Journal of Materials Chemistry B
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2015
·Vol. 3
·期 30
·6185-6193
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IF 4.726
Xubo Zhao,Peng Liu,Qilei Song,Nan Gong,Liangwei Yang,Winston Duo Wu
Polymeric nanoparticles are greatly advancing the field of nanomedicine due to their ability for targeted and controlled drug release. Here, monodisperse pH-responsive surface charge-reversible and hepatoma-targeting polyelectrolyte complex nanoparticles (GC/HA NPs) near 80 nm were prepared via the ionotropic gelification by simple and mild co-precipitation of galactosylated chitosan (GC) and hyaluronate (HA). Their surface charges could transfer from negative in neutral or basic media to positive in acidic media, indicating their potential application for delivering anti-tumor drugs in response to the extracellular pH of the tumor environment. The unique “electrostatic sponge” structure enhanced their drug-loading capacity and encapsulation efficiency towards the anti-cancer agent doxorubicin (DOX), as well as the pH-triggered controlled release. MTT assays and fluorescence microscopy analysis revealed that the DOX-loaded GC/HA NPs possessed the hepatoma-targeting capacity with favorable biocompatibility. These features make them advanced anti-cancer drug nanocarriers for intelligent drug delivery systems.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2015
·
IF 3.65
Yu. Lili,Mu. Ruihua,Li. Li,Liang. Fei,Yao. Lin,Su. Li
Redox-responsive micelles based on amphiphilic polyethylene glycol-polymethyl methacrylate with the introduction of disulfide containing cross-linked agent (mPEG-PMMA-SS) were developed for intracellular drug release. Benefiting from the amphiphilicity, mPEG-PMMA-SS could self-assembled into core cross-linked micelles in aqueous medium with tunable sizes (85–151 nm), appropriate zeta potential (−24.8 mV), and desirable critical micelle concentration (CMC) (0.18 mg/mL). Doxorubicin (DOX) could efficiently load into the micelles with satisfactory entrapment efficiency. As expected, the in vitro release studies displayed that DOX release from mPEG-PMMA-SS micelles was about 75% within 10 h under tumor-relevant reductive condition, whereas only about 25% DOX was released in non-reductive medium. SRB assays indicated that these mPEG-PMMA-SS micelles were biocompatible and nontoxic up to a concentration of 50 μg/mL. The cytotoxicity studies and the intracellular drug delivery demonstrated that the drug release behavior in cells was related to the concentration of GSH in cytoplasm. Furthermore, the cell experiments using fluorescence microscopy showed clearly that DOX was delivered by micelles to the cytoplasm, released in cytoplasm under reductive environment, and then accumulated in cell nucleus. These results suggest that such redox-responsive micelles may develop into an efficient cytoplasmic delivery for hydrophobic anticancer drugs .
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ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Chan Yu,Qing Zhou,Fan Xiao,Yihui Li,Hang Hu,Ying Wan,Zifu Li,Xiangliang Yang
Doxorubicin (DOX), a kind of wide-spectrum chemotherapeutic drug, can cause severe side effects in clinical use. To enhance its antitumor efficacy while reducing the side effects, two kinds of nanoparticles with desirable compositions and properties were assembled using optimally synthesized hydroxyethyl starch-grafted-polylactide (HES-g-PLA) copolymers and utilized as partner nanocarriers. The large empty HES-g-PLA nanoparticles (mean size, ca. 700 nm), at an optimized dose of 400 mg/kg, were used to block up the reticuloendothelial system in tumor-bearing mice 1.5 h in advance, and the small DOX-loaded HES-g-PLA nanoparticles (mean size, ca. 130 nm) were subsequently applied to the mice. When these partner nanocarriers were administered in this sequential mode, the released DOX had a significantly prolonged plasma half-life time and much slower clearance rate as well as a largely enhanced intratumoral accumulation as compared to free DOX. In vivo antitumor studies demonstrated that the DOX-loaded HES-g-PLA nanoparticles working together with their partner exhibited remarkably enhanced antitumor efficacy in comparison to free DOX. In addition, these HES-g-PLA partner nanocarriers showed negligible damage to the normal organs of the treated mice. Considering safe and efficient antitumor performance of DOX-loaded HES-g-PLA nanoparticles, the newly developed partner nanocarriers in combination with their administration mode have promising potential in clinical cancer chemotherapy.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2017
·
IF 3.887
You-Mei Li,Xiu-Peng Chang,Yin-Jia Cheng,Shu Chen,Feng He,Ren-Xi Zhuo
In this paper, four different kinds of mercaptan acids modified amphiphilic copolymers mPEG- b -PATMC- g -SRCOOH (R = CH 2 , CH 2 CH 2 , (CH 2 ) 10 and CH(COOH)CH 2 ) were successfully synthesized by thiol-ene “click” reaction between pendent carbon-carbon double bonds of PEG- b -PATMC and thiol groups of thioglycolic acid, 3-mercaptopropionic acid, 11-mercaptoundecanoic acid or 2-mercaptosuccinic acid. DLS and TEM measurements showed that all the mPEG- b -PATMC- g -SRCOOH copolymers could self-assemble to form micelles which dispersed in spherical shape with nano-size before and after DOX loading. The positively-charged DOX could effectively load into copolymer micelles via synergistic hydrophobic and electrostatic interactions. All DOX-loaded mPEG- b -PATMC- g -SRCOOH micelles displayed sustained drug release behavior without an initial burst which could be further adjusted by the conditions of ionic strength and pH. Especially in the case of mPEG- b -PATMC- g -S(CH 2 ) 10 COOH (P3) micelles, the suitable hydrophobility and charge density were not only beneficial to improve the DOX-loading efficiency, they were also good for obtaining smaller particle size, higher micelle stability and more timely drug delivery. Confocal laser scanning microscopy (CLSM) and MTT assays further demonstrated efficient cellular uptake of DOX delivered by mPEG- b -PATMC- g -SRCOOH micelles and potent cytotoxic activity against cancer cells.
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Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Baomei Zhang,Xiaoye Yang,Yang Wang,Guangxi Zhai
A novel nanocarrier of heparin (Hep) modified graphene oxide (GO) was fabricated via a linker (adipic dihydrazide) and used as a pH-sensitive drug delivery system for controlling the release of anticancer drug doxorubicin (DOX) for anti-tumor therapy. The finally obtained nanocarrier was GO-ADH-Hep with better stability, blood compatibility and biocompatibility confirmed by the hemolytic test and in vitro cytotoxicity study. Its safety issue was greatly improved via Hep modification. The amount of DOX loaded onto GO-ADH-Hep was significantly high and dependent on pH value. The release rate of DOX from GO- ADH-Hep/DOX was pH-sensitive and much-slower than that of free DOX solution suggesting the sustained drug-release capacity of this prepared nanocomplexes. In addition, the results of cytotoxicity study illustrated that this fabricated nanocomplexes displayed effective cytotoxicity to MCF-7 and HepG2 cells. What's more, the results of the in vivo pharmacokinetic study was also indicated that the GO-ADH-Hep/DOX nanocomplexes could significantly prolong the retention time of DOX in vivo and this was consistent with the in vitro drug release performance. And finally, according to the biodistribution study, DOX delivered by GO-ADH-Hep could reduce cardiotoxicity deriving from DOX solution and also decrease the pulmonary toxicity deriving from unmodified GO. Based on the in vitro and in vivo investigations, the fabricated GO-ADH-Hep could be a promising candidate as an ideal nano-carrier for drug delivery and anti-cancer therapy.
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Nanoscale
·
2017
·Vol. 9
·期 17
·5624-5640
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IF 7.367
Yu Gao,Xiaodong Xie,Fengqiao Li,Yusheng Lu,Tao Li,Shu Lian,Yingying Zhang,Huijuan Zhang,Hao Mei,Lee Jia
Rare circulating tumor cells (CTCs) cause >50% of primary colorectal cancer survivors to develop deadly metastasis at 3–5 years after surgery; the current chemotherapies can do nothing about these cells. Herein, we synthesized a novel doxorubicin (DOX)-entrapped mesoporous silica nanoparticle (MSN), covalently-conjugated with two aptamers, for simultaneously targeting EpCAM and CD44, the typical surface biomarkers of colorectal CTCs. The nanomissile can specifically capture the metastasis-prone CTCs spiked in healthy human blood in a competitive-binding manner. The binding not only accurately delivers DOX into the cancer cells via the biomarker-mediated endocytosis to inhibit CTC viability through the DOX-dependent mechanism, but also inhibits the adhesion of cancer cells to the endothelium and the consequent transmembrane migration through the DOX-independent mechanism. The molecular entity of the conjugate and its pharmaceutical DOX encapsulation-releasing capacity are well-demonstrated via various physiochemical characterizations including gel electrophoresis, which proves the >8-hour biostability of the nanomissile in blood, long enough for it to chase CTCs in mice and synergistically inhibit the CTC-induced lung metastasis more potently than its single aptamer-conjugated counterparts and DOX itself. The present strategy may pave a new avenue for safe and effective cancer metastasis chemoprevention.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yizhi Wang,Jiawen Han,Shifang Zhan,Chenyu Guo,Shuangneng Yin,Lin Zhan,Qianyi Zhou,Ruiying Liu,Hua Yan,Xiaoyan Wang,Dan Yan
Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.
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BIOMACROMOLECULES
·
2025
·
IF 5.4
Hua Guo,Huimin Wang,Yiyi Zhang,Hong Deng,Ching-Hsuan Tung,Weiqi Zhang
The complex of doxorubicin (Dox) and intracellular iron in cardiomyocytes generates reactive oxygen species (ROS), contributing to commonly observed cardiotoxicity. To enhance the anticancer potency and minimize the cardiotoxicity, here Dox was formulated into a hyaluronan (HA) nanogel using ferric ion (Fe3+) coordination to control the intracellular distribution and release of Dox. Taking advantage of the paramagnetic properties of iron and the fluorescence of Dox, we conveniently monitored the targeted delivery of the HA@Dox nanogel in murine breast tumors through both T1-weighted magnetic resonance imaging and fluorescence imaging. Compared with free Dox, HA@Dox nanogel affords a CD44-targeted delivery, lysosomal distribution, pH-responsive release, and significant tumor inhibition. Mechanistically, the lysosome-enriched HA@Dox produces ROS, causing lysosomal membrane permeabilization, which further promotes the intracellular Dox distribution. This HA@Dox nanogel not only provides a facile cancer-targeted delivery but also successfully relieves Dox toxicity, representing a potent delivery system for Dox.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2024
·
IF 4.5
Xiaopeng Yang,Le Chang,Qian Lin,Jianing Wang,Peiqi Su,Xin Chen,Zijuan Yi,Yanming Dong,Jingwen Luo
Transdermal drug delivery against skin cancer may be more effective than oral or injection delivery because patients may be more likely to complete the treatment and it may be less likely to trigger gastrointestinal side effects. Here we developed doxorubicin-loaded nanoparticles based on cationic polyethyleneimine-oleic acid for transdermal delivery , and we applied the nanoparticles to skin pre-treated with metal microneedles to facilitate their passage through the tough epithelial barrier. The cationic nanoparticles were extremely small, which probably also facilitated their transdermal passage. They accumulated in subcutaneous melanoma tumors in mice, slowing tumor growth and inducing apoptosis. These therapeutic effects were weaker but still significant when skin was not pretreated with microneedles. Our results suggest a promising new platform for transdermal treatment of skin cancer and potentially other skin diseases.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Hongying Xiao,Jinrui Liu,Minglong Huang,Wenfeng Zang,Bowen Zhang,Shufang Zheng,Xin Li,Zhonggui He,Xin Wang,Huaiwei Ding,Lingxiao Li,Bingjun Sun
The rational design of doxorubicin (DOX)-based delivery platforms with efficient and selective features remains a major challenge. The launch of Amphotec®, formed by assembling the positive electrical amphotericin B with negatively electrical sodium cholesterol sulfate (SCS), provides effective reference. Herein, we prepared an acid-sensitive prodrug (DOX-C14) by linking DOX with myristic acid (C14) via the acylhydrazone bond. Then, the positively electrical DOX-C14 was assembled with various negatively electrical cholesterol analogs in different molar ratios to optimize the stable DOX-C14 nanocomplex. Under the combined action of electrostatic and hydrophobic forces, nanocomplexes formed by DOX-C14 with SCS at ratios of 1:2 (DOX-C14-SCS (1:2)) and 1:3 (DOX-C14-SCS (1:3)) exhibited excellent performance. Subsequently, DOX-C14-SCS (1:2) and DOX-C14-SCS (1:3) were modified with DSPE-PEG 2k or CHOL-PEG 2k to further improve their stability and pharmacokinetic behavior. As a result, the obtained PEGylated nanocomplexes could efficiently accumulate in the tumor and then released DOX to exert antitumor effects under the stimulation of acidic environment. Meanwhile, there is no significant toxicity to normal tissues even at very high doses (10 mg/kg equivalent to DOX), demonstrating superior tumor selectivity. Our findings provide novel insights into the rational design of positive electrical drug for efficient and selective cancer therapy.
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MOLECULAR BIOLOGY REPORTS
·
2026
·Vol. 53
·期 1
·1836
·
IF 3.2
Zhang Hong-dou,Wang Yun-ting,Yang Ze-yu,Wang Hui-dan,Li Xi-yue,Zhang Chun-rui,Li Cheng-zhi,Li Peng
Introduction Floralozone(FL) is a medicinal compound with potential cardiovascular protective effects. Vascular endothelial growth factor receptor 1 (VEGFR1) signaling has been implicated in cardiovascular dysfunction. This study investigated whether floralozone ameliorates heart failure (HF) through regulation of VEGFR1. Methods HF was induced in rats by intraperitoneal injection of doxorubicin (DOX) for six weeks. VEGFR1 expression was analyzed by immunofluorescence and Western blotting. Oxidative stress was determined by DHE staining of myocardial ROS and serum MDA and SOD assays. Senescence associated β-galactosidase (SA-β-gal) staining was performed to evaluate the degree of myocardial aging. HE staining was used to observe cardiac morphology. Masson, argyrophilic and orcein staining were applied to detect the degree of myocardial fibrosis, and echocardiography was conducted to assess cardiac function in each group. Results Floralozone (FL) modulated VEGFR1 expression and alleviated DOX-induced oxidative stress, cardiac aging, myocardial fibrosis, and cardiac dysfunction in HF rats. The protective effects of FL on oxidative stress, cardiac aging, myocardial fibrosis, cardiac function, and VEGFR1 expression were attenuated by pharmacological activation of VEGFR1 with placental growth factor (PLGF), supporting the involvement of VEGFR1 signaling in the cardioprotective effects of FL. Discussion These findings suggest that floralozone exerts cardioprotective effects against DOX induced heart failure, at least in part, through modulation of VEGFR1 associated signaling and oxidative stress. Floralozone modulated VEGFR1 expression and was associated with reduced oxidative stress, cardiac aging, and myocardial fibrosis, ultimately improving cardiac dysfunction. However, the precise causal relationship between VEGFR1 signaling and oxidative stress remains to be determined. These findings suggest that floralozone may have therapeutic potential for DOX induced cardiac injury through modulation of VEGFR1 associated pathological processes.
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ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Tianhui Liu,Qingshuang Wang,Wenxin Geng,Xue Jiang,Changshun Lu,Zhe Zhang,Xiangru Feng
The cancer-associated fibroblasts (CAFs) in tumor stroma present substantial barriers to drug penetration, resulting in tumor resistance and progression. One promising strategy is to reprogram CAFs into a quiescent state, which necessitates novel approaches. Our study introduces a sequential treatment strategy using chitosan thermosensitive hydrogels loaded with α-Mangostin (α-M), a small molecule drug with antifibrotic properties, aimed at reprogramming CAFs within the breast cancer tumor microenvironment (TME). We developed glutathione (GSH)-responsive nanoparticles (NPc) that carry the chemotherapeutic drug doxorubicin (DOX). Treatment with α-M results in the downregulation of CAF-specific biomarkers and a remodeled TME, which improves the penetration of NPc/DOX deep into the tumor tissue. This strategy holds great promise in enhancing cancer therapeutic outcomes in tumors rich in CAFs, particularly in the case of breast cancer.
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