COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2020
·
IF 3.99
Yunran Zhang,Haiping Zhou,Zhe Zhang,Yijun Zhu,Tao Wang,Liguo Yu,Hongrui Song
Betulinic acid (BA) is a new class of anticancer drug , but its relatively short half-life and poor water solubility limit its therapeutic effect and clinical application. Herein, to tackle the dilemma, BA prodrugs were prepared by conjugating BA onto the polyethylene glycol (PEG) polymer via cleavable disulfide bonds. The prodrugs exhibited high water solubility (270-fold of free BA) and a relatively high drug-loading efficiency of 14.2 %. To further endow the BA prodrugs with a photothermal therapeutic effect, the near-infrared (NIR) agent Cypate was grafted on the Pluronic triblock copolymer . The different PEG polymers and different Pluronic polymers were chosen to obtain the optimal drug loading efficiency and the photothermal generation effect. The P-SS-BA/F68-Cy prodrug micelles integrate the redox-responsive BA prodrugs and the NIR-responsive amphiphilic triblock polymer into one single nanocomposite . The release of BA was less than 20 % in pH 7.4 PBS in the absence of glutathione (GSH), whereas the release of BA was obviously accelerated in pH 5.0 PBS with 10 mM GSH. In addition, the release of BA was further accelerated under the NIR irradiation. The P-SS-BA/F68-Cy micelles showed an excellent photothermal heating effect under NIR irradiation. The prepared P-SS-BA/F68-Cy micelles showed the synergistic thermochemotherapeutic effect on tumors both in vitro and in vivo . Therefore, the present study shows the great potential of dual-triggered drug delivery and thermochemotherapy for combination therapy.
研究领域:
药学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
高影响因子
Nanomaterials
·
2019
·Vol. 9
·期 6
·860
·
IF 4.034
Ji Chen,Guotao Li,Qihong Liu,Yan Liang,Miaochang Liu,Huayue Wu,Wenxia Gao
Accelerating degradation of prodrug is an effective strategy for improving the pharmacological action. A photocleavable amphiphilic prodrug of methotrexate-coumarin derivative-PEG conjugates (MTX-AMC-PEG) with photo-triggered breakage to release clinical drug under laser irradiation was fabricated and self-assembled into nanoparticles for chemotherapy. The nanoparticles exhibited good intracellular uptake and excellent photolysis release of MTX, which resulted in efficient anticancer activity in vitro with laser irradiation. This research provides a way to fabricate photocleavable prodrug nanoparticles with stimuli-triggered drug release behavior.Keywords:prodrug;photocleavable;stimuli-responsive release;methotrexate;chemotherapy
研究领域:
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2019
·
IF 2.606
Jiahui He,Wei Wang,Huicong Zhou,Pan She,Pantian Zhang,Yi Cao,Xuefei Zhang
A novel cytocompatible and pH-sensitive amphiphilic polymeric prodrug named as mPEG- b -norbornene functional PLA-graft-Doxorubicin (mPEG- b -PLA- g -DOX) was synthesized by ROP (ring-opening polymerization), then condensation and followed by click reaction. The polymeric carriers were grafted with triazo group. Doxorubicin (DOX) was modified by the cyclooctyne via condensation reaction and conjugated to the polymeric carriers through the SPAAC (Strain-Promoted Alkyne-Azide Cycloaddition) click reaction. There was a Schiff base between the DOX and cyclooctyne which could result in the pH stimuli-responsiveness for controlled release of anti-cancer drug. The resultant mPEG- b -PLA- g -DOX prodrug was characterized by the 1 H NMR, GPC and HPLC. The content of DOX in prodrug reached 17.4% as measured by the UV spectrum. The amphiphilic polymeric prodrug could self-assemble into micelle which was characterized by the dynamic light scattering (DLS) and scanning electron microscope (SEM). The profile of in vitro drug release exhibited enhanced drug release at acidic pH (pH = 5.3) compared with neutral pH (pH = 7.4). The results of MTT assay showed that the amount of DOX required for MCF-7 cells was reduced after DOX molecules were prepared into polymer prodrug, which was conducive to reducing side effects under the premise of ensuring inhibitory effect.
研究领域:
药学
·
肿瘤学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2017
·
IF 3.887
Jilian Wu,Huiyuan Zhang,Xu Hu,Ruiling Liu,Wei Jiang,Zhonghao Li,Yuxia Luan
Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7 nm and a low critical micelle concentration. Reductive-triggered drug release revealed a “smart” characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bosnian Journal of Basic Medical Sciences
·
2022
·
IF 3.759
Zhaopei Guo,Zian Wang,Ruifeng Liang,Huayu Tian,Xuesi Chen,Meiwan Chen
Camptothecin (CPT) has attracted much attention due to its potent antitumor activities. However, the undesirable physicochemical properties, including poor water solubility, unstable lactone ring, and severe adverse effects, limit its further application. In this study, two water-soluble prodrugs, CPT-lysine and CPT-arginine, were designed and synthesized by conjugating lysine or arginine with CPT, improving its solubility, pharmacokinetic properties, and tumor penetration. Importantly, the introduction of arginine into CPTR contributed to the mitochondria-specific delivery, which increased mitochondrial reactive oxygen species generation, induced mitochondria dysfunction, and enhanced cell apoptosis and in vivo anti-cancer effect. This strategy is believed to hold great potential for organelle-specific synergistic anti-tumor therapy.
研究领域:
肿瘤学
·
药物化学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Shasha Qin,Jiamin Li,Zhiling Pan,Can Wang,Bing-Feng Zhang
Prodrug nanoassemblies fabricated by anticancer drug conjugates exhibited more advantages in controlled drug release and bioavailability and favorable antitumor efficacy. In this paper, lactobionic acid (LA) was connected with polyethylene glycol through amido linkages, and paclitaxel was joined with polyethylene glycol by means of ester bonds to form the prodrug copolymer LA-PEG-PTX. Then, LA-PEG-PTX was automatically assembled into LA-PEG-PTX nanoparticles (LPP NPs) by dialysis. The LPP NPs had a relatively uniform size of approximately 200 nm, a negative potential (−13.68 mV), and a spherical shape under TEM. The drug loading of LPP NPs was 3.91%, which was measured by HPLC. The in vitro release profile of LPP NPs exhibited a sustained release feature. The results of the pharmacokinetic test in rats showed that LPP NPs had higher T 1/2 and AUC values than the control group (free PTX) and a prolonged in vivo circulation time, thus increasing the bioavailability of PTX. Remarkably, the LPP NPs were absorbed into HepG2 cells after galactose-directed internalization and enhanced cytotoxicity. Consequently, LPP NPs displayed notable antitumor activity in Kunming mice with H22 hepatocellular carcinoma. Collectively, these findings suggested that paclitaxel prodrug-based self-assembled nanoparticles were a promising alternative for improving the bioavailability and antitumor effect of PTX.
研究领域:
药剂学
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Haibin Lu,Weifang Tong,Meixu Jiang,Huimin Liu,Chen Meng,Kai Wang,Xupeng Mu
How to address the resistance of cisplatin (CDDP) has always been a clinical challenge. The resistance mechanism of platinum-based drugs is very complex, including nuclear DNA damage repair, apoptosis escape, and tumor metabolism reprogramming. Tumor cells can switch between mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis and develop resistance to chemotherapy drugs through metabolic variability. In addition, due to the lack of histone protection and a relatively weak damage repair ability, mitochondrial DNA (mtDNA) is more susceptible to damage, which in turn affects mitochondrial OXPHOS and can become a potential target for platinum-based drugs. Therefore, mitochondria, as targets of anticancer drugs, have become a hot topic in tumor resistance research. This study constructed a self-assembled nanotargeted drug delivery system LND-SS-Pt-TPP/HA-CD. β-Cyclodextrin-grafted hydronic acid (HA-CD)-encapsulated prodrug nanoparticles can target CD44 on the tumor surface and further deliver the prodrug to intracellular mitochondria through a triphenylphosphine group (TPP+). Disulfide bonds can be selectively degraded by glutathione (GSH) in mitochondria, releasing lonidamine (LND) and the cisplatin prodrug (Pt(IV)). Under the action of GSH and ascorbic acid, Pt(IV) is further reduced to cisplatin (Pt(II)). Cisplatin can cause mtDNA damage, induce mitochondrial dysfunction and mitophagy, and then affect mitochondrial OXPHOS. Meanwhile, LND can reduce the hexokinase II (HK II) level, induce destruction of mitochondria, and block energy supply by glycolysis inhibition. Ultimately, this self-assembled nano targeted delivery system can synergistically kill cisplatin-resistant lung cancer cells, which supplies an overcome cisplatin resistance choice via the disrupt mitochondria therapy.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 28
·6139-6147
·
IF 5.344
Fan Wang,Jian Yang,Yongsheng Li,Qixin Zhuang,Jinlou Gu
Enzyme-activated prodrug therapy (EAPT) is an effective cancer treatment strategy able to transport non-toxic prodrugs and subsequently convert them into drugs at specific times and locations. However, due to the limitation of easy biodegradability and the membrane-impermeable characteristic of exogenous enzymes, there is a need to exploit suitable carriers for the effective protection and simultaneous delivery of activating enzymes into cancer cells. Herein, hierarchically porous MOFs were employed for the loading of enzyme and prodrug in a single nanocarrier thanks to their different cavity sizes. The simple loading process allows entrapping of horseradish peroxidase (HRP) and a monocarboxyl-containing indole-3-acetic acid (IAA) prodrug with high loading capacities in different spaces, which keeps the catalytic activity of the enzyme perfectly intact and avoids the premature activation of the prodrug. The encapsulated HRP and IAA exhibit sustained and synchronized release behaviors. Compared to the native HRP enzyme, the current MOF nanocarriers not only facilitate enzyme delivery into cellular lysosomes and subsequent endosomal escape, but also effectively release enzyme and prodrug in the intracellular environment within 48 h. Eventually, HRP and IAA loaded MOF nanocarriers cause significant cell death with a low IC50 of 4.2 mg L−1, while the IAA prodrug alone is non-toxic even at high concentrations. Thus, hierarchically porous MOFs might offer a promising platform for EAPT with a highly consistent spatiotemporal distribution of enzymes and prodrugs in target tissues.
研究领域:
药学
·
纳米技术
·
癌症治疗
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2019
·
IF 7.901
Jean Felix Mukerabigwi,Wei Yin,Zengshi Zha,Wendong Ke,Yuheng Wang,Weijian Chen,Abd Al-Wali Mohammed Mohammed Japir,Yi Wang,Zhishen Ge
Therapeutic nanoreactors are currently emerging as promising nanoplatforms to in situ transform inert prodrugs into active drugs. Nevertheless, it is still challenging to engineer a nanoreactor with balanced key features of tunable selective membrane permeability and structural stability for prodrug delivery and activation in diseased tissues. Herein, we present a facile strategy to engineer a polymersome nanoreactor with tumor-specific tunable membrane permeability to load both hydrophobic phenylboronic ester-caged anticancer prodrugs ( e.g. , camptothecin or paclitaxel prodrug) and hydrophilic glucose oxidase (GOD) in the membranes and cavities, respectively. The nanoreactors maintain inactive during blood circulation and in normal tissues. Upon accumulation in tumors, the mild acidic microenvironment triggers selective membrane permeability to allow small molecules (glucose and O 2 ) to diffuse across the membrane and react under the catalysis of GOD. The massively generated H 2 O 2 triggers in situ transformation of innocuous prodrugs into toxic parental drugs through cleavage of the self-immolative degradable caging groups. The developed system showed significantly enhanced antitumor efficacy by H 2 O 2 production and prodrug activation via combined oxidation-chemotherapy. The well-devised polymersome nanoreactors with tumor-pH-tunable membrane permeability to coload H 2 O 2 -responsive prodrug and GOD represent a novel strategy to realize prodrug delivery and activation for enhanced therapeutic efficacy with low side toxicity.
研究领域:
纳米医学
·
癌症治疗
·
药物递送系统
·
生物化学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2020
·
IF 4.321
Yan Ma,Dong-Yang Zhang,Zhuo Peng,Shixia Guan,Junqiu Zhai
Combinational administration of photothermal therapy (PTT) and chemotherapy (CT) shows great potential in improving the efficiency of tumor treatment. Herein, we designed a novel nanocomposite Pt@Bi2Te3 composed of bismuth telluride (Bi2Te3) nanoparticles and platinum(IV) prodrugs (Pt) for PTT–CT combination therapy. The obtained Bi2Te3 was synthesized by a simple solvothermal method and modified by polyethylene glycol, which exhibited excellent photothermal (PT) efficiency and stability and could also serve as a bimodal bioimaging contrast agent in PT and photoacoustic (PA) imaging. In vitro experiment results showed that the nanocomposite Pt@Bi2Te3 could effectively increase the uptake of platinum in cancer cells, which could kill tumor cells through the combined effect of PTT and CT. Furthermore, combination therapy of cancer in vivo was achieved with obvious tumor-growth inhibition without inducing observed side effects. We revealed the great potential of Bi2Te3 nanocomposites in increasing therapeutic efficiency by PTT–CT therapy and PA–PT imaging.
研究领域:
肿瘤学
·
生物医学工程
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
CARBOHYDRATE RESEARCH
·
2014
·
IF 1.966
Rui-jian Jiang,Yu-lin Zhao,Yun-jian Chen,Dan Xiao,Fen Wang,Bin Han,Jian Yang,Xia-li Liao,Li-Juan Yang,Chuan-zhu Gao,Bo Yang
A novel series of artesunate-β-cyclodextrin (ATS-β-CD) conjugates, in which artesunate (ATS) was coupled covalently to one of the primary hydroxyl groups of β-cyclodextrin (β-CD) through amino bond formation, were synthesized and characterized by 1 H NMR, HRMS, 2D NMR (ROESY), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The results showed that the aqueous solubility of ATS-β-CD conjugates was 26–45 times better than that of free ATS. The cytotoxicity of the ATS-β-CD conjugates was evaluated on human colon cancer cell lines HCT116, LOVO, SW480, and HT-29, and the results indicated that ATS-2NβCD exhibited a very high cytotoxicity against HCT116, LOVO, and HT-29 with IC 50 values of 0.58, 1.62, and 5.18 μmol/L, respectively. In addition, the supposition of better cytotoxicity was further supported by the control experiment of fluorescent cyclodextrin .
研究领域:
药物化学
·
肿瘤学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 2
·407
·
IF 3.267
Jiaguo Li,Dian Xiao,Lianqi Liu,Fei Xie,Wei Li,Wei Sun,Xiaohong Yang,Xinbo Zhou
In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. InBRCA1- andBRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.Keywords:Talazoparib;PARP inhibitor;prodrug;o-nitro-benzyl;photoactivatable protecting groups
研究领域:
药物化学
·
肿瘤学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）