International Journal of Nanomedicine
·
2017
·
IF 4.3
Yuping Wei,Liang Ma,Liang Zhang,Xia Xu
An effective drug delivery system requires efficient drug uptake and release inside cancer cells. Here, we report a novel drug delivery system, in which paclitaxel (PTX) interacts with a novel cell penetrating peptide (CPP) through noncovalent interaction designed based on molecular simulations. This CPP/PTX complex confers high efficiency in delivering PTX into cancer cells not by endocytosis but by an energy-independent pathway. Once inside cells, the noncovalent interaction between PTX and the CPP may allow fast release of PTX within cells due to the direct translocation of CPP/PTX. This drug delivery system exhibits strong capacity for inhibition of tumor growth and offers a new avenue for the development of advanced drug delivery systems for anticancer therapy.
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2016
·
IF 4.342
Haijun Zhao,Qian Li,Zehui Hong
Although PEGylation allows a drug delivery vehicle to have prolonged blood circulation time, it faces the problem of reduced cellular uptake. Removal of the polyethylene glycol (PEG)-shell at the appropriate time through tumor-microenvironment triggers could be a feasible solution to this problem. Here, paclitaxel (PTX)-loaded mixed micelles (PTX-mM) self-assembled from stearate-modified hyaluronic acid (SHA), mPEG-b-poly(β-amino ester) (mPEG-b-PAE), and ethylene acetyl-b-poly(β-amino ester) (EA-b-PAE) were developed. In the preparation of PTX-mM, SHA micelles were coated with EA-b-PAE followed by coloading of PTX and mPEG-b-PAE. PTX-mM were capable of extracellular pH-triggered PEG-detachment and poly(β-amino ester) (PAE)-mediated endosomal escape. When the pH was changed from pH 7.4 to pH 6.8, the particle size of PTX-mM significantly decreased from 97.5 ± 4.4 to 71.5 ± 2.3 nm. It also resulted in rapid and complete release of mPEG-b-PAE from PTX-mM as monitored using quartz crystal microbalance (QCM) technology. PTX-mM capable of PEG detachment provided significant enhancement of PTX accumulation in SKOV-3 cells compared to PEG nondetachable PTX-mM. Interestingly, intracellular transport studies using confocal laser scanning microscopy (CLSM) showed that EA-b-PAE could promote the escape of micelles from endolysosomes. The half-maximal inhibitory concentration (IC50) of PTX-mM against SKOV-3 cells was 5.7 μg/mL, and PTX-mM containing 20 μg/mL of PTX induced apoptosis in 53.0% of the cell population. PTX-mM exhibited a highly prolonged elimination half-life (t1/2, 2.83 ± 0.37 h) and improved area under the curve (AUC, 7724.82 ± 1190.75 ng/mL/h) than the PTX-loaded SHA micelles (PTX-M). Furthermore, PTX-mM showed the highest tumor inhibition rate (64.9%) and the longest survival time (53 days) against the SKOV-3 ovarian cancer xenograft models among all formulations. Taken together, the results suggested that PTX-mM have potential as an efficient anticancer formulation in treatment of ovarian cancer.
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2016
·
IF 4.342
Meirong Huo,Yao Liu,Lei Wang,Tingjie Yin,Chen Qin,Yanyu Xiao,Lifang Yin,Jiyong Liu,Jianping Zhou
A redox-sensitive micellar system constructed from an O,N-hydroxyethyl chitosan–octylamine (HECS-ss-OA) conjugate with disulfide linkages between the hydrophobic alkyl chains and hydrophilic chitosan backbone was synthesized for triggered intracellular delivery of hydrophobic paclitaxel (PTX). In aqueous environments, conjugates formed micelles with high PTX loading (>30%). Mechanistically, the sensitivity of HECS-ss-OA micelles to reducing environments was investigated using the parameters of in vitro release and particle size. Intracellular release of nile red fluorescence alongside cytotoxicity studies further confirmed the potency of redox-sensitive micelles for intracellular drug delivery compared with redox-insensitive micelles. Additionally, an in vivo study confirmed the efficacy of PTX-loaded micelles in tumor-bearing mice with superior antitumor efficacy and diminished systemic toxicity when compared with the redox-insensitive micelles and a PTX solution. These results demonstrate the potential of redox-sensitive HECS-ss-OA micelles for intracellular trafficking of lipophilic anticancer drugs.
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2016
·
IF 4.843
Yawei Wang,Haiyan Zhang,Jing Hao,Bei Li,Ming Li,Wang Xiuwen
Context: Paclitaxel (PTX) and doxorubicin (DOX) are widely used for the combined chemotherapy of solid tumors. However, free drug combination has lower antitumor efficiency. It is necessary to design a drug delivery system to carry both of them.Objective: This study aimed to engineer a nano-drug delivery system for co-encapsulating PTX and DOX. This system was expected to resolve the multidrug resistance caused by single drug, and the dual–drug-loaded nanostructured lipid carriers were also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.Methods: In this paper, nanostructured lipid carriers for combination delivery of PTX and DOX were prepared by the melt-emulsification technique. In vitro cytotoxicity against NCL-H460 human non-small cell lung carcinoma (NSCLS) cell line was investigated, and in vivo anti-tumor of NLC was evaluated on mice models grafting NCL-H460 cells.Results: PTX-DOX NLC achieved the highest cytotoxic effect among all formulations in vitro, as compared to single drug delivery NLC. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and DOX possessed high tumor-targeting capacity and strong anti-tumor activity.Conclusion: The PTX-DOX NLC constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 17
·3111-3121
·
IF 4.543
Yan-Ling Luo,Xue-Yin Zhang,Yuan Wang,Fang-Jie Han,Feng Xu,Ya-Shao Chen
pH-Sensitive H-type multiblock copolymers, namely, poly(methacrylic acid)2-block-epoxidized hydroxyl-terminated polybutadiene-block-poly(methacrylic acid)2 (PMAA2-b-epoHTPB-b-PMAA2), were synthesized by atom-transfer radical polymerization and subsequent in situ epoxidation by peracetic acid and characterized by 1H NMR, FT-IR and SEC techniques. The impact of epoxidation on the physicochemical and biomedical properties of copolymer self-assembly micelle nanoparticles was investigated by fluorescence spectrometry, DLS, TEM and an MTT assay. The experimental results indicated that epoxidation resulted in the formation of more stable copolymer micelle nanoparticles with a lower critical micelle concentration, smaller micelle size, and higher loading capacity and encapsulation efficiency of drugs than those without epoxidation. In particular, epoxidized copolymer micelle nanoparticles exhibited reasonable pH sensitivity at a pH of 5.3–5.6. The hydrophobic anticancer drug paclitaxel (PTX) displayed faster release rates from epoxidized nanomicelles than from unepoxidized nanomicelles in a PBS solution of a pH of 4.8–6.6, whereas in PBS of a pH of 7.4 smaller amounts of PTX were released from epoxidized nanomicelles than from unepoxidized nanomicelles. Epoxidized copolymer nanomicelles were reasonably biodegradable after the drug was released, and their degradation rate was faster than that of their unepoxidized counterparts. An MTT assay was performed to determine the biocompatibility of epoxidized copolymer micelle nanoparticles and the anticancer activities of PTX-loaded nanomicelles, which were important for applications in the therapy of cancers as a controlled-release drug carrier.
研究领域:
材料科学
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药物递送
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生物医学工程
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DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 19
·15460-15468
·
IF 3.289
Chao Zhang,Tan Lu,Jingang Tao,Guang Wan,Hongxing Zhao
Herein, we have prepared PEGylated nano graphene oxide (NGO-PEG) that co-delivers paclitaxel (PTX) and indocyanine green (ICG) for tumor theranostics, integrating fluorescence imaging and chemotherapy. First, polyethylene glycol (PEG) with a dual-terminal amine was covalently conjugated with NGO to obtain the NGO-PEG. Furthermore, ICG, a near-infrared (NIR) Food and Drug Administration (FDA) approved fluorescent dye was covalently loaded onto NGO-PEG as a fluorescence contrast agent, NGO-PEG–ICG. PTX, a widely clinical used anti-cancer drug, was non-covalently immobilized onto the NGO surface via π–π stacking interaction and hydrogen bonding, giving the multifunctional nano-composite, NGO-PEG–ICG/PTX. The obtained nano-composite had great stability and biocompatibility. NGO-PEG showed (50 ± 2.1)% and (90 ± 1.6)% (w/w) of ICG and PTX loading ratios, respectively, which were determined from a UV-visible spectrometer. The fluorescence signal endowed by ICG was detected in the cytoplasm using confocal microscopy, demonstrating the high-efficiency human osteosarcoma (MG-63) cell uptake of NGO-PEG–ICG/PTX. Moreover, NGO-PEG–ICG/PTX could cause decreased cell viability compared to the same concentration of free PTX, revealing the excellent chemotherapeutic effect of NGO-PEG–ICG/PTX in vitro. In vivo fluorescence imaging results indicated a high MG-63 tumor accumulation of NGO-PEG–ICG/PTX, which could reach the maximum content in tumors at about 29.1% dose per g tissue at 24 h post injection with about eight days of tumor retention. Based on these encouraging results, the NGO-PEG–ICG/PTX was tail vein injected into tumor-bearing mice at day one and day eight, and the tumor-bearing mice showed complete tumor suppression or no relapse and treatment-induced major organ lesions over one-month of treatment. These results suggested that the synthesized versatile NGO-PEG–ICG/PTX with a high fluorescence contrast and chemotherapeutic effect can be a potential tumor theranostic nanoplatform.
研究领域:
纳米医学
·
生物材料
·
肿瘤学
✓ 已验证
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2014
·
IF 4.787
Yuling Bao,Yuanyuan Guo,Xiangting Zhuang,Dan Li,Bolin Cheng,Songwei Tan,Zhiping Zhang
To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration–time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2014
·
IF 7.261
Shixian Lv,Zhaohui Tang,Dawei Zhang,Wantong Song,Mingqiang Li,Jian Lin,Huaiyu Liu,Xuesi Chen
The synthesis of polymer–drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) with redox and pH dual sensitive behaviors. A simple polymer, 3,3′-dithiodipropionic acid functionalized poly(ethylene glycol)- b -poly( l -lysine) (mPEG- b -P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG- b -P(LL-DTPA) to obtain the disulfide-containing polymer–PTX conjugate (P(L-SS-PTX)). Another structural similar polymer–PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared to verify the function of disulfide linkages. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be promoted by the increased acidity (pH ≈ 5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice demonstrated the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery.
研究领域:
药学
·
生物医学工程
·
肿瘤学
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DOI
高影响因子
Nanoscale
·
2017
·Vol. 9
·期 35
·13142-13152
·
IF 7.367
Jingxin Mo,Li Wang,Xiaojia Huang,Bing Lu,Changye Zou,Lili Wei,Junjun Chu,Paul K. Eggers,Shen Chen,Colin L. Raston,Jun Wu,Lee Yong Lim,Wei Zhao
Ovarian cancer (OC) is the most lethal gynecologic cancer. Survival statistics have show no significant developments over the last three decades, highlighting the fact that current therapeutic strategies require substantial improvements. In this study, we designed a novel folic acid-PEG-conjugated p-phosphonated calix[4]arene nanoparticle (Fp-PCN) for the simultaneous delivery of paclitaxel (PAC) and carboplatin (CAR) at an optimal ratio (5 : 1, mol : mol) to utilize their potential synergistic effect against OC cells. The Fp-PCNs loaded with PAC and CAR (Fp-PCNPAC+CAR) resulted in a remarkable efficacy in the suppression of OC, both in vitro and in vivo. Compared to free drugs, Fp-PCNPAC+CAR showed stronger apoptosis induction as well as invasion and self-renewal capacity suppression in SKOV-3 cells. The molecular mechanism to address the synergism is that Fp-PCNPAC+CAR downregulated JMJD3 expression to modulate the H3K27me3 epigenetic mark of the promoters of HER2 and MYCN. Furthermore, the expressions of JMJD3 and HER2 were significantly associated with poor outcomes for ovarian patients. Our study demonstrates that co-delivery of PAC and CAR can be achieved with the Fp-PCNs, and reveals a previously unrecognized and unexpected role of the JMJD3-HER2 signaling axis in PAC and CAR treatment of OC.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
分子生物学
·
癌症治疗
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2022
·
IF 7.033
Juan Du,Lanlan Zong,Mengmeng Li,Keke Yu,Yonghui Qiao,Qi Yuan,Xiaohui Pu
Introduction Cancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists. Methods Here, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX. Results The PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice. Conclusion This work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.
研究领域:
药理学
·
肿瘤学
·
药物递送系统
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DOI
PubMed
高影响因子
Nanoscale
·
2021
·Vol. 13
·期 6
·3613-3626
·
IF 7.79
Shuangyu Liu,Dongsheng Shi,Ling Chen,Yu Yan,Xingqi Wang,Yingying Song,Shengyan Pu,Yijun Liang,Yang Zhao,Yu Zhang,Jun Xie
A combination of chemotherapy and targeted magnetic hyperthermia (TMH) via a designed magnetic nanocrystal (MNC) drug delivery system was considered as an effective tumor synergistic therapy strategy. In this paper, we successfully synthesized tumor neovascular-targeted Mn–Zn ferrite MNCs, which encapsulated paclitaxel (PTX) in a biocompatible PEG-phospholipid (DSPE-PEG2000) layer and surface, simultaneously coupled with a tripeptide of arginine-glycine-aspartic acid (RGD). The high-performance RGD-modified MNC loaded with PTX (MNCs-PTX@RGD) embodied excellent magnetic properties, including high-contrast magnetic resonance imaging (MRI) and remarkable magnetically induced heat generation ability. We established the mouse model bearing subcutaneous 4T1 breast tumor, and demonstrated that MNCs-PTX@RGD could be effectively located in the tumor neovascular epithelial cells under the guidance of in vivo MRI. Notably, MNCs-PTX@RGD could easily penetrate into the tumor tissue from the tumor-fenestrated vascular networks for capturing a sufficient temperature (around 43 °C) exposed to an alternative current magnetic field (ACMF, 2.58 kA m−1, 390 kHz), leading to an effective TMH effect. Subsequently, the TMH-mediated temperature elevation accelerated the PTX release from the inner lipid layer, promoting the synergetic thermo-chemotherapy in vivo. The amplifying synergistic treatment strategy obviously improved the anti-tumor efficacy of MNCs-PTX@RGD, and simultaneously increased the survival time of the mice to more than 46 days, which provided a broad development prospect in clinical applications.
研究领域:
纳米技术
·
肿瘤学
·
生物医学工程
·
药物递送系统
·
磁共振成像
·
热疗
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2016
·
IF 6.008
Jiulong Zhang,Xiufeng Zhao,Qing Chen,Xiaoyi Yin,Xiu Xin,Kexin Li,Mingxi Qiao,Haiyang Hu,Dawei Chen,Xiuli Zhao
Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH-responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) and folate acid-D-α-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis , into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. All these evidences demonstrated this pH-sensitive FA-TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR. Statement of Significance In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations have been made, which supported enough evidences for the efficient delivery of antitumor drug to MDR cells.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
药物递送系统
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）