Journal of Materials Chemistry B
·
2014
·Vol. 2
·期 35
·5910-5924
·
IF 0
Hongmei Liu,Chenmeng Qiao,Jun Yang,Jie Weng,Xin Zhang
Co-delivery of siRNAs and chemotherapeutic drugs to kill tumors have achieved superior tumor growth inhibition. However, due to siRNAs and chemotherapeutic drugs with different molecular properties, co-delivery carriers use more cationic materials to bind siRNAs and excessive inert materials to embed drugs, causing low drug-loading contents and systemic toxicity. To achieve this goal, doxorubicin (DOX) is chemically conjugated to stearoyl chloride (C18) through N-methyldiethanol amine (N) as cross-linker to form amphiphilic C18–N–DOX. C18–N–DOX contains a tertiary amine that can complex siRNAs at low pH (pH 3) and reduce the density of the positive charges on the surface of NPs at physiological pH (pH 7.4). C18–N–DOX, together with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000) DSPE-PEG2000, self-assemble into DOX-prodrug nanoparticles (DOX-prodrug NPs), which bind siRNAs in citrate buffer (pH 3) to form DOX-prodrug NPs/siRNA. After replacing citrate buffer (pH 3) with PBS (pH 7.4), DOX-prodrug NPs/siRNA have slight negative charges due to complexed more siRNAs. In this study, clear evidence is shown that DOX-prodrug NPs can deliver siRNA to the same tumor cells both in vitro and in vivo. Moreover, DOX-prodrug NPs/siRNA show a great effect on inhibiting tumor cell growth both in vitro and in vivo. Therefore, the DOX-prodrug NPs are promising candidates as siRNAs delivery system for tumor therapy.
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JOURNAL OF MATERIALS SCIENCE
·
2014
·Vol. 50
·期 6
·2429-2442
·
IF 2.305
Zhang Han,Xue Yanan,Huang Juan,Xia Xiaoyang,Song Meifang,Wen Kaikai,Zhang Xiaoxiao,Luo Xiaogang,Cai Ning,Long Sihui,Yu Faquan
A charge reversible, magnetic-targeted, and pH-responsive nano therapy system assembled from citraconic-modified dextran (Dex–COOH), glycine-stabilized superparamagnetic iron oxide nanoparticles (SPION–NH 2 ), and doxorubicin (DOX) through electrostatic interaction was designed for delivering therapeutics to tumor cells. Dex–COOH was first synthesized to build the pH-sensitive citraconic amide bond and further render charge reversal upon the cleavage of the linkage. The SPION–NH 2 anchored in the nanocarrier endows the carrier with magnetic migration. The vibrating sample magnetometer analysis exhibits the superparamagnetic behavior, and the magnetic saturation value is estimated to be 39.6 emu (g Fe) −1 . The change of size and the reversal of zeta potential from negative to positive in acidic environment confirmed these expected responsibilities. The DOX-loaded nanocarriers contain DOX up to 13.0 wt%. An in vitro release profile demonstrated an efficient DOX release of 80 % at pH 5.0 while of 27 % at pH 6.8 and 13 % at pH 7.4, suggesting a pH-induced release mechanism. Microscopic images of Prussian blue staining, quantification of cellular iron and protein concentration displayed apparent iron uptake by HeLa cells. Confocal laser scanning microscopy observations revealed that the nanocarriers could efficiently deliver and release DOX into the nuclei of HeLa cells. MTT assays testified that DOX-loaded nanocarrier exhibited high anti-tumor activity with IC 50 of 0.7 μg mL −1 , while plain nanocarriers were practically non-toxic. This drug delivery system has shown the ability to improve the chemotherapeutic efficacy and to reduce the side effects, indicating great potential for delivery of drugs to the targeted sites in patients.
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MOLECULAR PHARMACEUTICS
·
2015
·
IF 4.384
Yuan Sheng,Jinhui Xu,Yiwen You,Feifei Xu,Yun Chen
The extended use of doxorubicin (DOX) could be limited because of the emergence of drug resistance associated with its treatment. To reverse the drug resistance, two thiol-modified peptide sequences HAIYPRHGGC and THRPPMWSPVWPGGC were, respectively, conjugated to DOXO-EMCH, forming a maleimide bridge in this study (i.e., T10-DOX and T15-DOX). The structures and properties of peptide–DOX conjugates were characterized using 1H NMR, 13C NMR, mass spectrometry, and high-performance liquid chromatography. Their stability was also evaluated. By 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 these novel peptide–DOX conjugates to reverse drug resistance was accessed as compared with free DOX. As a result, the IC50 values for T10-DOX and T15-DOX significantly decreased (31.6 ± 1.6 μM and 27.2 ± 0.8 μM), whereas the percentage of apoptotic cell population increased (35.4% and 39.3%). The in vivo extent of inhibition was more evident in the mice groups treated with peptide–DOX conjugates (59.6 ± 8.99% and 46.4 ± 6.63%), which had DOX primarily accumulated in tumor. These conjugates also showed a longer half-life in plasma and cleared much more slowly from the body. Furthermore, T10-DOX may be more effective than T15-DOX with a higher efficacy and a lower side effect. Most importantly, evidence was provided to support the enhanced intracellular drug accumulation and the induction of lysosomal pathway of apoptosis underlying the drug resistance. As an endosomal/lysosomal marker, cathepsin D permealized the destabilized organelle membrane and was detected in the cytoplasm, leading to the activation of the effector caspase-3 in cell apoptosis. This report is among the first to demonstrate that peptide–DOX-like conjugates promote apoptosis through the initiation of the lysosomal pathway.
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INTERNATIONAL JOURNAL OF ONCOLOGY
·
2024
·Vol. 64
·期 4
·1-12
·
IF 4.5
Sujuan Li,Sen Wang,Anping Zhang,Lixia Luo,Jie Song,Guoli Wei,Zhijun Fang
The immunogenic cell death (ICD) has aroused great interest in cancer immunotherapy. Doxorubicin (DOX), which can induce ICD, is a widely used chemotherapeutic drug in liver cancer. However, DOX‑induced ICD is not potent enough to initiate a satisfactory immune response. Cucurbitacin IIa (CUIIa), a tetracyclic triterpene, is a biologically active compound present in the Cucurbitaceae family. The present study assessed the effects of the combination of DOX and CUIIa on the viability, colony formation, apoptosis and cell cycle of HepG2 cells. In vivo anticancer effect was performed in mice bearing H22 tumor xenografts. The hallmark expression of ICD was tested using immunofluorescence and an ATP assay kit. The immune microenvironment was analyzed using flow cytometry. The combination of CUIIa and DOX displayed potent apoptosis inducing, cell cycle arresting and in vivo anticancer effects, along with attenuated cardiotoxicity in H22 mice. The combination of DOX and CUIIa also facilitated ICD as manifested by elevated high‑mobility group box 1, calreticulin and ATP secretion. This combination provoked a stronger immune response in H22 mice, including dendritic cell activation, increment of cytotoxic T cells and T helper 1 cells. Moreover, the proportion of immunosuppressive cells including myeloid‑derived suppressor cells, T regulatory cells and M2‑polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 1
·312
·
IF 4.9
Rui Zhang,Siyuan Peng,Xuejuan Zhang,Zhengwei Huang,Xin Pan
Objective: The objective of this study was to explore the possibility of treating heart failure in rats by delivering mRNA of 24-dehydrocholesterol reductase (DHCR24) into the body through lipid nanoparticles (LNPs). Methods: We established a heart failure rat model using doxorubicin. The experiment was divided into blank, model, mRNA stock solution cardiac injection, mRNA stock solution intravenous injection, LNP-mRNA stock solution cardiac injection, and LNP-mRNA stock solution intravenous injection groups. We directly injected DHCR24-mRNA or LNP-DHCR24-mRNA into the myocardium in three regions through an insulin needle passing through the intercostal space under the guidance of B-ultrasound. We recorded the mortality rate, body weight, 6-min walk test return times, and organ weight of rats after administration and detected the cardiac structure and function using B-ultrasound and transmission electron microscopy (TEM). Additionally, we tested for HE staining; PRDX2, Sirt3, and TRX1 protein expression; and IL-1 β, IL-10, VEGF, NT proBNP, and BNP cytokine concentrations. Results: Compared with the model group, the administration of DHCR24-mRNA significantly reduced mortality; decreased weight loss, the ratio of heart to tibia length, and spleen weight; and improved rat motility. The administration of DHCR24-mRNA can postpone the pathological morphological alterations of myocardial cells and reduce inflammatory infiltration. In terms of biochemistry, the administration of DHCR24-mRNA can increase the expression of the PRDX2, Sirt3, and TRX1 proteins; increase the concentrations of IL-10 and VEGF; and reduce the concentrations of IL-1β, NT proBNP, and BNP. The administration of DHCR24-mRNA can also delay the process of heart failure. The delivery and therapeutic effect of DHCR24-mRNA encapsulated in LNPs were better when compared to the other groups. Conclusions: DHCR24-mRNA encapsulated in LNPs can be effectively administered to rats with heart failure and exhibits some curative effects.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Ke Du,Yuting Liu,Lu Zhang,Lixia Peng,Wenjing Dong,Yajie Jiang,Mingming Niu,Yuanchao Sun,Chuanhong Wu,Yujuan Niu,Yonghe Ding
Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.
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ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Hao Jiang,Ying Luo,Bo Li,Chunbiao Wu,Da Wang,Yingye Xin,Wei Xu,Jianru Xiao
Osteosarcoma (OS) is a lethal malignant orthotopic bone tumor that primarily affects children and adolescents. Biomimetic nanocarriers have attracted wide attention as a new strategy for delivering chemotherapy agents to the OS. However, challenges such as rapid clearance and limited targeting hinder the effectiveness of OS chemotherapy. In this study, we designed reactive oxygen species (ROS)-responsive nanoparticles (NPs) coated with an interleukin (IL)11-engineered macrophage membrane (MM). The camouflage by MMs prevents clearance of IL-11-engineered MM-coated NPs loaded with doxorubicin (IL-11/MM@NPs/Dox) by the immune system. Moreover, the macrophage membrane combined with surface-expressed IL-11 not only directed IL-11/MM@NPs/Dox to OS tissues but also selectively identified IL-11 receptor alpha (IL-11Rα)-enriched OS cells. Within these cells, elevated levels of ROS triggered the controlled release of Dox from the ROS-responsive NPs. The synergistic modification of targeted ligand conjugation and cell membrane coating on the ROS-responsive NPs enhanced drug availability and reduced toxic side effects, thereby boosting the efficacy of OS chemotherapy. In summary, our findings suggest that IL-11/MM@NPs/Dox represents a promising approach to improving OS chemotherapy efficacy while ensuring excellent biocompatibility.
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POLYMERS FOR ADVANCED TECHNOLOGIES
·
2025
·Vol. 36
·期 3
·e70136
·
IF 3.4
Ping Xie,Jing He,Yangjun Ou
Photothermal therapy is a promising adjunctive treatment technique requiring a nanoplatform with excellent biocompatibility, photothermal stability, and precise targeting capabilities. This study aims to develop such a nanoplatform by synthesizing two new manganese(II)-based coordination polymers. The polymers were created by integrating 1,4-bis(imidazol-1-yl)benzene with the ternary ligand tris( p -carboxyphenyl)phosphane oxide, resulting in the formulas {[Mn 3 (L) 2 (bib) 3 (H 2 O) 7 ]·12H 2 O} n (CP 1 ) and {[Mn(HL)(bib)]·H 2 O} n (CP 2 ). These structures, with large surface areas and porosity, enhance drug loading efficiency. Doxorubicin (DOX) was successfully incorporated into a biocompatible HA/CMCS hydrogel-CP composite (HA/CMCS-CPs@DOX), forming a robust nanotherapeutic platform. Under near-infrared light irradiation, these metal-hydrogel composites effectively induced localized hyperthermia, aiding ocular melanoma treatment. We evaluated the effect of HA/CMCS-CP 2 @DOX on the cell proliferation of the uveal melanoma cell line, and the regulatory effects of the system on lncRNA ARAP1-AS1/miR-149-3p/S100A4 were also explored.
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CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Shuiling Qin,Zhiwei Wen,Huajie Huang,Wei Wu
Our research aimed to enhance the oral bioavailability of doxorubicin hydrochloride (DOX·HCl) while minimizing the potential for myocardial toxicity. To achieve this goal, we developed a new method that utilizes a coating material to encapsulate the drug in liposomes, which can specifically target intestinal taurine transporter proteins. This coating material, TAU-CS, was created by combining taurine with chitosan. We characterized TAU-CS using various methods, including 1 H NMR, FT-IR, and scanning electron microscopy (SEM). The resulting liposomes exhibited a regular spherical morphology, with a particle size of 195.7 nm, an encapsulation efficiency of 91.23 %, and a zeta potential of +11.65 mV. Under simulated gastrointestinal conditions, TAU-CS/LIP@DOX·HCl exhibited good stability and slow release. Pharmacokinetic studies revealed that, compared with DOX·HCl, TAU-CS/LIP@DOX·HCl had a relative bioavailability of 342 %. Intracellular uptake, immunofluorescence imaging, and permeation assays confirmed that the taurine transporter protein mediates the intestinal uptake of these liposomes. Our study suggested that liposomes coated with TAU-CS could serve as an effective oral delivery system and that targeting the taurine transporter protein shows promise in enhancing drug absorption.
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MOLECULES
·
2024
·Vol. 29
·期 14
·3360
·
IF 4.2
Yun Teng,Zhige Li,Junsong Liu,Lesheng Teng,Hongdong Li
Doxorubicin (DOX) has been an effective antitumor agent for human liver cancer cells; however, an overdose might lead to major side effects appearing in clinical applications. In this work, we present a strategy of combining DOX and blue light (BL) irradiation for the antitumor treatment of HepG2 cells (one typical human liver cancer cell line). It is demonstrated that synergetic DOX and BL can significantly reduce cell proliferation and increase the apoptotic rate of HepG2 cells in comparison to individual DOX treatment. The additional BL irradiation is further helpful for enhancing the inhibition of cell migration and invasion. Analyses of reactive oxygen species (ROS) level and Western blotting reveal that the strategy results in more ROS accumulation, mitochondrial damage, and the upregulation of proapoptotic protein (Bcl-2) and downregulation of antiapoptotic protein (Bax). In addition to the improved therapeutic effect, the non-contact BL irradiation is greatly helpful for reducing the dosage of DOX, and subsequently reduces the side effects caused by the DOX drug. These findings offer a novel perspective for the therapeutic approach toward liver cancer with high efficiency and reduced side effects.
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RSC Advances
·
2015
·Vol. 5
·期 95
·77986-77995
·
IF 3.84
Nuannuan Li,Pei Zhang,Chunzhi Huang,Yunmei Song,Sanjay Garg,Yuxia Luan
In this paper, we synthesized the pH-sensitive and biodegradable amphiphilic polypeptide-based block copolymer methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K (mPEG2K-PCL4K-PGA1K). mPEG2K-PCL4K-PGA1K had low critical aggregation concentration and could self-assemble into polymersomes in aqueous solution revealed by transmission electron microscopy. Therefore, two hydrophilic drug doxorubicin hydrochloride (DOX) and verapamil hydrochloride (VER) were encapsulated into the mPEG2K-PCL4K-PGA1K polymersomes to form poly(DOX + VER) co-delivery system to reverse the multidrug resistance by inhibiting the expression of P-glycoprotein and improve the anti-cancer effect of DOX. The in vitro cytotoxicity experiments indicated the obviously higher inhibition ratio to MCF-7/ADR resistant cells of poly(DOX + VER) compared with that of free DOX solution and polyDOX. The release rate of the two drugs from poly(DOX + VER) were much slower than that from the free drug solutions, and their release behaviors exhibited high pH-sensitive character. Furthermore, the low hemolysis ratio of mPEG2K-PCL4K-PGA1K confirmed that the copolymer could be applied for intravenous injection safely. Therefore, all these findings indicated that the co-delivery of DOX and VER by mPEG2K-PCL4K-PGA1K polymersomes is very promising for cancer therapy.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
·
IF 4.845
Dianlong Jia,Yujiao Yang,Fengjiao Yuan,Qing Fan,Feifei Wang,Yujiao Huang,Hao Song,Ping Hu,Rui Wang,Guangyong Li,Renmin Liu,Jun Li
Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors . In this study, we exploited a high-affinity EGFR-antagonistic affibody (Z EGFR ) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR + A431 tumor cells in vitro and in vivo . The in vitro studies revealed that the Dox liposomes coupled with Z EGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR + A431 cells but not in EGFR − B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo , AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with Z EGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with Z EGFR might be developed as a potential tool for therapy of EGFR + tumors.
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