Nano Research
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2021
·Vol. 15
·期 4
·3367-3375
·
IF 8.897
Wang Xin,Li Lingxiao,Wang Danping,Zuo Shiyi,Liu Tian,Dong Fudan,Zhang Xuanbo,He Zhonggui,Sun Bingjun,Sun Jin
Prodrug-based nanoassembly emerges as a hopeful way for the efficient delivery of antitumor drugs, with carrier-free structure and ultra-high drug loading. Carbon chains are widely used to design self-assembling prodrugs. The impacts of the length of carbon chains on the self-assembly stability, drug delivery efficiency and antitumor effect of prodrugs have not been fully elucidated. Here, three paclitaxel prodrugs were synthesized by conjugating paclitaxel with octanol (C 8 ), decanol (C 10 ) or dodecanol (C 12 ) through disulfide bond. The three prodrugs could form homogeneous nanoparticles, with over 50% drug loading and redox dual-responsivity. Interestingly, the length extension of carbon chains ameliorates the self-assembly and the colloidal stability of prodrugs, thus improving the drug delivery efficiency. The optimal paclitaxel-dodecanol prodrug nanoassemblies exhibit better antitumor efficacy than Taxol and Abraxane. These findings are meaningful for the rational design of advanced nanomedicines in cancer therapy.
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高影响因子
DRUG DELIVERY
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2020
·
IF 4.902
Longfa Kou,Rui Sun,Shuyi Xiao,Xiao Cui,Jin Sun,Vadivel Ganapathy,Qing Yao,Ruijie Chen
Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo. As the presence or absence of the mucus layer was the primary difference between in vitro/in situ versus in vivo, the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ, but interfered with the absorption in vivo. Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo, this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2013
·
IF 3.554
Haitao Huang,Xiaolan Zhang,Jiahui Yu,Junping Zeng,Peter R. Chang,Haibo Xu,Jin Huang
This work is aimed at the development of a reduction-sensitive drug carrier for the delivery of the anti-cancer drug paclitaxel (PTX). N,N′-bis(acryloyl)cystamine (CBA) was reacted with ethanolamine (AEOL) via Michael addition to synthesize cationic poly(CBA-AEOL) (PCA) containing disulfide bonds. Subsequently, polycaprolactone (PCL) was grafted from PCA to form a novel reduction-sensitive copolymer (PCA-g-PCL). The PCA-g-PCL copolymer self-assembled as spherical micelles with a mean size of ca. 108 nm. The disulfide bonds in the PCA-g-PCL copolymer contributed to the reduction-sensitivity of the micelles, observed as stepwise aggregation under simulated reduction conditions. To improve the stability of PCA-g-PCL micelles in aqueous media, carboxyl-terminated poly(ethylene glycol) methyl ether (mPEG-COOH) was conjugated with the PCA-g-PCL copolymer via electrostatic interaction to produce polyion complex micelles with a hydrophilic PEG surface. The in vitro release of PTX from the mPEG@PCA-g-PCL micelle showed a reduction sensitive profile, namely the rate of drug release strongly depended upon the concentration of the reducing agent. Leakage of PTX was limited to below 30% under normal conditions while almost all the drug was released in 9 h under reduction conditions with 40 mM DTT. In conclusion, the assembled mPEG@PCA-g-PCL micelle with reduction-sensitive controlled release shows great potential for improving the therapeutic effect of paclitaxel.
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高影响因子
International Journal of Nanomedicine
·
2012
·
IF 3.13
Xiaowei Ma,Huan Wang,Shubin Jin,Yan Wu,Xing-Jie Liang
Background There is an urgent need to develop drug-loaded biocompatible nanoscale packages with improved therapeutic efficacy for effective clinical treatment. To address this need, a novel poly (2-hydroxyethyl methacrylate)-poly (lactide)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [PHEMA-g-(PLA-DPPE)] copolymer was designed and synthesized to enable these nanoparticles to be pH responsive under pathological conditions.Methods The structural properties and thermal stability of the copolymer was measured and confirmed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and thermogravimetric analysis. In order to evaluate its feasibility as a drug carrier, paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles were prepared using the emulsion-solvent evaporation method.Results The PHEMA-g-(PLA-DPPE) nanoparticles could be efficiently loaded with paclitaxel and controlled to release the drug gradually and effectively. In vitro release experiments demonstrated that drug release was faster at pH 5.0 than at pH 7.4. The anticancer activity of the PHEMA-g-(PLA-DPPE) nanoparticles was measured in breast cancer MCF-7 cells in vivo and in vitro. In comparison with the free drug, the paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles could induce more significant tumor regression.Conclusion This study indicates that PHEMA-g-(PLA-DPPE) nanoparticles are promising carriers for hydrophobic drugs. This system can passively target cancer tissue and release drugs in a controllable manner, as determined by the pH value of the area in which the drug accumulates.
研究领域:
药剂学
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肿瘤学
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生物材料科学
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JOURNAL OF NANOPARTICLE RESEARCH
·
2026
·Vol. 28
·期 9
·221
·
IF 3.5
Li Rongye,Zhu Congying,Song Xiaoping,Zhang Xiaodong,Hamdi Marwa,Chen Jiahong
Recent advances in polymeric nanocarriers have highlighted the potential of amphiphilic block copolymers for the simultaneous delivery of chemotherapeutic agents with different physicochemical properties. In this study, asymmetric poly(ethylene glycol)-b-polylactide-b-poly(ethylene glycol) (PEG- b -PLA- b -PEG) triblock copolymers were synthesized via ring-opening polymerization, end-group functionalization, and click coupling, and subsequently evaluated as biodegradable nanocarriers for the co-delivery of paclitaxel (PTX) and cisplatin (CDDP). The copolymers were characterized by 1 H nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC). Self-assembly in aqueous media yielded spherical micelles with uniform size distributions, as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The micelles exhibited efficient encapsulation of PTX and CDDP with high drug-loading capacities and encapsulation efficiencies. Hydrolytic degradation studies conducted at 37 °C for 45 days revealed progressive cleavage of the ester bond, reduction in molecular weight, and gradual disintegration of the micellar structure. In vitro release studies of single- and dual-drug-loaded micelles demonstrated sustained release of both drugs over time. Analysis of the release data using the Korsmeyer–Peppas model provided insight into the release behavior and suggested contributions from both diffusion and polymer degradation processes. The biocompatibility of the unloaded triblock copolymer micelles was assessed through cytocompatibility, hemocompatibility, and zebrafish embryo assays, which indicated low intrinsic toxicity and minimal hemolytic activity. Collectively, these results demonstrate that PEG- b -PLA- b -PEG triblock copolymer micelles can be recognized as biodegradable carriers capable of dual-drug encapsulation and sustained release, providing a useful platform for further investigation of combination drug delivery systems. Graphical abstract Asymmetric PEG- b -PLA- b -PEG triblock copolymers were synthesized and self-assembled into uniform micelles capable of co-encapsulating Paclitaxel and Cisplatin. The micellar architecture provided controlled degradation and synchronized dual-drug release over 45 days. The combination of tunable structure, sustained release, and excellent biocompatibility highlights these triblock copolymer micelles as efficient nanocarriers for combinational cancer therapy
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Advanced Healthcare Materials
·
2019
·Vol. 8
·期 23
·1900965
·
IF 6.27
Yao Yang,Zhengwei Huang,Jinyuan Li,Ziran Mo,Ying Huang,Cheng Ma,Wenhao Wang,Xin Pan,Chuanbin Wu
Combination therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR TKIs) with other chemotherapeutic agents is a feasible strategy to overcome resistance that often occurs after 9–13 months of EGFR TKIs administration in nonsmall cell lung cancer (NSCLC). In this study, a pulmonary microspheres system that codelivers afatinib and paclitaxel (PTX) is developed for treatment of EGFR TKIs resistant NSCLC. In this system, afatinib is loaded in stearic acid-based solid lipid nanoparticles, then these nanoparticles and PTX are loaded in poly-lactide- co -glycolide-based porous microspheres. These inhaled microspheres systems are characterized including geometric particle size, drug encapsulation efficiency, morphology by scanning electron microscopy, specific surface area, in vitro drug release, and aerodynamic particle size. Cell experiments indicate that afatinib and PTX have a synergistic effect and the codelivery system shows a superior treatment effect in drug-resistant NSCLC cells. The biocompatibility, pharmacokinetic, and tissue distribution experiments in Sprague–Dawley rats show that afatinib and PTX in the system can maintain 96 h of high lung concentration but low concentration in other tissues, with acceptable safety. These results demonstrate that this system may be a prospective delivery strategy for drug combination treatment in cancers developing resistance, especially drug-resistant lung cancer.
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JOURNAL OF NANOPARTICLE RESEARCH
·
2015
·Vol. 17
·期 10
·1-10
·
IF 2.184
Chen Daquan,Wang Guohua,Song Weiguo,Zhang Qiang
Most anticancer drugs cannot kill cancer stem cells (CSCs) effectively, which lead to the failure of anticancer chemotherapy, such as relapse and metastasis. In this study, we prepared a multifunctional oligosaccharides of hyaluronan (oHA) conjugates, oHA-histidine-menthone 1,2-glycerol ketal (oHM). The oHM conjugates possess pH-sensitive menthone 1,2-glycerol ketal (MGK) as hydrophobic moieties and oHA as the target of CD44 receptor. Anticancer drugs, curcumin(Cur) and paclitaxel(PTX), were loaded into oHM micelles via self-assembly. Then, oHM micelles were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method to fabricate the “nano-eggs.” The formed nano-eggs had a smaller size (120.6 ± 4.5 nm) than oHM micelles (158.6 ± 6.4 nm), indicating that mineralization made the appearance of compact nanoparticles. Interestingly, when the nano-eggs were put into the acidic conditions (pH 6.5), their outer shell(inorganic minerals) will be destroyed with the larger size, while the “nano-eggs” were stable under pH 7.4. For both nano-eggs and oHM micelles, the Cur and PTX were released in a sustained manner depending on the pH of the solution. However, the nano-eggs showed much lower released than the oHM micelles due to the dissolution of the inorganic minerals and pH-sensitive ketal at mildly acidic environments (pH 6.5). In vivo study, the nano-eggs could get to the tumor site more effectively than oHM micelles. CSCs were sorted by a side population assay from MDA-MB-231 breast cancer cell lines over-expressing CD44 receptors. Antitumor activity was also evaluated on MDA-MB-231 xenografts in nude mice. The antitumor efficacy indicated that nano-eggs with co-delivery of Cur and PTX produced the strongest antitumor efficacy, and nano-eggs showed strong activity against cancer stem cells. These double pH-sensitive nano-eggs may provide a promising strategy for drug delivery to both cancer cells and cancer stem cells.
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International Journal of Nanomedicine
·
2023
·
IF 8
Jing Lin,Chaoyue Zhao,Cuijuan Liu,Shiyao Fu,Luying Han,Xinping Lu,Chunrong Yang
Introduction The development of nanodrug carriers utilizing tumor microenvironment has become a hotspot in reversing multidrug resistance (MDR).Materials and methods This study synthesized a redox-sensitive copolymer, Pluronic F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate (FSST), through the connection of the reduction-sensitive disulfide bond between F127 and d-α-tocopheryl polyethylene glycol 1000 succinate. This polymer could induce the elevation of reactive oxygen species (ROS) levels, ultimately resulting in cytotoxicity. Moreover, the redox-responsive mixed micelles, F127-folate (FA)/FSST/P123 (FFSSTP), based on FSST, Pluronic F127-FA, and Pluronic P123, were prepared to load paclitaxel (PTX).Results The in vitro release study demonstrated that FFSSTP/PTX accelerated the PTX release through the breakage of disulfide bond in reductive environment. In cellular experiment, FFSSTP/PTX induced significant apoptosis in PTX-resistant MCF-7/PTX cells through inhibiting adenosine triphosphate (ATP)-binding cassette proteins from pumping out PTX by interfering with the mitochondrial function and ATP synthesis. Furthermore, FFSSTP/PTX induced apoptosis through elevating the intracellular levels of ROS.Conclusion FFSSTP could become a potential carrier for the treatment of MDR tumors.
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JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS
·
2016
·Vol. 105
·期 5
·1114-1125
·
IF 2.881
Shu-Di Yang,Wen-Jing Zhu,Qiao-Ling Zhu,Wei-Liang Chen,Zhao-Xiang Ren,Fang Li,Zhi-Qiang Yuan,Ji-Zhao Li,Yang Liu,Xiao-Feng Zhou,Chun Liu,Xue-Nong Zhang
The development of effective and stable carriers of small interfering RNA (siRNA) is important for treating cancer with multidrug resistance (MDR). We developed a new gene and drug co-delivery system and checked its characteristics. Low-density lipoprotein (LDL) was coupled with N-succinyl chitosan (NSC) Lipoic acid (LA) micelles and co-delivered MDR1 siRNA and paclitaxel (PTX-siRNA/LDL-NSC-LA) to enhance antitumor effects by silencing the MDR gene of tumors (Li et al., Adv Mater 2014;26:8217-8224). In our study, we developed a new type of containing paclitaxel-loaded micelles and siRNA-loaded LDL nanoparticle. This “binary polymer” is pH and reduction dual-sensitive core-crosslinked micelles. PTX-siRNA/LDL-NSC-LA had an average particle size of (171.6 ± 6.42) nm, entrapment efficiency of (93.92 ± 1.06) %, and drug-loading amount of (12.35% ± 0.87) %. In vitro, MCF-7 cells, high expressed LDL receptor, were more sensitive to this delivery system than to taxol ® and cell activity was inhibited significantly. Fluorescence microscopy showed that PTX-siRNA/LDL-NSC-LA was uptaken very conveniently and played a key role in antitumor activity. PTX-siRNA/LDL-NSC-LA protected the siRNA from degradation by macrophage phagocytosis and evidently down-regulated the level of mdr1 mRNA as well as the expression of P-gp. We tested the target ability of PTX-siRNA/LDL-NSC-LA in vivo in tumor-bearing nude mice. Results showed that this system could directly deliver siRNA and PTX to cancer cells. Thus, new co-delivering siRNA and antitumor drugs should be explored for solving MDR in cancer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1114–1125, 2017.
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Journal of Biomedical Nanotechnology
·
2014
·Vol. 10
·期 6
·948-958
·
IF 7.578
Liu Yongjun,Liu Chunxi,Li Min,Liu Fengxi,Feng Lixia,Zhang Li,Zhang Na
Multifunctional nanoparticles assembled from multi-block polymers are now one of the most convenient and convincing carriers for target drug delivery. Multi-block polymers could provide multi-functions such as sufficient drug loading capability and efficient target ligand coupling potency.
In this article, novel multi-block polymer poly(lactic acid)–poly(ethylene glycol)–poly(L-lysine) (PLA-PEG-PLL) with relatively precise block molecular weight were synthesized by new method which we called polymer–polymer conjugation. This method conjugated different polymer
blocks by reactions between the terminal active groups of different blocks, thus simplified the synthesis procedure. The obtained PLA-PEG-PLL was characterized by 1H NMR and gel permeation chromatography. The controlled drug delivery capability and the target ligand coupling potency
of PLA-PEG-PLL were verified using paclitaxel (PTX) as model drug and vascular endothelial growth factor (VEGF) antibody as target ligand. The PTX-loaded PLA-PEG-PLL nanoparticles (PNP) and VEGF antibody modified PTX-loaded PLA-PEG-PLL nanoparticles (VPNP) were prepared using solvent diffusion
methods. The two nanoparticles showed spherical or ellipsoidal shapes with uniform particle size distribution (190.1 ± 1.27 nm and 203.6 ± 4.10 nm for PNP and VPNP, respectively) and positive zeta potential (23.76 ± 0.72 mv and 20.76 ± 0.34 mv for PNP and VPNP,
respectively). The cellular cytotoxicity, cellular uptake, in vivo therapeutic effects of the two nanoparticles were investigated. Cytotoxicity of VPNP against HepG2 cells was superior to that of PNP and Taxol®. The VPNP and PNP showed better antitumor efficacy in a murine model
bearing H22 compared with Taxol® and VPNP was the best. The study on cellular uptake indicated that the better antitumor efficacy of VPNP was attributed to the increased uptake of drug by tumor cells. These results demonstrated that PLA-PEG-PLL was a favorable multifunctional
material for drug target delivery and polymer–polymer conjugation was a promising method to fabricate novel multi-block polymers.
研究领域:
药学
·
纳米技术
·
药物递送系统
·
癌症研究
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高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2025
·
IF 2.2
Yanli Zhao,Yimu Li,Yan Chen,Yuanyuan Li,Lingbing Li,Wei Xu
Objective The aim of this study was to develop a chemotherapy drug paclitaxel (PTX) and a tumor specific ROS generation agent β-lapachone(LAP) co-loaded human serum albumin (HSA) based nanoparticles (ANPs) for synergistic anticancer therapy.Significance: Albumin based nanoparticles (ANPs) offer unique advantages for antitumor drug delivery system, including non-immunogenicity and inherent tumor-targeting capacity. In this study, we mimicked the natural fatty-acid binding process in vivo to construct ANPs to synergistically elevate ROS with β-lapachone for cooperative cancer therapy.Methods: Firstly a polyethylene glycol monostearate(PGM) modified redox-sensitive paclitaxel prodrug(PTX-SS-PGM) was synthesized and stearic acid capable of binding with HSA was introduced. Furtherly, a LAP/PTX-SS-PGM complex was engineered through the π − π stacking interaction and H-bonding between LAP and PTX. The PTX and LAP co-loaded ANPs (PTX-SS-PGM&LAP@HSA) were obtained through the binding between LAP/PTX-SS-PGM complex and HSA.Results: The percentage of apoptosis for PTX, Abraxane®, PTX-SS-PGM@HSA ANPs and PTX-SS-PGM&LAP@HSA ANPs was 8.17%, 9.53%, 15.17% and 28.6%, respectively, demonstrating synergistic cytotoxicity effect. The in vivo imaging test confirmed that PTX-SS-PGM&LAP@HSA had targeting ability to tumor tissues. The obtained ANPs exhibited better tumor growth inhibition in vitro and in vivo.
研究领域:
肿瘤学
·
纳米医学
·
药物递送
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生物材料
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分子药理学
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转化医学
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2019
·
IF 2.606
Shaohui Xu,Zhu Jin,Zhipeng Zhang,Wei Huang,Yuanyuan Shen,Zhongmin Wang,Shengrong Guo
It is necessary for effective combinational effects that multiple chemotherapeutic agents enter and act on the same tumor cells simultaneously at a suitable ratio. Due to their individual physicochemical or biopharmaceutical properties, they cannot reach the same cells at its predetermined ratio after co-administration. Herein, we report a novel system with precise ratiometric co-loading, co-delivery and intracellular co-release of paclitaxel (PTX) and curcumin (CUR), to investigate their synergistic effects. We prepared the system by conjugating PTX and CUR at different ratios onto the same gold nanorods (GNRs). We demonstrated that PTX and CUR could be precisely ratiometric co-loaded to form dual-drug conjugated biotin-PEG modified GNRs (abbreviated as PTX/ [email protected] ), which could co-deliver dual drugs into tumor cells with a predetermined ratio and co-release them intracellularly. The PTX/ [email protected] with the mass ratio of PTX and CUR at 1:1 exhibited the best synergistic effect on multidrug resistant MCF-7/ADR cells while the free PTX and CUR mixture with the mass ratio of at 1:0.75 displayed the strongest synergism. Cytotoxicity studies showed that PTX/ [email protected] are superior to free drug mixture. Furthermore, PTX/ [email protected] could remarkably induce apoptosis of MCF-7/ADR cells under near-infrared irradiation. Moreover, we found that PTX/ [email protected] significantly inhibited P-glycoprotein (P-gp) expression in MCF-7/ADR cells.
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