ORGANIC & BIOMOLECULAR CHEMISTRY
·
2019
·Vol. 17
·期 15
·3853-3860
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IF 3.49
Leixia Mei,Keming Xu,Ziran Zhai,Suyun He,Tingting Zhu,Wenying Zhong
Drug incorporation in hydrogels often brings undesirable effects on the stability or mechanical properties of the system. To address this problem, we report the design and synthesis of a RGD-derived peptide conjugate (1-RGDH) for its co-assembly with a commonly used chemotherapeutic drug, doxorubicin (DOX), that formed electrostatic interactions with the 1-RGDH peptide and reinforced the supramolecular network of nanofibers within the matrix of the hydrogel. The hybrid hydrogel demonstrated excellent viscoelastic and shear-thinning properties that greatly facilitated the development of injectable drug delivery systems. Furthermore, it demonstrated a unique pH responsive release of DOX under weakly acidic conditions, paving ways for the controlled release of drug cargos in a typical tumor microenvironment with mild acidity. Finally, the DOX-incorporated hydrogel exhibited a superior anti-tumor efficacy in non-small-cell lung cancer cells A549 compared to the aqueous solution of free DOX, with an integrin receptor-mediated endocytosis pathway revealed for the cellular uptake of DOX-incorporated nanofibers.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Lili Chen,Yuanyuan Zheng,Longbao Feng,Zonghua Liu,Rui Guo,Yuanming Zhang
The aim of this work was to examine the formation and properties of a novel polyelectrolyte complex of drug carrier system for the delivery of doxorubicin (DOX), which consists of hyaluronic acid (HA) coated hydrophobically modified chitosan (CS). Various batches of polyelectrolyte complexes with the molar ratio of deoxycholic acid (DCA) and chitosan (CS) of 0.1, 0.2, 0.3 were prepared, and were termed as CS-DCA 10 , CS-DCA 20 , and CS-DCA 30 respectively. The samples were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Transmission electron microscopy (TEM), nuclear magnetic resonance hydrogen spectrum ( 1 H NMR) and dynamic light scattering (DLS). Particle sizes of synthesized polyelectrolyte complex nanoparticles (PCNs) were found to be in the range of 280–310 nm, larger than those of uncoated nanoparticles (~150 nm). The PCNs have large zeta potentials (about 26 mV) which make them stable and no sizes' change was determined. DOX could be easily incorporated into the PCNs with encapsulation efficiency (56%) and kept a sustained release manner without burst effect when exposed to PBS (pH 7.4) at 37 °C. Overall, these findings confirmed the potential of these PCNs for drug carrier and prolonged and sustained delivery in the bloodstream.
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ACS Biomaterials Science & Engineering
·
2018
·
IF 4.432
Guoqing Ma,Jie Liu,Jinlin He,Mingzu Zhang,Peihong Ni
The development of novel stimuli-responsive and biodegradable polyphosphoester-anticancer prodrugs is of importance in designing water-soluble prodrugs utilized in the field of drug delivery. In this study, the focus is on the synthesis of biocompatible and biodegradable diselenide-containing polyphosphoester [PEEP-b-PBYP-Se]2 using reduction-responsive di(1-hydroxylundecyl) diselenide as an initiator to polymerize 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP) and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP). After that, a doxorubicin (DOX) derivative containing an azide group was linked onto the side chain of [PEEP-b-PBYP-Se]2 via the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reaction to yield a pH/reduction-responsive polymeric prodrug, namely [PEEP-b-(PBYP-hyd-DOX)-Se]2. The chemical structures of various polymers were characterized by nuclear magnetic resonance spectroscopy, ultraviolet–visible spectrophotometer, Fourier transform infrared spectroscopy, and high-performance liquid chromatography. The self-assembly behavior measured by dynamic light scattering and transmission electron microscopy clearly supported the formation of the prodrug nanoparticles (NPs). The results indicated that the polymeric prodrug NPs were relatively uniform spheres that could maintain stability in a physiological condition but be cleaved in acidic or reductive medium. Furthermore, the pH- and reduction-responsive properties of the prodrug NPs were investigated via drug release in vitro in different media. It turned out that the drug was efficiently released in acidic or reductive medium compared with that under physiological conditions. The results of methyl thiazolyl tetrazolium assays confirmed the favorable biocompatibility of [PEEP-b-PBYP-Se]2. Moreover, the cell cytotoxicity and intracellular uptake experiments were carried out to verify the efficient cellular proliferation inhibition. This finding contributes to the design of a novel diselenide-containing polyphosphoester-doxorubicin prodrug.
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Nano Research
·
2018
·Vol. 11
·期 6
·3396-3410
·
IF 7.994
Wu Dongyan,Wang Huaisong,Hou Xiaoshuang,Chen Huan,Ma Yu,Hou Yanglong,Hong Jin,Ding Ya
Studies on the influence of one critical parameter (e.g., size), targeting a specific disease, while keeping other factors unchanged, are important for improving understanding and application of the molecular design of biomedical nanomaterials. In this study, we used doxorubicin (Dox)-conjugated gold nanoparticles (GNPs) to investigate the effects of the size of the gold core (10, 20, or 60 nm) on the performance of their conjugates. We found that all three conjugates differed slightly in their physicochemical properties, facilitating a direct and accurate assessment of the size effects of GNP-Dox conjugates on their in vitro and in vivo performance. The cytological properties (the cell penetration rate and efficiency, as well as the cytotoxicity) and antitumor performance (the intratumoral penetration, treatment efficacy, and biodistribution) were highly correlated to the size of the inorganic core. Among all test groups, although the conjugate with a 60-nm gold core had the highest drug loading and release efficiency, the conjugate with a 10-nm gold core displayed the best antitumor efficacy toward the liver cancer models. This was because it showed the deepest tumor permeability and the highest tumor cell-killing ability of Dox transported by the relatively small GNPs. This study provides important evidence for better understanding the effect of size on in vitro and in vivo properties of potential therapeutic nanosystems and their structure design.
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JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
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2018
·Vol. 18
·期 7
·4464-4470
·
IF 1.354
Ji Fan,Zhang Kun,Li Jie,Gu Yuanliang,Zhao Jinshun,Zhang Jianfeng
Cancer chemotherapy has limitations such as nonselective distribution of drugs, detrimental side effects on normal tissues; here we reported a smart pH and magnetic sensitive drug delivery system (DDS) based on PEGylated Fe3O4 superparamagnetic nanoparticles. The
citric-coated Fe3O4 (CIO) nanoparticles were firstly synthesized and further functionalized by biocompatible poly(ethylene glycol) bis(carboxymethyl ether) (COOH-PEG-COOH), thus PEGylated CIO (GCIO) nanoparticles were obtained. Doxorubicin (DOX) was conjugated as a model
drug to the nanoparticles via hydrazone bond. The roughly sphere GCIO nanoparticles were comparatively strong magnetism with high drug loading capability (~89%) in relatively uniform size. Drug release study revealed that the GCIO-DOX performed pH-responsive drug-release properties. MTT assay
demonstrated that GCIO nanoparticles possessed low cytotoxicity and good physiological stability. Further, cell viability results indicated that the GCIO-DOX showed effective cytotoxicity only a bit lower than free DOX. All obtained data indicated that the combined pH-responsive and magnetic
multifunction drug delivery system can has excellent potential applications in cancer therapy.
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Biomaterials Science
·
2018
·Vol. 6
·期 9
·2527-2540
·
IF 5.831
Hui Xiong,Jiang Ni,Zhijie Jiang,Fengchun Tian,Jianping Zhou,Jing Yao
Drug efflux induced by multidrug resistance (MDR) overexpression, as well as secondary drug resistance caused by subtoxic drug microenvironments as a result of inefficient drug release of nanoscopic drug carriers in tumor cells, are major bottlenecks for chemotherapy. In order to overcome these limitations, we have devised a synergism-based polymer supramolecular nanoassembly (LH) by combining hyaluronic acid (HA) modified curcumin (HA-CUR) with a pH-sensitive low molecular weight heparin (LMWH) derivative modified doxorubicin (L-DOX). Our study proved that HA modification not only facilitated tumor targeting drug delivery efficiency through CD44 receptors-mediated active tumor-targeting strategy but also significantly enhanced the MDR reversion effect of CUR by improving its biological stability in different physiological environments. Also, the L-DOX in LH could trigger rapid and effective DOX release under a varied pH value environment, thereby overcoming secondary drug resistance. More importantly, a synergistic antitumor effect was achieved by optimizing the ratio of HA-CUR and L-DOX in LH. Furthermore, LH showed a superior therapeutic effect over free DOX in two mouse models of human cancer. Taken together, these results demonstrated that LH might serve as an efficient platform for delivery of therapeutic payloads to overcome MDR.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Ying Wang,Feng Bai,Qiang Luo,Mingliang Wu,Gang Song,Hongmei Zhang,Jian Cao,Yanqing Wang
Lycium barbarum polysaccharide-doxorubicin (LBP-DOX) nanoparticles were synthesized via a one-step Schiff base reaction between oxidized Lycium barbarum polysaccharide (oxidized LBP) and doxorubicin (DOX). The structure of LBP-DOX nanoparticles was characterized by multi-spectral methods, 1 H nuclear magnetic resonance ( 1 H NMR), transmission electron microscopy (TEM), and thermo gravimetric analysis (TGA). The rheological properties of LBP-DOX nanoparticles were studied. With the increase of shear rate, the viscosity of LBP and LBP-DOX nanoparticles gradually decreases at 25 °C. Under the same strain, the storage modulus (G′) and loss modulus (G″) of LBP-DOX nanoparticles were inferior to LBP. The DOX release from LBP-DOX nanoparticles was pH-dependent and was accelerated by decreasing pH. Cytotoxicity study showed that the LBP-DOX nanoparticles have significantly enhanced cytotoxicity in vitro, especially for human Hepatic cancer cell line HepG2.
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CELL PROLIFERATION
·
2018
·Vol. 51
·期 5
·e12488
·
IF 4.936
Tingting Kong,Liying Hao,Yuanyuan Wei,Xiaoxiao Cai,Bofeng Zhu
Objectives Carbon dots (CDs) are one of the most promising carbon-based materials in bioimaging and drug/gene delivery applications. In this study, we have attempted to study the drug carrying capacity of highly fluorescent CDs for delivery of doxorubicin (DOX) and investigate the therapeutic activity of the CDs-DOX drug delivery system. Materials and methods Carbon dots were synthesized by means of a hydrothermal approach with mixing citric acid and ethylenediamine. The properties of CDs were characterized in respects of spectral property, zeta potential, particle morphology and chemical composition. The drug loading efficiency (DLE) and release profile of CDs-DOX were determined by a fluorescence spectrophotometer. We investigated the cellular toxicity and pharmaceutical activity of CDs and CDs-DOX in L929 cells and MCF-7 cells by the CCK-8 assay. We also studied the cellular uptake of CDs-DOX with the methods of confocal microscopy and flow cytometry. In addition, the effect of CDs-DOX on cell apoptosis was assessed by flow cytometry. Results The obtained CDs possessed good biocompatibility and showed a potential capacity of promoting proliferation. DOX was successfully conjugated to CDs through electrostatic interaction, and the results of the DLE and loading content (DLC) suggested a relatively high drug loading capacity of CDs. Compared with free DOX, the CDs-DOX complex had a higher cellular uptake and better anti-tumour efficacy on MCF-7 cells. Conclusions The results of this study indicated that the CDs-DOX drug delivery system had a potential value in cancer chemotherapeutic application.
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RSC Advances
·
2014
·Vol. 4
·期 95
·53344-53351
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IF 3.708
Mengxia Chen,Wei Feng,Si Lin,Chuanglong He,Yu Gao,Hongsheng Wang
A co-delivery system with two or more anticancer drugs has been proposed to minimize the dosage of drug and to achieve the synergistic therapeutic effect in cancer therapy. In this study, we present a dual drug delivery system for the co-release of two anticancer drugs doxorubicin hydrochloride (DOX) and hydroxycamptothecin (CPT). To achieve this goal, DOX and CPT were first separately loaded into mesoporous silica and hydroxyapatite nanocarriers, thus, the two prepared drug loaded nanocarriers were then simultaneously incorporated into poly(lactic-co-glycolic acid) (PLGA) nanofibers by electrospinning. The as-prepared medicated nanofibers were well-characterized by different assays, and the results demonstrated that both of the two drug loaded nanocarriers were successfully incorporated into PLGA nanofibers. The in vitro release study indicated that the loaded DOX and CPT exhibited a sustained and controlled release behavior from the dual drug loaded nanofibers. Furthermore, the dual drug loaded nanofibers displayed a superior capacity of inhibiting HeLa cells in vitro to the single drug loaded PLGA nanofibers. Thus, the synthesized dual drug loaded composite nanofibers may find a promising application for cancer therapy.
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MATERIALS TECHNOLOGY
·
2015
·
IF 1.227
H. Wu,J. Peng,S. Wang,B. Xie,L. Lei,D. Zhao,H. Nie
Controlled delivery of dual chemical drugs may increase the efficiency of chemotherapy. In this work, doxorubicin (DOX) was bound to adamantanecarboxylic acid (AD-COOH) through covalent linkage to form AD-DOX, while graphene oxide (GO) was modified by ethylenediamino-β-cyclodextrin (EDA-CD) to form graphene oxide-β-cyclodextrin (GO-CD), then GO-CD was assembled with as-produced AD-DOX via host–guest interaction. In contrast to the conjugation of DOX via covalent linkage, topotecan (TPT) was loaded onto GO through π–π stacking interaction. It was found that TPT/GO-CD/AD-DOX nanoparticles synchronised the delivery of DOX and TPT, and pH value played a critical role in determining the release profiles of dual drugs. Moreover, in vitro cellular investigations proved that TPT/GO-CD/AD-DOX nanoparticles were superior to free drugs and single-drug loaded nanoparticles in inhibiting the growth of HeLa cells. As a kind of injectable biomaterials, this controlled drug delivery device offers a solution to simultaneous delivery of dual chemical drugs in cancer lesion positions. Authors expect that this platform can be exploited for controlled delivery of various drug combinations for combination chemotherapy.
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JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY
·
2013
·Vol. 51
·期 15
·3213-3226
·
IF 3.543
Li Zhang,Yakai Feng,Hong Tian,Miao Zhao,Musammir Khan,Jintang Guo
Well-defined amphiphilic multiblock copolymers PDMAEMA-b-P(IBMD- co -PDO)-b-PEG-b-P(IBMD- co -PDO)-b-PDMAEMA [PDMAEMA-PIBMD-PPDO-PEG], based on poly(2-(dimethylamino)ethyl methacrylate) block (PDMAEMA), poly(3( S )-isobutyl-morpholine-2,5-dione- co-p -dioxanone) block (P(IBMD- co -PDO)), and poly(ethylene glycol) block (PEG) were successfully synthesized by combination of ring-opening polymerization (using 3( S )-isobutyl-morpholine-2,5-dione and p -dioxanone initiated by hydroxyl end of PEG) and atom transfer radical polymerization (ATRP). Furthermore, all these copolymers were characterized by 1 H NMR, 13 C NMR, Fourier transformed-infrared, gel permeation chromatography, differential scanning calorimetry, and thermogravimetric analysis measurements. The degradation experiments showed that the molecular weight of PDMAEMA-PIBMD-PPDO-PEG decreased along with degradation time. In addition, these copolymers could readily self-assemble into nanosized microspheres in phosphate buffered solution. Ibuprofen (IBU) and doxorubicin (DOX) as a kind of combined model drugs were loaded into these microspheres by the combination of ionic interaction and hydrophobic effect. These copolymer microspheres exhibited high loading capacity (LC, up to 26.88%), encapsulation efficiency (EE, up to 61.29%), and sustained release behavior of IBU–DOX in phosphate buffered solution. The results of transmission electron microscopy and dynamic light scattering showed that the microspheres were well-defined uniform spherical particles with average diameter less than 120 nm. Therefore, it can be envisaged that these copolymer systems are promising candidates for controlled release application. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3213–3226
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BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
·
2016
·
IF 3.687
Yinghuan Li,Lei Gao,Xi Tan,Feiyang Li,Ming Zhao,Shiqi Peng
The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts ( B ) into saturable binding ( SB ) and nonsaturable binding ( NSB ) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e. , cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40 mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20 mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.
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