POLYMER INTERNATIONAL
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2018
·Vol. 67
·期 9
·1186-1193
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IF 2.352
Dengcheng Huang,Yu Zhou,Yuan Xiang,Meijie Shu,Hongxiang Chen,Bing Yang,Xinghua Liao
In order to obtain a pH-sensitive delivery carrier for doxorubicin (DOX), DOX-loaded polyurethane (PU·DOX) nanoparticles were readily prepared in water by electrostatic interactions between amphiphilic polyurethane with carboxyl pendent groups (PU-COOH) and doxorubicin hydrochloride (DOX·HCl). The structures of the products obtained were characterized by Fourier transform infrared spectroscopy, 1 H NMR spectroscopy, gel permeation chromatography, UV–visible spectroscopy, dynamic light scattering and transmission electron microscopy. The average hydrodynamic size of the PU·DOX nanoparticles was around 182 nm with negative surface charge (−1.1 mV) and a spherical or rodlike shape. PU·DOX nanoparticles had a higher drug-loading content of 14.1 wt%. The in vitro drug release properties of PU·DOX nanoparticles were investigated at pH 4.0, 5.0 and 7.4, respectively. PU·DOX nanoparticles exhibited a good pH-sensitive drug release property, but there was almost no release of DOX from PU·DOX nanoparticles at pH 7.4. The in vitro cellular uptake assay and the Cell Counting Kit-8 assay demonstrated that PU·DOX nanoparticles had a higher level of cellular internalization and higher inhibitory effects on the proliferation of human breast cancer (MCF-7) cells than pure DOX. The enhancement of the inhibition effects resulted from increasing apoptosis-inducing effects on MCF-7 cells, which was related to the enhancement of Bax expression and the reduction of Bcl-2 expression confirmed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, real-time polymerase chain reaction (PCR) assay and western blot assay. © 2018 Society of Chemical Industry
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Journal of Materials Chemistry B
·
2018
·Vol. 6
·期 14
·2089-2103
·
IF 4.776
Yi Lin,Yidi Yang,Jianqin Yan,Jun Chen,Jun Cao,Yuji Pu,Li Li,Bin He
In this study, redox/ATP switchable theranostic nanoparticles (TNs) with precise specificity and controllable mobility were developed for the real-time monitoring of the release of an anticancer drug. A fluorescent probe (FAM) and a quencher (BHQ-1) were covalently conjugated to one end of an adenosine-5′-triphosphate (ATP) aptamer and its complementary DNA (cDNA), respectively. Then, doxorubicin (DOX) was intercalated within the DNA duplex to form a stable physical conjugate (FBA@DOX). Poly(ethylene glycol)-block-poly (aspartic acid-graft-cystamine) (PAS), a glutathione-sensitive cationic polymer, was synthesized and complexed with the FBA@DOX, endowing it with excellent stability in physiological solutions. Fluorescence recovery/quenching, DNase degradation, in vitro drug release, cellular uptake, and intracellular trafficking results revealed that the TNs remained in the “OFF” state, with a minimal FAM fluorescent signal and negligible DOX premature release, in low-glutathione and/or low-ATP environments. In contrast, the TNs turned “ON” and rapidly released FBA@DOX in glutathione-rich environments after internalization in cancer cells. The intracellular ATP triggered the conformational changes in FBA@DOX, thereby enabling the controlled release of DOX and simultaneous recovery of the fluorescence for monitoring the DOX release. In a cytotoxicity and apoptosis study, the redox/ATP switchable TNs demonstrated strong anticancer effects, attributable to their selective release of the drug. Overall, our findings may offer a promising strategy for developing a new generation of “smart” theranostic platforms.
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Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 10
·2127-2136
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IF 4.726
Wei Zhang,Xiaoyan Zhou,Tao Liu,Dong Ma,Wei Xue
The co-delivery of multiple drugs has become the primary strategy in cancer therapy in recent years, because this technique could promote synergistic actions, reduce side effects and deter the development of drug resistance. To achieve a controlled and sustained release of the loaded drugs, a supramolecular hydrogel based on the host–guest interactions between a hyperbranched polyglycerol derivative and α-cyclodextrin was prepared and used to co-load camptothecin and doxorubicin for sustainedly synergistic tumor therapy. The gelation kinetics, hydrogel strength and supramolecular structure of the obtained hydrogel were studied by dynamic and steady rheometry under various concentrations of α-CD. The sustained dual drug release from the supramolecular hydrogel in vitro, and their synergistic effect in vitro and in vivo were also explored. Moreover, the supramolecular hydrogel showed receivable blood compatibility and non-cytotoxicity by in vitro and in vivo assays. Therefore, this supramolecular hydrogel could potentially be applied in sustainedly synergistic tumor therapy.
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REACTIVE & FUNCTIONAL POLYMERS
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2013
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IF 2.505
Li Zhang,Yakai Feng,Hong Tian,Changcan Shi,Miao Zhao,Jintang Guo
Novel biodegradable amphiphilic ABA triblock copolymers , i.e. poly(3(S)-methyl-morpholine-2,5-dione- co - p -dioxanone)-block-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione- co - p -dioxanone) [P(MMD- co -PDO)- b -PEG- b -P(MMD- co -PDO)], were successfully prepared by ring-opening polymerization of 3(S)-methyl-morpholine-2,5-dione (MMD) and p -dioxanone (PDO) in the presence of poly(ethylene glycol) 6000 as an initiator. These triblock copolymers were characterized by 1 H NMR, 13 C NMR, Fourier transform infrared, gel permeation chromatography and differential scanning calorimetry measurements. P(MMD- co -PDO)- b -PEG- b -P(MMD- co -PDO) could self-assemble into stable nanosized microspheres with critical micellar concentrations of 0.41–0.66 μg/mL. The microspheres showed high hydrolytic degradation. In addition, doxorubicin (DOX) was chosen as a model drug and successfully encapsulated into the microspheres by hydrogen-bond interaction and hydrophobic effect . The transmission electron microscopy and dynamic light scattering measurements revealed that these microspheres were ellipsoidal nanoparticles with diameters ranged from 50 to 100 nm. These copolymer microspheres exhibited high loading capacity (LC), encapsulation efficiency (EE) of DOX and sustained drug release behavior in phosphate buffered solution (PBS). Moreover, the release rate of DOX from those microspheres in pH 4.0 PBS was faster than that in pH 7.4 due to pH sensitivity of the polymer–drug systems and the degradation of the matrix polymers . These amphiphilic depsipeptide multiblock copolymers would be potential promising carriers for anti-tumour drug delivery.
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RSC Advances
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2015
·Vol. 5
·期 128
·105901-105907
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IF 3.84
Guan-Hai Wang,Hui-Kang Yang,Yi Zhao,Da-Wei Zhang,Li-Ming Zhang,Jian-Tao Lin
In this work, novel biodegradable cationic micelles were prepared based on poly-(N-ε-carbobenzyloxy-L-lysine) (PZLL) and chitosan (CS) by click reaction, and applied for co-delivery of doxorubicin (DOX) and p53 plasmid. The structure of the copolymer was characterized by 1H NMR and FTIR. The loading amount of DOX in the micelles was 12.8%. Fluorescence spectra confirmed that DOX interacted via π–π stacking with micelles when DOX was encapsulated into the micelles. In particular, its complexation with plasmid DNA was investigated using agarose gel electrophoresis, flow cytometry, zeta potential, and particle size analyses as well as transmission electron microscopy observations. The results showed that the copolymers have a strong pDNA condensation ability and provide protection of pDNA against deoxyribonuclease I degradation. CS-g-PZLL/DOX/p53 nanoparticles showed good gene transfection efficiency in vitro. Fluorescence images and flow cytometry tests revealed that p53 and DOX could be efficiently transported into Hela tumor cells simultaneously, and the optimum N/P ratio for p53 transfection was 20/1. For co-delivery analysis, the obtained CS-g-PZLL/DOX/p53 complexes showed a better inhibitory effect on Hela tumor cells than DOX or p53 used singly.
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RSC Advances
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2016
·Vol. 6
·期 62
·57552-57562
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IF 3.289
Feng Liu,Yang Zhang,Xiuwei Pan,Lei Xu,Yudong Xue,Weian Zhang
Combination therapy has gained enormous attention due to its high effectiveness in killing cancer cells. Herein, a novel reduction-responsive drug carrier based on amphiphilic dendritic copolymer was constructed for the combination treatment of chemotherapy with photodynamic therapy (PDT). The porphyrin (TPP) disulfide coupled third-generation dendronized poly(ethylene glycol) (PEG-G3-OH) copolymer (TPP-S-S-G3) was synthesized via disulfide linkages between dendritic polyester and porphyrin photosensitizers, which could further self-assemble into spherical micelles in aqueous solution. Compared to the linear TPP-S-S-G0 copolymer, the dendritic TPP-S-S-G3 copolymer could have a higher drug loading content and efficiency. The uptake of doxorubicin (DOX)-loaded TPP-S-S-G3 micelles by MCF-7 cells and intracellular release of porphyrin and DOX was investigated by flow cytometry and CLSM, respectively, and the results exhibited a fast uptake of TPP-S-S-G3 micelles and drug release. Cytotoxicity assay of DOX-loaded TPP-S-S-G3 micelles were evaluated by MTT assay. It indicated that DOX-loaded TPP-S-S-G3 micelles exhibited a higher cellular proliferation inhibition than free DOX, free porphyrin and DOX-loaded linear TPP-S-S-G0 micelles under light irradiation. Thus, the reduction-responsive dendritic copolymer presented the great potential in the combination therapy between chemotherapy and PDT.
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ACS Applied Materials & Interfaces
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2016
·
IF 7.145
Xiaoli Cai,Yanan Luo,Weiying Zhang,Dan Du,Yuehe Lin
In this paper, we reported a ZnO quantum dots-based pH-responsive drug delivery platform for intracellular controlled release of drugs. Acid-decomposable, luminescent aminated ZnO quantum dots (QDs) were synthesized as nanocarriers with ultrasmall size (∼3 nm). The dicarboxyl-terminated poly(ethylene glycol) (PEG) had been introduced to NH2–ZnO QDs, which rendered it stable under physiological fluid. Moreover, a targeting ligand, hyaluronic acid (HA), was conjugated to ZnO QDs for specifically binding to the overexpressed glycoprotein CD44 by cancer cells. Doxorubicin (DOX) molecules were successfully loaded to PEG functionalized ZnO QDs via formation of metal–DOX complex and covalent interactions. The pH-sensitive ZnO QDs dissolved to Zn2+ in acidic endosome/lysosome after uptake by cancer cells, which triggered dissociation of the metal–drug complex and a controlled DOX release. As result, a synergistic therapy was achieved due to incorporation of the antitumor effect of Zn2+ and DOX.
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Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 11
·1557-1564
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IF 4.521
Li Shuai,Tan Longfei,Xu Wenhan,Liu Chong,Wu Qiong,Fu Changhui,Meng Xianwei,Shao Haibo
Local recurrence has become the main problem of tumor thermal ablation for hepatocellular carcinoma (HCC). Nanotechnology could potentially aid in improving the situation. MoS2 nanomaterials, as ideal photothermal therapy (PTT) agents, have gathered great interest due to
their excellent surface plasmon resonance features, high photothermal conversion efficiency, good biocompatibility and low cost. In this work, we synthesized layered MoS2 hollow spheres (LMHSs; diameter ∼300 nm) via the solvent-controlled ultrasonic nebulization method. Compared
to LMHSs previously synthesized by our group (approx. 600 nm), the current ones showed better efficacy, as well as enhanced permeability and retention, due to their ideal size. In addition, the LMHSs are developed with both layered and hollow structures, which are extremely suitable for loading
anticancer agents. In this study, doxorubicin (DOX) was loaded into the nanoparticles (NPs) using the vacuum negative pressure loading method, and the drug loading capacity was as high as 32.5%. Therefore, the efficacy of cancer cell killing by photothermal ablation was markedly enhanced by
DOX released from the LMHSs. As we expected, the as-made DOX@MoS2 NPs exhibited excellent photothermo-chemotherapy effect, both in vitro and in vivo. Tumor cell viability was inhibited up to 73% at the power density of 1.2 W cm–2, and tumors in mice
models achieved complete response, with no recurrence. The PTT with DOX@MoS2 NPs had a much better synergistic therapeutic efficacy than each individual treatment, showing great promise for HCC treatment.
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Theranostics
·
2017
·
IF 8.766
Gan Liu,Hsiang-i Tsai,Xiaowei Zeng,Yixiong Zuo,Wei Tao,Jun Han,Lin Mei
The efficient delivery of anticancer drugs into tumor tissues to improve therapeutic efficacy remains an urgent demand. To satisfy this demand, a drug delivery system based on a stealthy nanocapsule was developed. This nanocapsule was fabricated by encapsulating stealthy cross-linked poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and benzaldehyde groups around the protein bovine serum albumin (BSA) followed by conjugation of doxorubicin (Dox) through a pH-responsive benzoic-imine bond. The in vitro results show that the Dox-conjugated nanocapsule (nBSA-Dox) released the drug under an acidic tumor microenvironment (pH ~6.5) and killed HepG2 human liver cancer cells. The half-life of Dox conjugated to nBSA in mice was significantly prolonged, and the area-under-curve of plasma Dox of the mice treated with nBSA-Dox was as much as 242 fold of free Dox. The in vivo results confirmed that this nanocapsule efficiently accumulated in tumor tissue and significantly suppressed the tumor growth.
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ACS Biomaterials Science & Engineering
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2017
·
IF 3.234
Lu Han,Ya-Nan Hao,Xing Wei,Xu-Wei Chen,Yang Shu,Jian-Hua Wang
A novel core–shell nanostructure, hollow copper sulfide nanosphere–doxorubicin (DOX)/graphene oxide (GO) (CuS–DOX/GO), is constructed for the purpose of controlled drug delivery and improved photothermo-chemotherapeutic effect. The CuS–DOX/GO nanocomposite is configured by employing dual photothermal agents, where the core, hollow CuS nanoparticle, acts as delivery-carrier for doxorubicin, and the shell, PEGylated GO nanosheet, prohibits leakage of the drug. DOX can be efficiently loaded onto the hollow CuS nanoparticles, and its subsequent release from CuS–DOX/GO nanocomposite is triggered in a pH- and near-infrared light-dependent manner. Moreover, integration of the two photothermal agents significantly improves the photothermal performance of this system. Ultimately, the combination of phototherapy and chemotherapy based on this system results in a much higher HeLa cell killing efficacy with respect to that for a single chemotherapy mode, as demonstrated by in vitro cytotoxicity tests.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2016
·
IF 3.994
Yuan Sheng,Yiwen You,Yun Chen
The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance associated with its treatment. In addition to the overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), other mechanisms including apoptosis evasion and tumor cell survival may also be important contributor to drug resistance. Within this context, targeting extracellular signal-regulated kinases (ERK), one of the principle protein molecules in cell apoptosis has emerged as an attractive therapeutic concept. In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer ( i.e ., GGCG) and transferrin receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using 1 H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC 50 (20.8 ± 1.1 μM) and its in vivo extent of inhibition in mice was more evident (72.2 ± 4.6%). Induction of various apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in cancer therapy.
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BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Jun Liu,Xiaoyu Hu,Guanghao Yu,Qingrong Wang,Liwei Gu,Jianying Shen,Qinghe Zhao,Hao Sun,Shi Wang,Zhongyuan Guo,Yu Zhao,Hai Ma
Alpha-enolase (ENO1), a multifunctional protein with carcinogenic properties, has emerged as a promising cancer biomarker because of its differential expression in cancer and normal cells. On the basis of this characteristic, we designed a cell-targeting peptide that specifically targets ENO1 and connected it with the drug doxorubicin (DOX) by aldehyde–amine condensation. A surface plasmon resonance (SPR) assay showed that the affinity for ENO1 was stronger (KD = 2.5 µM) for the resulting cell-targeting drug, DOX-P, than for DOX. Moreover, DOX-P exhibited acid-responsive capabilities, enabling precise release at the tumor site under the guidance of the homing peptide and alleviating DOX-induced cardiotoxicity. An efficacy experiment confirmed that, the targeting ability of DOX-P toward ENO1 demonstrated superior antitumor activity against colorectal cancer than that of DOX, while reducing its toxicity to cardiomyocytes. Furthermore, in vivo metabolic distribution results indicated low accumulation of DOX-P in nontumor sites, further validating its targeting ability. These results showed that the ENO1-targeted DOX-P peptide has great potential for application in targeted drug-delivery systems for colorectal cancer therapy.
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