JOURNAL OF CELLULAR PHYSIOLOGY
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2019
·Vol. 235
·期 5
·4814-4823
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IF 4.522
Jun Lei,Hongjian Wang,Daoming Zhu,Yibin Wan,Lei Yin
CD8 + T cells play a vital role in cancer immunotherapy and can be shaped by metabolism. Avasimibe is an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor, which has been clinically verified safe in other phase Ⅲ clinical trials. It can potentiate the killing function of CD8 + T cells by modulating cholesterol metabolism. Doxorubicin (DOX) is an anticancer drug widely used in many cancers to induce tumor cell apoptosis. Unfortunately, DOX also can induce toxic and side effects in many organs, compromising its usage and efficacy. Herein, we report the combinational usage of avasimibe and a safe pH sensitive nano-drug delivery system composing of DOX and metal–organic frameworks nanoparticles (MNPs). Our findings demonstrated that DOX–MNPs treatment inhibited tumor growth with good safety profile and avasimibe treatment combined DOX–MNPs treatment exhibited a better efficacy than monotherapies in 4T1 breast cancer therapy.
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Biomedical Engineering-Biomedizinische Technik
·
2019
·Vol. 65
·期 2
·229-236
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IF 1.007
Weifan Xu,Yi Lou,WangShenjie Chen,Yifan Kang
Effective cancer therapy usually requires the assistance of well-designed drug carriers. In order to increase the drug accumulation to tumor tissue as well as to reduce the side effects of drug carriers, the hybrid drug delivery system (DDS) was developed by integrating folic acid (FA) and a metal-organic framework (MOF). The anticancer drug doxorubicin (DOX) was preloaded into the MOF nanoparticles during the synthesis process of the MOF nanoparticles. After surface modification with FA, the resulting FA/MOF/DOX nanoparticles were capable of serving as a biocompatible osteosarcoma targeting a DDS to enhance the chemotherapy of osteosarcoma. The dynamic light scattering method revealed that the obtained FA/MOF/DOX nanoparticles were particles with a size around 100 nm. Moreover, FA/MOF/DOX nanoparticles could enhance the delivery efficacy of DOX into MG63 (human osteosarcoma) cells as compared to FA free nanoparticles (MOF/DOX), in which a folate receptor (FR) might be involved. It was worth mentioning that in vitro [methylthio tetrazole (MTT) study in the MG63 cells] and in vivo (anticancer study in the MG63 xenograft model) assays both revealed that FA/MOF/DOX nanoparticles possessed stronger anticancer capability than free DOX or MOF/DOX nanoparticles.
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RSC Advances
·
2020
·Vol. 10
·期 2
·689-697
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IF 3.119
Caixia Li,Hanxue Li,Jiahao Guo,Liang Li,Xiaowei Xi,Yanyan Yu
A series of injectable and biocompatible delivery DOX-loaded supramolecular hydrogels were fabricated by using presynthesized DOX-2N-β-CD, Pluronic F-127 and α-CD through host–guest interactions and cooperative multivalent hydrogen bonding interactions. The compositions and morphologies of these hydrogels were confirmed by PXRD and SEM measurements. Moreover, the Rheological measurements of these hydrogels were studied and the studies found that they showed a unique thixotropic behavior, indicting a fast self-healing property after the continuous oscillatory shear stress. Using α-CD as a capping agent, slow and sustained DOX release was observed at different pH values after 72 h. The amount of DOX released at pH 7.4 was determined to be 49.0% for hydrogel 1, whereas the releasing amount of the DOX was increased to 66.3% for hydrogel 1 during the same period at pH 5.5 (P < 0.05), indicating a higher release rate of the drug under more acidic conditions. Taking hydrogel 1 as a representative material, the toxicities of DOX and hydrogel 1 on ovarian cancer cells (SKOV-3) at different exposure durations were examined. The results revealed that hydrogel 1 was less cytotoxic than free DOX to SKOV-3 cells (P < 0.05), suggesting sustained release by these hydrogels in the presence of ovarian cancer cells. It is anticipated that this exploration can provide a new strategy for preparing drug delivery systems.
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International Journal of Nanomedicine
·
2019
·
IF 4.471
Tianfeng Yang,Guowen Du,Yuxin Cui,Runze Yu,Chen Hua,Wei Tian,Yanmin Zhang
Background Doxorubicin (DOX) is one of the most effective treatments for hepatocellular carcinoma (HCC), but is restricted by its poor pharmacokinetics. Herein, we exploited efficient targeted drug delivery systems and they have been found to be a worthy strategy for liver cancer therapy. Materials and methods We investigated polymeric nanoparticles which were synthesized based on host–guest interaction between β-cyclodextrin and benzimidazole. The properties of nanoparticles with regard to size/shape, encapsulation efficiency, and drug release were investigated using conventional experiments. Cell proliferation assay in vitro, cell uptake assay, and cell apoptosis analysis were used to investigate cytotoxicity, uptake, and mechanism of targeted supramolecular prodrug complexes (TSPCs)-based self-assemblies and supramolecular prodrug complexes (SPCs)-based self-assemblies. Results The pH-sensitive lactobionic acid (LA)-modified pH-sensitive self-assemblies were synthesized successfully. The results of in vitro released assay showed that the accelerated released of DOX from TSPCs-based self-assemblies with the decrease of pH value. When TSPCs-based self-assemblies were taken up by HepG2 cells, they demonstrated a faster release rate under acidic conditions and proved to have higher cytotoxicity than in the presence of LA. A mechanistic study revealed that TSPCs-based self-assemblies inhibited liver cell proliferation by inducing cell apoptosis. Conclusion The pH-sensitive nanocomplex, as liver-targeted nanoparticles, facilitated the efficacy of DOX in HepG2 cells, offering an appealing strategy for the treatment of HCC.
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Journal of Nanomaterials
·
2019
·
IF 2.233
Yun Zhou,Ke Li,Fan Li,Shuang Han,Yang Wang,Xueping Li,Yonghua Zhan
For the patients with hepatocellular carcinoma (HCC), conventional chemotherapy is insufficient or has no benefit. Although combination chemotherapy has been proven as an efficient strategy to enhance anti-HCC efficacy, some barriers, such as low bioavailability and side effects, are limiting clinical development. In order to overcome disadvantages of combination chemotherapy in HCC, targeted nanoparticles (NPs) simultaneously loaded with doxorubicin (DOX) and ABT-199 in an optimal synergistic ratio were developed. First, the most synergistic combination with DOX was screened from ABT-199, ABT-263, and ABT-737. Among them, ABT-199 showed optimal synergy with DOX in a ratio of 10 : 1. Then, cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were used in coencapsulations of those two drugs. Dual-drug synergistic nanoparticles (DDS NPs) were constructed by absorption of DOX NPs around ABT-199 micelles with an optimal ratio via electrostatic interaction. The shape of DDS NPs was similar to a raspberry, and the size was . The encapsulation efficiencies of DOX and ABT-199 in DDS NPs were and , respectively; meanwhile, the drug loadings were and , respectively. After 72 h of dialysis, 95% of ABT-199 remained and less than 50% of DOX was released. In vitro investigation showed that the drugs in DDS NPs maintained the treated effect in three HCC cell lines; moreover, DDS NPs could perform intracellular delivery of dual drugs and exhibited continuous release of the drugs into different targets. Low in vivo toxicity was found after the acute toxicity test. In vivo fluorescent imaging revealed that DDS NPs could efficiently target and accumulate in the tumor tissues and be maintained more than 72 h after intravenous injection. Compared with free drugs, DDS NPs with the same dosages exhibited a more significant antitumor effect in the HCC xenograft mouse model. The results indicated that DDS NPs have great potential in HCC chemotherapy.
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AAPS PHARMSCITECH
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2019
·Vol. 20
·期 5
·1-13
·
IF 2.608
Li Cong,Lai Chaoyang,Qiu Qiujun,Luo Xiang,Hu Ling,Zheng Huangliang,Lu Yi,Liu Min,Zhang Hongxia,Liu Xinrong,Deng Yihui,Song Yanzhi
Mannose receptor (CD206) and E-selectin are selectively expressed in M2-like tumor-associated macrophages (M2-TAMs) and activated endothelial cells of vessels surrounding tumor tissues. With the knowledge that d -mannose is the natural ligand of mannose receptors and l -fucose is the key calcium chelator for tumor-associated carbohydrate antigens (TACAs) binding to E-selectin, herein, we firstly reported d -mannose polyethylene glycol (PEG) conjugates (Man-PEG) and l -fucose PEG conjugates (Fuc-PEG) co-modified liposomal doxorubicin (DOX-MFPL) to improve tumor-targeting ability. The dual-ligand modified PEGylated liposomes (DOX-MFPL) were assessed by both in vitro and in vivo trials. Compared with the single-ligand d -mannose- or l -fucose-modified liposomes (DOX-MPL or DOX-FPL), DOX-MFPL achieved an increased distribution of DOX in tumor tissues. The antitumor study based on S180 tumor-bearing mice was conducted and the superior tumor inhibitory rate was shown with DOX-MFPL, probably owing to the superior tumor-targeting effect of DOX-MFPL and the modulation of the tumor microenvironment with the exhaustion of TAMs. In general, the dual-ligand drug delivery systems are expected to be promising in the development of specific and efficient methods for tumor treatment.
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2019
·
IF 3.131
Ying Wang,Jingwen Chen,Qianqian Han,Qiang Luo,Hongmei Zhang,Yanqing Wang
Lentinan(LNT) has many kinds of pharmacological activities such as antioxidative activities, hypoglycemic effect, anti-hyperlipidemic effect and so on. Here, LNT was used as the skeleton material to couple with doxorubicin(DOX) by forming the LNT–DOX conjugates in order to enhance anticancer effects and reduce the systemic side effects of DOX. Based on the screening results, we observed that LNT can acted as an antitumor carrier for release of DOX with pH-responsive. DOX release from conjugates was 63.1% at pH 5.0 for up to 48 h, whereas 13.6% of DOX release was observed at pH 7.4 in phosphate buffered saline . The grafting rate of LNT-DOX conjugates was 6.5±0.65 mg/100 mg DOX content. The morphology results showed that LNT-DOX conjugates were considerably more amorphous than LNT. LNT linked by DOX basically maintained the original structure and rheology in water solution. The in vitro anticancer activity of LNT–DOX conjugates was higher than that of free DOX. It is important that LNT–DOX conjugates can enhance anticancer effects in breast cancer cells and decrease the cytotoxocity effects against human normal cells. This work proved that the LNT–DOX conjugates might be suitable for building anticancer drug platform in the course of chemotherapy.
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Biomaterials Science
·
2019
·Vol. 7
·期 8
·3277-3286
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IF 5.251
Jun Li,Zu-E. Hu,Xian-Ling Yang,Wan-Xia Wu,Xiu Xing,Bo Gu,Yan-Hong Liu,Na Wang,Xiao-Qi Yu
Dual stimuli-responsive camptothecin polymeric prodrugs (CPT Prodrugs) with grafted structures were designed via chemoenzymatic methods and combined with doxorubicin (DOX) for synergistic drug delivery to improve anticancer efficiency. The CPT Prodrugs loaded DOX with a high efficiency through the cooperative contribution of several interaction forces. The produced amphiphilic polymeric prodrugs loaded with DOX, referred to as DOX@CPT Prodrugs, formed homogeneous spherical micelles of appropriate sizes (sub-50 nm). The DOX@CPT Prodrug micelles showed excellent stability in release experiments under in vitro physiological conditions and maintained over 80% drug loading after 4 weeks when stored at 4 °C. Under weakly acidic pH and reduced glutathione (GSH) conditions, the DOX@CPT Prodrugs with high disulfide and tertiary amine content achieved synergistic release of the two loaded drugs and biodegraded into low-molecular-weight compounds. The cell experiments confirmed that the internalization of DOX@CPT Prodrugs into cancer cells was greatly improved by nearly 30% compared with that of free drugs. Furthermore, the synergistic drug delivery system exhibited superior anticancer efficiency with highly improved cell selectivity ratios (up to 127.0%) and greatly enhanced synergistic effects (up to 23.9%) benefiting from good long-term stability, better internalization by cells and sensitive pH and GSH dual-responsivity. In addition, the DOX@CPT Prodrugs with suitable sizes and good water solubility also exhibited a greater penetrability in the case of simulating solid tumors than the free drugs. These results demonstrate the potential of DOX@CPT Prodrugs as biodegradable, dual-responsive combination therapy nanocarriers for synergistic anticancer treatment.
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SENSORS AND ACTUATORS B-CHEMICAL
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2019
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IF 6.393
Kai-Yuan Huang,Hong-Xing He,Shao-Bin He,Xiang-Ping Zhang,Hua-Ping Peng,Zhen Lin,Hao-Hua Deng,Xing-Hua Xia,Wei Chen
Doxorubicin (DOX), an anthraquinone-based anticancer drug, is effective for the treatment of a variety of human tumors. However, due to its narrow therapeutic window, serum levels need to be closely monitored. Herein, we report the development of a novel fluorescence probe based on gold nanoclusters co-modified with dithiothreitol (DTT) and carboxylated chitosan (CC) (CC/DTT-AuNCs) for the determination of DOX. The emission from the CC/DTT-AuNCs is significantly suppressed by DOX. The fluorescence-quenching mechanism involving DOX was systematically explored, and photoinduced electron transfer was identified to play a dominant role. DOX readily binds to the CC/DTT-AuNC surface through electrostatic attraction, after which it accepts the electron from the photoexcited CC/DTT-AuNC and quenches its fluorescence. We found that other anthraquinone structures (e.g., alizarin and emodin) devoid of –NH 2 groups exhibited almost no CC/DTT-AuNCs fluorescence-quenching effect due to weak electrostatic interactions between these anthraquinones and the NCs. A linear relationship between photoluminescence suppression and the concentration of DOX was observed in the 0.05–2 μM range under the optimal experimental conditions, with a detection limit as low as 5 nM. This new sensing approach was also used to successfully measure DOX in human serum samples with satisfactory results obtained.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2018
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IF 2.297
Yunfei Wang,Jin Ren,Yonghua Liu,Rong Liu,Liangliang Wang,Qinglan Yuan,Jianming He,Yamin Nie,Jing Xu,Jingmou Yu
In this study, novel folic acid modified succinylated gelatin (FA-SG) micelles were prepared and used as drug carrier in folate-receptor (FR) targeted antitumor therapy. FA-SG copolymer was synthesized and characterized by 1 H NMR and fluorescence spectroscopy. Doxorubicin-loaded FA-SG (DOX-FA-SG) micelles were prepared by a dialysis method. The shape of DOX-FA-SG micelles was almost spherical by transmission electron microscopy analysis. The mean diameter of DOX-FA-SG micelles was 277 nm , and the DOX-loading content was 12.4%. In vitro drug release of DOX-loaded micelles showed sustained release behavior for 168 h. DOX-FA-SG demonstrated significantly greater cellular uptake and cytotoxicity against FR-positive MCF-7 cells than the non-targeted DOX-loaded micelles. Importantly, DOX-FA-SG micelles exhibited higher antitumor activity in MCF-7 tumor-bearing mice than doxorubicin hydrochloride (DOX⋅HCl) and DOX-loaded micelles without FA modification. Taken together, FA-SG micelles could be an effective carrier for targeted drug delivery .
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2018
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IF 3.997
Min Yang,Houqiang Ding,Yixin Zhu,Yanxiu Ge,Lingbing Li
A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo .
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2015
·Vol. 408
·期 3
·683-693
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IF 3.436
Chen Xing,Jiang Guimei,Wang Zhili,Hong Shanni,Zhang Yuanyuan,Guo Yahui,Cheng Hui,Wang Jine,Pei Renjun
Doxorubicin (Dox) is a DNA-targeting anthracycline antibiotic active against a wide spectrum of cancers. The interaction between Dox and double-stranded DNA (dsDNA) was used to load Dox using DNA duplexes as carriers. More importantly, the interesting DNA sequence-dependent fluorescence response of Dox could be exploited in the design of efficient Dox release systems and efficient fluorescence sensors. In this work, we demonstrated that separate introduction of G and C bases into T-rich single-stranded DNA (ssDNA) sequences afforded the best discrimination of Dox binding between dsDNA and ssDNA. For the first time, we successfully utilized this interesting DNA sequence-dependent fluorescence response of Dox as a signal transduction mechanism for the sensitive detection of biothiols in human serum. Cysteine, homocysteine, and glutathione were detected at as low as 26 nM, 37 nM, and 29 nM, respectively. The biosensors exhibited not only good selectivity, stability, and sensitivity in aqueous solutions but also a sensitive response in human serum, demonstrating their potential for diagnosis.
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