Advanced Healthcare Materials
·
2013
·Vol. 3
·期 2
·261-272
·
IF 0
Chun-Yang Sun,Shuang Dou,Jin-Zhi Du,Xian-Zhu Yang,Ya-Ping Li,Jun Wang
Polyphosphoesters with repeating phosphoester linkages in the backbone can be easily functionalized, are biodegradable and potentially biocompatible, and may be potential candidates as polymer carriers of drug conjugates. Here, the efficacy of a polyphosphoester drug conjugate as an anticancer agent in vivo is assessed for the first time. With controlled synthesis, doxorubicin conjugated to poly(ethylene glycol)- block -polyphosphoester (PPEH–DOX) via labile hydrazone bonds form spherical nanoparticles in aqueous solution with an average diameter of ≈60 nm. These nanoparticles are effectively internalized by MDA-MB-231 breast cancer cells and release the conjugated doxorubicin in response to the intracellular pH of endosomes and lysosomes, resulting in significant antiproliferative activity in cancer cells. Compared with free doxorubicin injection, PPEH–DOX injection exhibits much longer circulation behavior in the plasma of mice and leads to enhanced drug accumulation in tumor cells. In an MDA-MB-231 xenograft murine model, inhibition of tumor growth with systemic delivery of PPEH–DOX nanoparticles is more pronounced compared with free doxorubicin injection, suggesting the potential of polyphosphoesters as carriers of drug conjugates in cancer therapy.
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Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 16
·3297-3305
·
IF 4.726
Haibo Wang,Xiangsheng Liu,Yin Wang,Yangjun Chen,Qiao Jin,Jian Ji
Ideal drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells. Herein, a pH-sensitive small-molecule phospholipid prodrug based on phosphorylcholine (PC) was designed to overcome these challenges. The prodrug was synthesized by conjugating doxorubicin (DOX) to 11-mercaptoundecyl phosphorylcholine via an acid-labile hydrazone linker (UnPC-hyd-DOX). This phospholipid prodrug can self-assemble into core–shell micelles with exact and very high drug loading content (56.2%). Interestingly, the PC prodrug micelles can strongly minimize nonspecific phagocytosis by macrophages. They exhibited better ability to be internalized by cancer cells than that of the PEG prodrug micelles, which indicated that the PC shell facilitated cancer cell internalization. Moreover, in vitro results further demonstrated that DOX of phospholipid prodrug micelles can effectively escape from endo/lysosomes to the cytosol and enter the nucleus. An in vivo study demonstrated that these PC prodrug micelles exhibited much lower cardiotoxicity than free DOX. Importantly, PC prodrug micelles showed significantly slower blood clearance than PEG prodrug micelles and free DOX.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Yue Yang,Xiaoyu Lu,Qi Liu,Yu Dai,Xiaojie Zhu,Yanli Wen,Jiaqiu Xu,Yang Lu,Di Zhao,Xijing Chen,Ning Li
Combination therapy with two drugs and nanoparticle-based drug delivery systems are widely applied to reduce the adverse effects of traditional treatment by chemotherapeutic drugs. Palmitoyl ascorbate (PA) as a lipophilic derivative of ascorbic acid shows the advantages in cancer treatment. The aim of the study was to prepare a doxorubicin (DOX) and PA co-loaded liposome to synergistically treat tumor and effectively alleviate the toxicity caused by DOX. The effects were evaluated by in vitro and in vivo studies. The liposomes (weight ratio of DOX to PA = 1:20, DOX 1 /PA 20 -LPs) exhibited the strongest synergistic effects, combination index was 0.38, 0.56, and 0.05 in MCF-7, HepG2, and A549 cells, respectively. In vitro cellular uptake study, the intercellular concentration of DOX in DOX 1 /PA 20 -LPs was 2.5-fold greater than DOX loaded liposome, and DOX 1 /PA 20 -LPs was taken in not only by macropinocytosis, but also by clathrin-mediated endocytosis. Intracellular distribution experiment showed that DOX 1 /PA 20 -LPs efficiently concentrated in the nucleus. In vivo studies indicated that co-encapsulated liposome not only showed the strongest antitumor ability by tumor growth suppression, but also significantly enhanced the safety by the change of body weight and reduced damages to other tissues (evidenced by histopathology study). These results indicated that DOX and PA co-delivery liposome successfully enhanced the anticancer efficacy and mitigated the toxicities of DOX, which displayed potential for clinical application with enhanced safety and efficacy.
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Biomaterials Science
·
2015
·Vol. 4
·期 3
·412-417
·
IF 3.831
Chao Chen,Pan Zheng,Ziyang Cao,Yinchu Ma,Jie Li,Haisheng Qian,Wei Tao,Xianzhu Yang
Redox-responsive polymers exhibit great potential as drug delivery systems. Herein, a redox-responsive PEGylated hyperbranched polyphosphoester (PPE) was synthesized through (A2 + B3) type polycondensation. The obtained hyperbranched PPE can self-assemble into nanoparticles in water. The biocompatibility of the nanoparticles was evaluated. The hydrophobic chemotherapy drug doxorubicin (DOX) can be efficiently encapsulated into the obtained nanoparticles. Such DOX-loaded nanoparticles exhibited excellent stability due to the PEGylation, and showed redox-responsive drug release behavior. In addition, flow cytometric analyses demonstrated that the redox-responsive nanoparticles could be efficiently internalized into the human breast cancer cell line MDA-MB-231, and intracellular glutathione enhanced the intracellular drug release from the redox-responsive hyperbranched PPE based nanoparticles. Therefore, such nanoparticles resulted in the enhanced inhibition of tumor cell growth, suggesting the potential of redox-responsive PEGylated hyperbranched PPE in anticancer drug delivery.
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ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Ye Zhang,Congjun Zhang,Jing Chen,Li Liu,Mengyue Hu,Jun Li,Hong Bi
Multidrug resistance (MDR) has been recognized as a major obstacle to successful chemotherapy for cancer in the clinic. In recent years, more and more nanoscaled drug delivery systems (DDS) are constructed to modulate drug efflux protein (P-gp) and deliver chemotherapeutic drugs for overcoming MDR. Among them, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely used as a drug carrier due to its capability of inhibiting overexpression of P-gp and good amphiphilicity favorable for improving permeation and long-circulation property of DDS. In the present work, a novel kind of mitochondria-targeting nanomicelles-based DDS is developed to integrate chemotherapeutics delivery with fluorescence imaging functionalities on a comprehensive nanoplatform. The mitochondria-targeting nanomicelles are prepared by self-assembly of triphenylphosphine (TPP)-modified TPGS and fluorescent carbon quantum dots (CQDs) in an n-hexane/H2O mixed solution, named CQDs-TPGS-TPP. Notably, although the drug loading content of doxorubicin (DOX) in the as-prepared nanomicelles is as low as 3.4%, the calculated resistant index (RI) is greatly decreased from 66.23 of free DOX to 7.16 of DOX-loaded nanomicelles while treating both parental MCF-7 cells and drug-resistant MCF-7/ADR cells. Compared with free DOX, the penetration efficiency of DOX-loaded nanomicelles in three-dimensional multicellular spheroids (MCs) of MCF-7/ADR is obviously increased. Moreover, the released DOX from the nanomicelles can cause much more damage to cells of drug-resistant MCs. These results demonstrate that our constructed mitochondria-targeting nanomicelles-based DDS have potential application in overcoming MDR of cancer cells as well as their MCs that mimic in vivo tumor tissues. The MDR-reversal mechanism of the DOX-loaded CQDs-TPGS-TPP nanomicelles is also discussed.
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MOLECULES
·
2024
·Vol. 29
·期 8
·1709
·
IF 4.2
Yanru Hu,Peng Liu
The diselenide bond has attracted intense interest in redox-responsive drug delivery systems (DDSs) in tumor chemotherapy, due to its higher sensitivity than the most investigated bond, namely the disulfide bond. Here, a diselenide-bridged doxorubicin dimeric prodrug (D-DOXSeSe) was designed by coupling two doxorubicin molecules with a diselenodiacetic acid (DSeDAA) molecule via α-amidation, as a redox-triggered drug self-delivery system (DSDS) for tumor-specific chemotherapy. The drug release profiles indicated that the D-DOXSeSecould be cleaved to release the derivatives selenol (DOX-SeH) and seleninic acid (DOX-SeOOH) with the triggering of high GSH and H2O2, respectively, indicating the double-edged sword effect of the lower electronegativity of the selenide atom. The resultant solubility-controlled slow drug release performance makes it a promising candidate as a long-acting DSDS in future tumor chemotherapy. Moreover, the interaction between the conjugations in the design of self-immolation traceless linkers was also proposed for the first time as another key factor for a desired precise tumor-specific chemotherapy, besides the conjugations themselves.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
·
IF 3.973
Qin-Qin Gao,Chuan-Min Zhang,En-Xia Zhang,Hui-Ying Chen,Yu-Hong Zhen,Shu-Biao Zhang,Shu-Fen Zhang
As zwitterionic polymers show great promise in drug delivery, hyaluronic acid (HA) was deacetylated and grafted with dodecylamine to prepare a pH-sensitive zwitterionic polymer dHAD used as a carrier for antitumor drugs. The polymer was negatively charged at pH 7.4 and became positive at pH 6.2. In vitro delivery of DOX against MCF-7 cells showed that the blank micelle dHAD had low cytotoxicity and the dHAD-DOX micelles could greatly prohibit the growth of the MCF-7 cells. In addition, the dHAD-DOX micelles had higher cellular uptake, indicating that the micelles were rapidly internalized into the cells via CD44 receptor-mediated endocytosis. The in vivo delivery of DOX to tumor-bearing mice confirmed that the dHAD-DOX micelles greatly inhibited the tumor growth and significantly reduced systemic toxicity of DOX. These results demonstrated that biocompatible pH-responsive zwitterionic dHAD micelles are promising carriers for the delivery of DOX.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Sijia Tian,Haoying Li,Yanxin Niu,Xueyan Hu,Yongxue Guo
Transcatheter arterial chemoembolization (TACE) is an important method in the treatment of liver cancer and identification of an ideal microsphere for embolization is a key step in its development. Here, we used a microfluidic device to prepare uniformly sized Photopolymerized pH-Responsive GelMA Microspheres with Doxorubicin Modification (DOX-GelMA) that integrated embolization and drug delivery properties. The acid-sensitive doxorubicin (DOX) prodrug was synthesized through a three-step reaction and coupled during curing of the microspheres under UV irradiation. The microspheres exhibited significant pH-responsive drug release in the tumor microenvironment and had a good degradation performance over 18 days. Microscopic images and scanning electron microscopy results showed that the microspheres had good sphericity and uniform particle size (96.61 ± 0.046 μm), and that the particle size and their degree of swelling were suitable for embolization therapy. In vitro cytotoxicity and blood compatibility experiments showed that the microspheres were good biocompatible. The drug-loaded microspheres had obvious inhibitory effect on HepG2. A rabbit ear embolization study demonstrated that the microspheres could effectively block arterial blood flow. The DOX-GelMA microspheres simultaneously achieved physical targeted therapy and chemotherapy, and had great prospects in TACE therapy.
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FOOD AND CHEMICAL TOXICOLOGY
·
2025
·
IF 3.5
Nan Wang,Zhengshan Gao,Honghong Zhan,Lin Jing,Fancheng Meng,Min Chen
Doxorubicin (DOX) is a potent anticancer drug, while its toxic side effects involve multi-organ toxicity, including hepatotoxicity. This study aims to investigate the therapeutic potential of salidroside against DOX-induced hepatotoxicity and elucidate its underlying mechanisms. Result showed that salidroside exhibited a liver protective effect in DOX-induced hepatotoxicity in mice, represented by the decreased serum ALT, AST and LDH levels, as well as the rescue of pathological changes in mice livers. Further study showed salidroside reduced the expression level of pyroptosis-associated proteins, including NLRP3, cleaved- caspase 1, gasdermin D (GSDMD-N) and mature IL-1β in mice liver tissues. In vitro study confirmed salidroside exerted a similar effect in AML12 cells. Mechanistically, salidroside alleviated mitochondrial dysfunction by activating the PGC-1α /Mfn2 signaling pathway, and restrained the endoplasmic reticulum (ER) stress, represented by the downregulation of GRP78 and p-PERK/PERK level. Subsequent investigations revealed that salidroside activated the Sestrin2/AMPK pathway, while the application of AMPK inhibitors, PGC-1α siRNA or Sestrain2 siRNA reversed the effects of salidroside on ameliorating mitochondrial dysfunction and ER stress, suggesting salidroside could be a promising therapeutic strategy for alleviating DOX-induced hepatotoxicity.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2020
·
IF 4.389
Zhoujiang Chen,Guanghui Hong,Zhiyan Liu,Dayun Yang,Ranjith Kumar Kankala,Wenguo Wu
Despite the success, the applicability of traditional chemotherapy still faces several challenges in treating cancer-related ailments, such as enormous toxicity and adverse effects. Combinatorial chemotherapy at reduced doses can offer augmented therapeutic efficiency through multiple mechanisms and even substantially circumvents the issues of toxicity and adverse effects. To demonstrate these facts, herein, two kinds of antitumor drugs, doxorubicin (DOX) and gambogic acid (GA), are encapsulated in bovine serum albumin (BSA) nanoparticles distinctly, resulting in DNP and GNP, respectively. These drug-loaded albumin nanocomposites, DNPs, and GNPs, showed a synergistic effect in ablating HepG2 tumor cells at a combination index (CI) of 0.38. Further, the ex vivo fluorescence imaging investigation confirmed the enriched drug internalization in the tumor precisely, which could be due to the enhanced permeation and retention (EPR) effect, resulting in the augmented therapeutic efficiency of designed nanoformulation. Notably, the synergistic tumor inhibition efficacy is more significantly attained at a 3-fold lesser dose of combined treatment than that of single full dose treatment in vivo . As anticipated, these conditions resulted in reduced organ toxicity. Together, this combinatorial strategy using BSA-based composites is an appropriate approach for application in medicine.
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Science of Advanced Materials
·
2015
·Vol. 7
·期 5
·855-860
·
IF 2.598
Yu Huijuan,Xi Chenbin,Hu Jianhua,Du Ming,Yang Dong
An amphiphilic copolymer, PEG-b-PLA-b-(PAA-co-PNIPAM), was synthesized via atom transfer radical polymerization of tert-butyl acrylate and N-isopropyl acryamide using PEG-b-PLA-Br as a macroinitiator and CuBr/Me6 TREN as a catalytic
system, followed by selectively hydrolyzing tert-butyl groups to carboxyl groups. Then, doxorubicin (DOX) was loaded to the hydrophobic core, and the PAA segments were cross-linked by cystamine to get disulfide cross-linked and DOX loaded micelles. The transmission electron microscopy
images showed that the cross-linked DOX loaded micelles were spherical nanoparticles, with a mean diameter of 100 nm. The drug release behavior of the cross-linked DOX loaded micelles was redox responsive. The cumulative release amount of DOX was 33.1% with the presence of 10 mM of glutathione
(GSH) at 37 °C, much higher than that without the presence of GSH, which was only 4.3%. Furthermore, the cumulative release amount of DOX was 50.9% at 25 °C, higher than that at 37 °C, indicating that the cross-linked DOX loaded micelles were also thermo-sensitive.
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Materials Science & Engineering C-Materials for Biological Applications
·
2016
·
IF 3.42
Ying Zhang,Xiang Wang,Yanli Su,Dongya Chen,Wenxing Zhong
Samarium (Sm) incorporated mesoporous bioactive glasses (MBG) microspheres have been prepared using the method of alginate cross-linking with Ca 2 + ions. The in vitro bioactivities of Sm/MBG/alginate microspheres were studied by immersing in simulated body fluid (SBF) for various periods. The results indicated that the Sm/MBG/alginate microspheres have a faster apatite formation rate on the surface. To investigate their delivery properties further, doxorubicin (DOX) was selected as a model drug. The results showed that the Sm/MBG/alginate microspheres exhibit sustained DOX delivery, and their release mechanism is controlled by Fickian diffusion according the Higuchi model. In addition, the delivery of DOX from Sm/MBG/alginate microspheres can be dominated by changing the doping concentration of Sm and the values of pH microenvironment. These all revealed that this material is a promising candidate for the therapy of bone cancer.
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