查找使用阿拉丁产品的科研文献

Nanocrystal-Loaded Micelles for the Enhanced In Vivo Circulation of Docetaxel

Meng Cheng,Qiaoming Liu,Tiantian Gan,Yuanying Fang,Pengfei Yue,Yongbing Sun,Yi Jin,Jianfang Feng,Liangxing Tu

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.Keywords:nanocrystals;micelles;circulation;in vivo;docetaxel

Docetaxel and Doxorubicin Codelivery by Nanocarriers for Synergistic Treatment of Prostate Cancer

Li Ke,Zhan Wenhua,Chen Yulong,Jha Rajiv Kumar,Chen Xueli

Combination chemotherapy has been proven to be an efficient strategy for the treatment of prostate cancer (PCA). However, the pharmacokinetic distinction between the relevant drugs is an insurmountable barrier to the realization of their synergistic use against cancer. To overcome the disadvantages of combination chemotherapy in the treatment of PCA, targeted nanoparticles (NPs), which can codeliver docetaxel (DOC) and doxorubicin (DOX) at optimal synergistic proportions, have been designed. In this study, the DOC and DOX codelivery nanoparticles (DDC NPs) were constructed by hyaluronic acid (HA) and cationic amphipathic starch (CSaSt) through a self-assembly process. Human PCA cell lines (PC-3, DU-145, and LNCap) and mouse models were then used for evaluation in vitro and in vivo, respectively, of delivery and antitumor effects. The DDC NPs were spherical with rough surfaces, and the size and zeta potential were 68.4 ± 7.1 nm and -22.8 ± 2.2 mV, respectively. The encapsulation efficiencies of DOC and DOX in the NPs were 96.1 ± 2.3% and 91.4 ± 3.7%, respectively, while the total drug loading was 9.1 ± 1.7%. Moreover, the ratio of DOC to DOX in the DDC NPs was approximately 1:400, which aligned with the optimal synergistic proportions of the drugs. The DDC NPs exhibited excellent loading capacities, performed sustained and enzymatic release, and were stable in PBS, medium, and serum. After investigations in vitro, the DDC NPs were as effective as the dual drug combination in terms of cytotoxicity, antimigration, and apoptosis. Internalization results indicated that the DDC NPs could effectively deliver and fully release the payloads into PCA cells, and the process was mediated by the ligand-receptor interaction of HA with the CD44 protein. Low toxicity in vivo was confirmed by acute toxicity and hemolytic assays. The distribution in vivo showed that DDC NPs could enhance the accumulation of drugs in tumors and decrease nonspecific accumulation in normal organs. More importantly, DDC NPs significantly promoted the curative effect of the DOC and DOX combination in the PCA cell xenograft mouse model, indicating that the drugs with NPs did indeed act synergistically. This study suggests that the DDC NPs possess noteworthy potential as prospects for the development of PCA clinical chemotherapy.

Mitochondrial-targeted prodrug cancer therapy using a rhodamine B labeled fluorinated docetaxel

Cheng Xie,Jun Chang,Xiao-Dong Hao,Jian-Ming Yu,Hong-Rui Liu,Xun Sun

The aim of this work was to track the distribution and conversion of paclitaxel based prodrug by fluorescence imaging, which would help to up-regulate the therapeutic efficacy and reduce cytotoxicity of paclitaxel and docetaxel . We developed a novel prodrug for tumor treatment, in which a fluorinated docetaxel derivative, 4FDT as a chemotherapeutic reagent and rhodamine B as an imaging reporter as well as targeting domain were conjugated via a biodegradable ester bond. In vitro image studies demonstrated the morphological changes of tubulin and chromosomal alterations of human liver cancer cells HepG2, which were similar to the phenomena observed after treatment with the active drug 4FDT. At 48   h post-treatment, the cytotoxicity of 4FDT-RhB was 18.5% of that of 4FDT. However, this value increased to 49.3% of 4FDT at 72   h post-incubation. These experimental results implied the consistent release of the active drug from the prodrug throughout the incubation period via the linear increase in the cytotoxicity observed as a function of time. It also showed good stability in both plasma and complete blood. Additionally, the specific delivery of the prodrug to mitochondria was observed by fluorescent microscopy.

MicroRNA‑122 regulates docetaxel resistance of prostate cancer cells by regulating PKM2

Zhirong Zhu,Guiliang Tang,Jiajun Yan

Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, is the second leading cause of cancer death worldwide. MicroRNAs (miRs/miRNAs) are reported to have important applications in the field of cancer diagnosis and treatment. The present study aimed to investigate the function of miRNA‑122 in the chemoresistance of PCa cells and the underlying mechanism. Significantly decreased miR‑122 and increased pyruvate kinase (PKM2) levels were observed in docetaxel‑resistant PCa cells, and PKM2 was negatively correlated with miR‑122. MiR‑122 mimic transfection in docetaxel‑resistant LNCaP cells significantly inhibited cell proliferation, promoted apoptosis and decreased glucose uptake and lactate production, which was counteracted by PKM2 overexpression. Inhibition of miR‑122 in LNCaP cells had an opposite effect to miR‑122 mimic transfection. In addition, miR‑122 mimic transfection significantly increased the sensitivity of docetaxel‑resistant LNCaP cells to docetaxel, while inhibition of miR‑122 significantly decreased the sensitivity of LNCaP cells to docetaxel. Luciferase reporter assays showed that miR‑122 regulated PKM2 expression by binding to the 3'‑untranslated region of PKM2. The results suggest that upregulation of miR‑122 could enhance docetaxel sensitivity, inhibit cell proliferation and promote apoptosis in PCa cells,possibly through the downregulation of its target protein PKM2.

Vascular targeted chitosan-derived nanoparticles as docetaxel carriers for gastric cancer therapy

Enhui Zhang,Ronge Xing,Song Liu,Kecheng Li,Yukun Qin,Huahua Yu,Pengcheng Li

A gastric cancer angiogenesis marker peptide, GX1, is promising to be a desirable ligand for anti-angiogenesis targeted drug of gastric cancer treatment. In this study, GX1 was utilized to fabricate a multifunctional vascular targeting docetaxel (DCT)-loaded nanoparticle with N -deoxycholic acid glycol chitosan (DGC) as the carrier and GX1-PEG-deoxycholic acid (GPD) conjugate as the targeting ligand. The mean size of obtained GX1-DGC-DCT was 150.9 nm with a narrow size distribution and their shape was spherical with smooth surface texture. The in vitro drug release test revealed a sustained release manner and an acid pH could accelerate the release compared with the neutral pH. Furthermore, GX1-DGC-DCT showed stronger cytotoxicity against co-cultured gastric cancer cells and human umbilical vein endothelial cells (co-HUVEC) than DCT within 100 μM. In addition, GX1 efficiently enhanced the cellular uptake of nanoparticles in co-HUVEC cells as confirmed by confocal fluorescence scanning microscopy. Moreover, in vivo delivery of GX1-DGC-DCT was demonstrated to inhibit tumor growth in SGC791 tumor-bearing mice with tumor inhibition rate (TIR) of 67.05% and no weight loss of mice was observed. The anti-tumor effects were further confirmed by H&E and TUNEL analysis. Therefore, this new drug delivery system represents a potential strategy for gastric cancer therapy.

Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes

Guolian Ren,Mengjuan Jiang,Weiling Guo,Bingjun Sun,He Lian,Yongjun Wang,Zhonggui He

A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

Functionalized docetaxel-loaded lipid-based-nanosuspensions to enhance antitumor efficacy in vivo

Xiuping Pang,Tianqi Wang,Dandan Jiang,Weiwei Mu,Bo Zhang,Na Zhang

Multifunctional gold nanorods and docetaxel-encapsulated liposomes for combined thermo- and chemotherapy

Haiying Hua,Nan Zhang,Dan Liu,Lili Song,Tuanbing Liu,Shasha Li,Yongxing Zhao

Personalized and precise nanomedicines are highly demanded for today’s medical needs. Liposomes are ideal candidates for the construction of multifunctional drug delivery systems. In this study, a liposome was used to improve the clinical issues of docetaxel (Doc), a potent antimitotic chemotherapy for prostate cancer (PC). RLT, a low-density lipoprotein receptor (LDLR)-binding peptide, and PEG were conjugated to the liposomes, and gold nanorods (GNRs) were also incorporated into the liposomes. The GNRs/Doc-liposome-RLT (GNRs/DocL-R) was tested in PC-3 cells and in PC-3 tumor-bearing nude mice. Results showed that GNRs/DocL-R possessed a diameter approximately 163.15±1.83 nm and a zeta potential approximately −32.8±2.16 mV. GNRs/DocL-R showed enhanced intracellular entrance, increased accumulation in the implanted tumor region, and the highest tumor inhibition in vitro and in vivo. Therefore, the multifunctional GNRs/DocL-R was a potential cancer treatment via combined chemo- and thermotherapy.

Construction and cellular uptake evaluation of redox-responsive docetaxel prodrug self-assembled nanoparticles

Guolian Ren,Pei Chen,Jiaqi Tang,Rongrong Wang,Shuai Duan,Ruili Wang,Yin Xie,Shuqiu Zhang

Docetaxel (DTX) solution has some serious adverse side effects. A redox-responsive DTX prodrug synthesized in our laboratory was used to prepare DTX prodrug self-assembled nanoparticles (DSNPs) with the method of nanoprecipitation. This study aimed at optimizing the formulation to develop stable preparation for the delivery of DTX. Single-factor test was used to evaluate the effects of the preparation concentration of DTX prodrug, stirring speed, the types of stabilizers and temperature on the prescription process of DSNPs. The particle size and polydispersity index were selected as the evaluation indexes. The entrapment efficiency, drug-loading, size distribution and zeta potential were characterized by UPLC and Zetasizer, respectively. The stability and cellular behavior of DSNPs were investigated by Zetasizer, LC–MS/MS and confocal laser scanning microscope, respectively. The particle size, entrapment efficiency and drug-loading of DSNPs were 173.8 ± 1.4 nm, 98.8% ± 0.1%, and 47.8% ± 0.9%, respectively. DSNPs showed good stability during the storage of 30 days, and were taken into the cells in a time-dependent and concentration-dependent manner. The method of nanoprecipitation could be used to entrap DTX. The preparation method was simple, and the quality of DSNPs was stable and reliable. Through the optimization of the formulation, we obtained uniform and stable DSNPs, which could escape from lysosomes of tumor cells. The optimized formulations were stable for intravenous administration. This study could provide scientific support for the development of nano-drug delivery system of small anti-tumor drug.

An Exosome-Inspired Docetaxel Prodrug Nanoplatform for Potent STING Activation and Synergistic Chemoimmunotherapy

Xinying Wang,Xianlu Zhang,Zixuan Jiao,Shipeng Ning,Hanping Wang,Hui Liu,Lifen He,Haonan Li,Mingzhong Li,Kaiyuan Wang,Zhonggui He,You Pan

The treatment of triple-negative breast cancer (TNBC) is significantly hampered by its immunosuppressive tumor microenvironment and limited T-cell infiltration. Activating the STING pathway presents a promising therapeutic avenue due to its potential to trigger a robust innate immune response and remodel the immunosuppressive landscape, thereby sensitizing tumors to immunotherapy. To harness this potential, we developed an exosome-mimetic nanoplatform (EMMDs). EMMDs is fabricated by co-loading a disulfide-linked docetaxel prodrug (DTX-SS-PA) and the STING agonist MSA-2 into polymeric micelles and further decorated with homotypic tumor cell-derived exosomal membrane (EM). This biomimetic design confers superior tumor-targeting capability. Upon reaching the tumor site, the prodrug is specifically activated to release cytotoxic docetaxel (DTX), while MSA-2 is concurrently released to potently activate the STING pathway. This dual action initiates a powerful antitumor immune response and reverses immunosuppression, leading to a synergistic chemo-immunotherapeutic outcome. In the murine TNBC model, EMMDs demonstrated remarkable antitumor efficacy, obviously provoking a robust STING-mediated type I interferon response and inhibiting tumor growth. This work presents a promising biomimetic strategy for remodeling the tumor immune microenvironment via efficient STING activation.

OCTN2-targeted and ROS-responsive hybrid polymeric micelles for oral delivery of docetaxel

Haihan Sun,Jingxin Gou,Xiaoshuang Bi,Jiayin Song,Boyuan Liu,Xiaoyu Jin,Bowen Sui,Xiangqun Jin

Our previous research identified that an oral mPEG- b -PCL polymeric micelle (PM) maintained satisfactory integrity but exhibited limited transcytosis efficiency. To enhance transcytosis and enable ROS-responsive release, we developed a series of hybrid PMs by blending a synthesized L-carnitine-grafted, thioketal-linked LC-PEG 5k -TK-PCL 7k polymer with mPEG 5k -PCL 7k . These hybrid PMs, similar in particle size (120 nm) and drug loading (10%) to the PM composed of pure mPEG 5k -PCL 7k (5-7E), retained good stability in SGF and SIF. However, the hybrid PM with a 40% LC-PEG 5k -TK-PCL 7k proportion showed reduced integrity and penetration in mucus layer. In Caco-2/E12 (7:3) cells, the hybrid PM with a 20% LC-PEG 5k -TK-PCL 7k proportion (20%Hybrid 5-7E) demonstrated superior uptake, low cytotoxicity, and a 3.37-fold higher transcytosis than that of 5-7E. In 4T1 cells, prepared PMs exhibited similar uptake but hybrid PMs showed obvious ROS-responsive dissociation and cytotoxicity. The in vivo integrity and biocompatibility of 20%Hybrid 5-7E were confirmed by plasma concentration and hemolysis test, and the bio-distribution results demonstrated its tumor accumulation. Pharmacokinetics revealed a 10-fold increase in docetaxel (DTX) bioavailability due to the 20%Hybrid 5-7E encapsulation. Consequently, orally administered 20%Hybrid 5-7E (DTX 40 mg/kg) achieved comparable antitumor activity but reduced systemic toxicity relative to intravenously injected DTX solution (10 mg/kg) in 4T1 tumor-bearing BALB/c mice.

PEG-conjugated triacontanol micelles as docetaxel delivery systems for enhanced anti-cancer efficacy

Lu Xiaoyu,Fang Min,Yang Yue,Dai Yu,Xu Jiaqiu,Zhao Di,Lu Yang,Chen Xijing,Lu Shan,Li Ning

PEGylated triacontanol (mPEG 2k -b-TRIA) was developed as a dual-functional polymer with remarkable biocompatibility. The polymer could self-assemble to micelles with critical micelle concentration (CMC) 17.62 μg mL −1 . Docetaxel-loaded mPEG 2k -b-TRIA micelles (DTX PMs) were fabricated to evaluate the feasibility of mPEG 2k -b-TRIA as drug delivery system. DTX PMs achieved desirable particle size of 93.7 nm, drug loading of 6.66%, and drug encapsulation efficiency of 89.87%. The drug release was based on first-order kinetics model, thus enabling prolonged release. Meanwhile, pharmacokinetic study also revealed that DTX PMs could improve the exposure level of DTX and prolong its systemic circulation time. Furthermore, DTX PMs demonstrated significantly enhanced cytotoxicity and cellular uptake in vitro compared with DTX solution. The in vivo tumor inhibition study carried out on MCF-7 bearing BALB/c mice model also validated that DTX PMs exhibited stronger anti-tumor activity but low toxicity. Notably, mPEG 2k -b-TRIA made some contribution to inhibit the growth of breast cancer cells in vitro and in vivo, indicating the potential as anti-tumor complementary agents. All the results suggested that mPEG 2k -b-TRIA polymer as a vehicle in the formulation of anti-cancer drugs may provide an effective way to improve their therapeutic efficacy. Consequently, the mPEG 2k -b-TRIA polymers would be another promising carrier for hydrophobic anti-cancer drugs delivery.