3p/MEF2C is a prospective target for OS treatment.
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Nanoscale
·
2022
·Vol. 14
·期 3
·898-909
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IF 8.307
Chunlin Zhang,Jianping Hu,Yingying Jiang,Shuo Tan,Kunpeng Zhu,Chao Xue,Yunlu Dai,Feng Chen
Osteosarcoma, occurring most frequently in children, teens, and young adults, is a lethal bone cancer with a high incidence of distant metastases and drug resistance. Developing a therapeutic platform that integrates targeting, curing and imaging is highly desirable for enhanced osteosarcoma therapy, yet quite challenging. In this work, we demonstrate a novel biomineralization-inspired strategy for the synthesis of a fructose incorporated manganese phosphate (Fru–MnP) nanoplatform for tumour targeting, drug-free therapy, and MRI imaging. Benefitting from the glucose transporter 5 (GLUT5)-mediated endocytosis, our Fru–MnP nanoplatform produces a high level of reactive oxygen species (ROS) via the Mn2+-driven Fenton reaction within osteosarcoma cells, leading to efficient cancer cell killing due to caspase-mediated apoptosis. By virtue of the T1 signal enhancement of Mn2+, our Fru–MnP nanoplatform also acts as an effective tumour-specific MRI contrast agent, realizing the MRI-monitored chemodynamic therapy. The proposed synergistic therapeutic platform opens new possibilities for high efficacy therapy for osteosarcoma.
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Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 36
·7401-7408
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IF 6.331
Yong-Chao Wang,Hong-Lian Dai,Ze-Hao Li,Zhi-Yuan Meng,Yao Xiao,Zheng Zhao
In this paper, MPDA@hydroxyapatite nanocomposites (MPHA NCs) were prepared and applied to develop a novel reactive oxygen species (ROS)-triggered nitric oxide (NO)-enhanced photothermal therapy nanocomposite system composed of indocyanine green (ICG)/L-arginine-MPDA@HAp (AI-MPHA NCs) for displaying both NO gas therapy and photothermal osteosarcoma treatment. The nanosystem exhibited a mesoporous and core–shell structure and high ICG loading efficiency (about 90%). Under near infrared (NIR) irradiation, the AI-MPHA NCs could not only produce heat but also generate reactive oxygen species (ROS), inducing the catalysis of L-Arg to obtain NO. Under NIR irradiation, the AI-MPHA NCs achieved osteosarcoma ablation by a synergistic combination of photothermal therapy and NO-gas therapy. Additionally, the cell viability of MG-63 cells decreased to 23.6% (co-incubated with AI-MPHA NCs) under irradiation with a power density at 1.0 W cm−2 for 10 min. The study proposed a novel nano-platform for NO-enhanced photothermal therapy of osteosarcoma.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2021
·Vol. 25
·期 11
·4962-4973
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IF 5.31
Mingyu He,Gege Yan,Yang Wang,Rui Gong,Hong Lei,Shuting Yu,Xiaoqi He,Guanghui Li,Weijie Du,Tianshuai Ma,Manqi Gao,Meixi Yu,Shenzhen Liu,Zihang Xu,Elina Idiiatullina,Naufal Zagidullin,Valentin Pavlov,Benzhi Cai,Ye Yuan,Lei Yang
Osteosarcoma (OS) is the most common primary malignant bone tumour in adolescence. Lately, light-emitting diodes (LED)-based therapy has emerged as a new promising approach for several diseases. However, it remains unknown in human OS. Here, we found that the blue LED irradiation significantly suppressed the proliferation, migration and invasion of human OS cells, while we observed blue LED irradiation increased ROS production through increased NADPH oxidase enzymes NOX2 and NOX4, as well as decreased Catalase (CAT) expression levels. Furthermore, we revealed blue LED irradiation-induced autophagy characterized by alterations in autophagy protein markers including Beclin-1, LC3-II/LC3-I and P62. Moreover, we demonstrated an enhanced autophagic flux. The blockage of autophagy displayed a remarkable attenuation of anti-tumour activities of blue LED irradiation. Next, ROS scavenger N-acetyl-L-cysteine (NAC) and NOX inhibitor diphenyleneiodonium (DPI) blocked suppression of OS cell growth, indicating that ROS accumulation might play an essential role in blue LED-induced autophagic OS cell death. Additionally, we observed blue LED irradiation decreased EGFR activation (phosphorylation), which in turn led to Beclin-1 release and subsequent autophagy activation in OS cells. Analysis of EGFR colocalization with Beclin-1 and EGFR-immunoprecipitation (IP) assay further revealed the decreased interaction of EGFR and Beclin-1 upon blue LED irradiation in OS cells. In addition, Beclin-1 down-regulation abolished the effects of blue LED irradiation on OS cells. Collectively, we concluded that blue LED irradiation exhibited anti-tumour effects on OS by triggering ROS and EGFR/Beclin-1-mediated autophagy signalling pathway, representing a potential approach for human OS treatment.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Yongtang Wang,Lan Chen,Zhanfeng Zhou,Yuhan Liang,Tong Zhang,Rongbang Sun,Yueling Tian,Yang Liu,Yifu Fu,Huihan Wang,Guang Feng,Jianhua Miao,Xinhui Zheng,Kai Yang
This work fabricated FeOOH/arginine composite coatings firmly bonded onto Mg alloy substrates, which greatly enhanced the corrosion resistance of biodegradable magnesium implants. • The composite coating achieves NIR and TME dual-responsive controlled NO release, and the PTT-CDT-NO synergistic therapy suppresses core oncogenic signaling pathways to induce efficient osteosarcoma cell death, while low-concentration NO facilitates anti-inflammation and angiogenesis. • By utilizing the concentration-dependent bidirectional effects of NO, the constructed multifunctional coating offers a simple and low-cost design strategy for intelligent magnesium alloy implants toward clinical postoperative bone tumor therapy. Osteosarcoma is prone to recurrence after surgery and is accompanied by extensive bone defects. Traditional treatment methods struggle to achieve tumor suppression and bone repair simultaneously. Degradable magnesium alloys are ideal bone implant materials, yet they have drawbacks, including overly rapid degradation and a lack of anti-tumor activity. Although nitric oxide (NO) shows promise for its anti-inflammatory and regenerative properties, its clinical translation is limited by its short half-life and uncontrolled release, which do not meet the postoperative requirements for osteosarcoma. Herein, in this work, a porous PEO (plasma electrolytic oxidation) coating was first prepared on Mg alloys to improve corrosion resistance, and then Fe 2+ and L-arginine were simultaneously introduced to synthesize the FeOOH-Arg coating in situ, which was then coated with polydopamine to obtain a responsive composite coating. This composite coating achieved interfacial bonding and seals the PEO porous structure through covalent bonding, and can realize the controllable release of NO and reactive oxygen species (ROS) with near-infrared light irradiation and tumor microenvironment, not only synergistically combining the photothermal therapy (PTT) and chemodynamic therapy (CDT) to induce the apoptosis of osteosarcoma cells efficiently, but also regulate the immune microenvironment and promote angiogenesis both in vitro and in vivo. This work offers a novel, feasible, multifunctional modified magnesium alloy implant for integrated anti-tumor and bone-regeneration treatment following osteosarcoma surgery.
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