查找使用阿拉丁产品的科研文献

Implantable Sandwich-like Scaffold/Fiber Composite Spatiotemporally Releasing Combretastatin A4 and Doxorubicin for Efficient Inhibition of Postoperative Tumor Recurrence

Youqiang Fang,Zheng Liu,Haixia Wang,Xing Luo,Yanteng Xu,Hon Fai Chan,Shixian Lv,Yu Tao,Mingqiang Li

Tumor recurrence is a critical conundrum in the postoperative therapy, on account of severe bleeding with disseminated tumor cells, residual tumor cells, and the rich nutrient and oxygen supply transported to tumors by the abundant blood vessels. Biodegradable drug-loaded implants, inserted in the resection cavity right away upon the surgery, possess bleeding prevention and efficient chemotherapeutic capabilities, considered to be a promising strategy to efficiently inhibit the recurrence of the solid tumor. Here, we developed a sandwich-like composite consisting of the combretastatin A4 (CA4)-loaded 3D-printed scaffold and doxorubicin (DOX)-loaded electrospun fiber (Scaffold-CA4@Fiber-DOX), presenting hemostatic, chemotherapeutic, and antibacterial potencies. The lyophilized 3D-printed scaffold with a porous structure rapidly absorbed and clotted the blood cells and disseminated tumor cells to prevent bleeding and tumor metastasis. Subsequently, the preferentially released CA4 from the scaffold disrupted the microtubules of the vascular endothelial cell, resulting in vascular deformation and consequent insufficient nutrient supply to the solid tumor. The sustained release of DOX from the sandwiched electrospun fiber dramatically inhibited the peripheral tumor cell proliferation. This all-in-one multifunctional implant system, combining efficient vascular disruption and chemotherapy, provides a promising strategy for postoperative tumor therapy.

An Acid-Sensitive Nanofiber Conjugate Based on a Short Aromatic Peptide for Targeted Delivery of Doxorubicin in Liver Cancer

Ju Liang,Runfa Guo,Maosong Xuan,Qiankun Sun,Wenlan Wu

Purpose This study aimed to construct a DOX conjugate with liver tumor targeting and acid sensitivity based on a short aromatic peptide FFYEE, which could amplify the tumor inhibition efficacy of DOX and alleviate tissue toxicity. Methods A novel DOX-peptide conjugate, D-gal-FFYEE-hyd-DOX, was constructed by linking DOX to the side chain of FFYEE with acid-sensitive hydrazone bond and by modifying the C-terminal of peptide with α-D-galactosamine (D-gal) as targeting ligand. The structure of D-gal-FFYEE-hyd-DOX was characterized by mass spectrometry, infrared spectroscopy (IR), and UV-Vis spectroscopy (UV-Vis). The assembly characteristics of pentapeptide FFYEE and D-gal-FFYEE-hyd-DOX were observed by transmission electron microscope (TEM). In vitro drug release, cytotoxicity, endocytosis, in vivo antitumor experiment and histopathology analysis were investigated. Results Peptide FFYEE endowed the D-gal-FFYEE-hyd-DOX with self-assembly performance and improved biocompatibility. D-gal-FFYEE-hyd-DOX can self-assemble into nanofibers with a diameter of ~ 40 nm in neutral aqueous solution and significantly reduced the cytotoxicity of free DOX to L02 cells. In vitro drug release results showed that D-gal-FFYEE-hyd-DOX had acid sensitivity and controlled release characteristics. The cytotoxicity and endocytosis investigations confirmed that D-gal-FFYEE-hyd-DOX enhanced the cellular uptake of DOX and inhibition effect on HepG2 cells. In vivo antitumor experiment indicated that D-gal-FFYEE-hyd-DOX could significantly inhibit the growth of liver tumor in mice and reduce the side effects of DOX. Conclusion The conjugate D-gal-FFYEE-hyd-DOX with liver tumor targeting and acid sensitivity has the characteristics of strong tumor inhibition and low toxicity, hinting the great clinical application potential for targeted delivery of DOX in cancer treatment.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer

Nan Zhang,Jing Li,Wenxia Gao,Wangwei Zhu,Jianqin Yan,Ziyun He,Li Li,Fang Wu,Yuji Pu,Bin He

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

Cardioprotective Effect of Paeonol on Chronic Heart Failure Induced by Doxorubicin via Regulating the MiR-21-5p/SKP2 Axis

Chen Cong,Liu Shuhong,Cao Gaozhen,Hu Yang,Wang Run,Wu Min,Liu Mingya,Yiu Kai Hang

Background: This study primarily explored the role of paeonol in doxorubicin (DOX)-induced chronic heart failure (CHF), considering the cardioprotective effect of paeonol on an epirubicin-induced cardiac injury.Methods: DOX-induced CHF-modeled rats were treated with paeonol. Cardiac function and myocardial damage in rats were evaluated by using the multifunction instrument, and the histopathology, apoptosis, and the expression of miR-21-5p and S-phase kinase-associated protein 2 (SKP2) in myocardium were detected. The target gene of miR-21-5p was confirmed by a dual-luciferase reporter assay. After the required transfection or paeonol treatment, the viability, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) of the DOX-induced cardiomyocytes were determined. Reverse-transcription quantitative-PCR (RT-qPCR) and Western blot were performed to quantify the expressions of miR-21-5p, SKP2, and apoptosis-related factors.Results: Paeonol improved cardiac function and also ameliorated the cardiac damage of CHF-modeled rats, where the downregulation of abnormally elevated myocardial damage markers, including brain natriuretic peptide, lactate dehydrogenase, renin, angiotensin II, aldosterone, and endothelin 1, was observed. Paeonol alleviated the histopathological injury and suppressed the apoptosis in CHF-modeled rats, inhibited miR-21-5p expression, and upregulated SKP2 expression in vitro and in vivo. miR-21-5p targeted SKP2. Paeonol and SKP2 increased the viability and MMP, but reduced apoptosis and ROS in the DOX-induced cardiomyocytes. miR-21-5p exerted effects opposite to PAE and SKP2, and it downregulated the expression of Bcl-2 and mitochondrion-Cytochrome c (Cyt c) and upregulated the expression of Bax, C-caspase-3, and cytoplasm-Cyt c. miR-21-5p reversed the effects of paeonol, and its effects were further reversed by SKP2.Conclusion: Paeonol shows a cardioprotective effect on DOX-induced CHF via regulating the miR-21-5p/SKP2 axis.- Paeonol inhibited miR-21-5p expression in doxorubicin-induced chronic heart failure rats and in doxorubicin-induced cardiomyocytes.- SKP2 was targeted by miR-21-5p and it was down-regulated in chronic heart failure rats and doxorubicin-induced cardiomyocytes.- Paeonol showed cardioprotective effects on doxorubicin-induced chronic heart failure via regulating miR-21-5p/SKP2/PI3K/AKT axis.

Self-assembled amphiphilic copolymers–doxorubicin conjugated nanoparticles for gastric cancer therapy with low in vivo toxicity and high efficacy

Xiaoqi Qian,Chenmei Xia,Xia Chen,Qianqian Li,Dong Li

Amphiphilic copolymers have long been utilized to turn hydrophobic anticancer drugs into nanoparticles administered to patients with cancer. A lack of stability in these monotherapies may be blamed for their poor clinical results in patients with cancer. We propose novel nanotherapies based on polymeric small prodrugs that preserve pharmacologic effectiveness while significantly reducing the toxicity of the fabricated drugs in animals to overcome this problem. Doxorubicin is attached to the end of the PLA fragments through a hydrolyzable ester bond utilizing methoxypolyethylene glycol-block-poly(d, l-lactic acid) (mPEG-PCL(2K)) with conjugates to mimic the self-assembly of colloidal nanotherapies. In a gastric cancer xenograft model, this nanotherapy displays a long-lasting suppression of tumor growth once a reasonable dosage is administered. Our findings imply that a toxic chemical and hydrophobic can be converted into therapeutic effective self-delivery nanotreatment.

Combinational Chemoimmunotherapy for Breast Cancer by Codelivery of Doxorubicin and PD-L1 siRNA Using a PAMAM-Incorporated Liposomal Nanoplatform

Qing Hu,Jiayi Yao,Xiaoqin Wang,Yanfang Wang,Xiaoling Fu,Ju Ma,Han Lin,Jiaqi Xu,Longhua Shen,Xiangbin Yu

Chemoimmunotherapy can synergistically enhance the therapeutic effects and decrease the side effects by a combined method. However, the effective targeted codelivery of various chemotherapeutic agents and siRNAs remains challenging. Although nanomedicine-based chemoimmunotherapy has shown great potential in cancer treatment in recent years, further effort is needed to simplify the nanocarrier designs and maintain their effective functions. Here, we report a simple but robust multifunctional liposomal nanocarrier that contains a pH-sensitive liposome (LP) shell and a dendritic core for tumor-targeted codelivery of programmed cell death ligand 1 (PD-L1) siRNA and doxorubicin (DOX) (siPD-L1@PM/DOX/LPs). siPD-L1@PM/DOX/LPs had a suitable particle size and zeta potential, excellent stability in serum, and pH-sensitive drug release in vitro. They exhibited significant cell proliferation inhibition compared to free DOX and DOX-loaded LPs and could escape endosomes, effectively release siRNA into the cytoplasm of MCF-7 cells, and significantly reduce the PD-L1 expression on tumor cells. In vivo imaging confirmed high accumulation of siPD-L1@PM/DOX/LPs at the tumor site. More importantly, compared with siPD-L1@PM/LPs or DOX alone, siPD-L1@PM/DOX/LPs were more effective in inhibiting tumor growth and activating cytotoxic T cells in vivo. In conclusion, this nanocarrier may hold promise as a codelivery nanoplatform to improve the treatment of various solid tumors.

Instrumental and transcriptome analysis reveals the chemotherapeutic effects of doxorubicin-loaded black phosphate nanosheets on abiraterone-resistant prostate cancer

Haoyang Xu,Jiaqi Liu,Xiangkai Li,Jiawei Li,Xiao Lin,Zhuowei Li,Tong Dou,Li Gao,Rong Li,Keng Po Lai

Prostate cancer is the second most common cause of cancer-related deaths in men and is common in most developed countries. Androgen deprivation therapy (ADT) that uses abiraterone acetate (AA) is an effective second-line treatment for prostate cancer. However, approximately 20–40% of patients develop primary resistance to abiraterone post-treatment. In this study, we aimed to understand the molecular mechanisms underlying the development of abiraterone resistance in prostate cancer cells and the potential use of black phosphorus nanosheets (BPNS) for treating abiraterone-resistant prostate cancer. We first established abiraterone-resistant prostate cancer PC-3 cells and found that these cells have higher migration ability than normal prostate cancer cells. Using comparative transcriptomic and bioinformatics analyses between abiraterone-sensitive PC-3 and abiraterone-resistant PC-3 cells, we highlighted the differentially expressed genes (DEGs) involved in the biological processes related to prostate gland morphogenesis, drug response, immune response, angiogenesis. We further studied the therapeutic effects of BPNS. Our results show that BPNS reduced the proliferation and migration of abiraterone-resistant PC-3 cells. Bioinformatics analysis, including gene ontology, Kyoto encyclopedia of genes and genomes enrichment analysis, and ingenuity pathway analysis (IPA) of the DEGs, suggested that BPNS treatment controlled cancer cell proliferation, metastasis, and oncogenic signaling pathways. Furthermore, the IPA gene network highlighted the involvement of the MMP family, ATF, and notch families in the anti-prostate cancer function of BPNS. Our findings suggest that BPNS may have a chemotherapeutic function in treating abiraterone-resistant prostate cancer.

In vitro comparative study of multimodal imaging nano-assembled microspheres with two clinical drug-eluting beads loaded with doxorubicin

Yiwei He,Tiancheng Xu,Tingting Ding,Yuanchuan Gong,Hui Zeng,Zihan Xi,Yuanxin Ye,Ziyang Song,Ting Pan,Zhewei Zhang,Qian Ma,Lihua Li,Yuqing Zhang,Guoliang Shao

pH-Responsive doxorubicin-loaded magnetosomes for magnetic resonance-guided focused ultrasound real-time monitoring and ablation of breast cancer

Na Tang,Yi Zhu,Ziwei Lu,Jiali Deng,Jiajing Guo,Xinyi Ding,Jingyi Wang,Rong Cao,An Chen,Zhongyi Huang,Hongwei Lu,Zhongling Wang

MR-guided focused ultrasound surgery (MRgFUS) is driving a new direction in non-invasive thermal ablation therapy with spatial specificity and real-time temperature monitoring. Although widely used in clinical practice, it remains challenging to completely ablate the tumor margin due to fear of damaging the surrounding tissues, thus leading to low efficacy and a series of complications. Herein, we have developed novel pH-responsive drug-loading magnetosomes (STPSD nanoplatform) for increasing the T2-contrast and improved the ablation efficiency with a clinical MRgFUS system. Specifically, this STPSD nanoplatform is functionalized by pH-responsive peptides (STP-TPE), encapsulating superparamagnetic iron oxide (SPIO) and doxorubicin (DOX), which can cause drug release and SPIO deposition at the tumor site triggered by acidity and MRgFUS. Under MRgFUS treatment, the increased vascular permeability caused by hyperthermia can improve the uptake of SPIO and DOX by tumor cells, so as to enhance ultrasound energy absorption and further enhance the efficacy of chemotherapy to completely ablate tumor margins. Moreover, we demonstrated that a series of MR sequences including T2-weighted imaging (T2WI), contrast-enhanced T1WI imaging (T1WI C+), maximum intensity projection (MIP), volume rendering (VR) and ADC mapping can be further utilized to monitor the MRgFUS ablation effect in rat models. Overall, this smart nanoplatform has the capacity to be a powerful tool to promote the therapeutic MRgFUS effect and minimize the side effects to surrounding tissues.

Preparation and in vitro evaluation of doxorubicin loaded alendronate modified hollow gold nanoparticles for bone-targeted chemo-photothermal therapy

Yang Lei,Hu Yumin,Liu Yuanfen,Liu Yanyan,Miao Si,Li Zhen,Xu Bohui,Shen Yan

The treatment of malignant bone tumors (including primary bone tumors and metastatic bone tumors) has always been a clinical challenge. The purpose of this study is to design a bone-targeted nano-carrier with photothermal effect to achieve chemo-photothermal therapy (CPT), which allows the minimal use of photothermal agents and chemical drugs to target bone tumors. Alendronate modified hollow gold nanoparticles (HGNPs- ALN) were synthesized using mercapto polyethylene glycol carboxyl (SH-PEG2000-COOH) as the connecting arm, fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) data show that HGNPs-ALN with a particle size of about 80 nm has been successfully synthesized. The hydroxyapatite affinity experiment in vitro indicated that HGNPs-ALN exhibited a high affinity to bone. In addition, the temperature of HGNPs-ALN under near-infrared laser irradiation can rise to 53 °C, which can achieve effective photothermal therapy for bone tumors. Bone-targeted hollow gold nanoparticles (DOX@HGNPs-ALN) loaded with doxorubicin hydrochloride (DOX) were synthesized by one-pot method. By comparing the stability and drug loading of HGNPs-ALN, it was concluded that the optimal mass ratio of HGNPs-ALN (calculated by the amount of gold) to DOX was about 1:2. HGNPs-ALN and DOX@HGNPs-ALN both have good photothermal stability and photothermal transformation properties, and confirmed the safety of HGNPs on human osteosarcoma cells. MTT experiments showed that DOX@HGNPs-ALN had the strongest killing effect on MG-63 osteosarcoma cells under laser irradiation (the killing rate is about 65%). According to these results, it can be considered that DOX@HGNPs-ALN has the potential of CPT synergistic targeting therapy for bone tumors.

Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

Yinxian Yang,Bingjun Sun,Shiyi Zuo,Ximu Li,Shuang Zhou,Lingxiao Li,Cong Luo,Hongzhuo Liu,Maosheng Cheng,Yongjun Wang,Shujun Wang,Zhonggui He,Jin Sun

Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond–bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS for cancer therapy.

Preparation and characterization of amphiphilic nanoparticles based on chondroitin sulfate A conjugated with hydrophobic drug for enhanced doxorubicin delivery

Xie Xin,Yuan Zhen,Yuan Qinglan,Huang Yuyou,Yu Qunying,Ren Jin,Liang Liang,Jin Hongguang,Yu Jingmou

Novel chondroitin sulfate A conjugated doxorubicin (CSA-DOX) was synthesized and characterized. The mean diameter of CSA-DOX was 152 nm analyzed by dynamic light scattering (DLS). Further, DOX was physically encapsulated into the CSA-DOX nanoparticles. Total amounts of DOX in three kinds of DOX-loaded CSA-DOX (CSA-DOX/DOX) nanoparticles were from 21.8 to 24.2%. The mean diameters of three CSA-DOX/DOX nanoparticles were in the range of 167–177 nm. The shape of CSA-DOX/DOX nanoparticles was almost spherical. DOX released from DOX-loaded nanoparticles exhibited a biphasic way in phosphate buffered saline (PBS, pH 7.4). Cellular uptake studies exhibited that CSA-DOX and CSA-DOX/DOX nanoparticles could enhance the uptake of DOX into CD44 receptor-positive A549 cells. Moreover, the cytotoxicity of CSA-DOX/DOX nanoparticles against A549 cells significantly improved in contrast with free DOX and CSA-DOX nanoparticles. These results suggested that CSA-DOX copolymer could be a potential carrier for antitumor drug delivery. Graphical abstract