Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy

Zhu, Qiao-Ling; Zhou, Yi; Guan, Mingyu; Zhou, Xiaofeng; Yang, Shu-di; Yang, Liu; Chen, Wei‐Liang; Zhang, Chun-ge; Yuan, Zhiqiang; Liu, Chun; Zhu, Aijun; Xue-nong, Zhang

doi:10.1016/j.biomaterials.2014.03.088

Cited by 98 publications

(60 citation statements)

References 29 publications

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“…225 Increased expression of LDL-R was found in HCC compared with adjacent liver tissue. 226 N-succinyl chitosan NPs were coupled with LDL for target co-delivery of cholesterol-conjugated siRNA and DOX by Zhu et al 227 The LDL-decorated delivery system exhibited superior cytotoxicity against HepG2 cells over non-targeted system and also manifested enhanced liver tumor-targeting effects and relatively lower systemic toxicity in mice bearing hepatoma cell tumor, suggesting their potential for HCC therapy. LDL was also utilized to modify osthole-loading N-succinyl chitosan NPs, attaining high targeting efficacy indicated by investigations in vitro and in vivo.…”

mentioning

confidence: 99%

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Li¹,

Zhang²,

Wang³

et al. 2016

IJN

118

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mentioning

confidence: 99%

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Li¹,

Zhang²,

Wang³

et al. 2016

IJN

118

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“…Much attention has been paid to the design of novel nanocarriers based on LDL, 18,19,31,32 due to the overexpression of LDLR in many tumor cells, which offers the advantage of tumor targeting for LDL-based nanocarriers. However, an LDL-based nanocarrier is less than ideal as a targeted drugdelivery system, not only because the quantity of natural LDL extracted from human serum is low but also because it is difficult to isolate the ApoB, which is large and aggregates easily during purification.…”

Section: Discussionmentioning

confidence: 99%

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

Ye¹,

Xia²,

Dong³

et al. 2016

IJN

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There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy.

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“…Preparation of sirNa/lDl complex LDL was isolated from virus-inactivated human plasma by sequential density gradient ultracentrifugation 41 and then stored at 4°C within 2 weeks. Protein concentration was determined using the bicinchoninic acid (BCA) method, and the particle distribution of LDL was measured by dynamic light scattering (DLS) (Zeta-Sizer; Malvern Nano-ZS90, Malvern, UK).…”

Section: Zhu Et Almentioning

confidence: 99%

“…Chol-siRNA (2 optical density) was dissolved in 125 µL of diethyl pyrocarbonate-treated water and then stored at −20°C. The siRNA solution and LDL (mole ratio of 30:1) 41,42 were mixed at room temperature and then incubated for 0.5 h to obtain siRNA/LDL complex.…”

Section: Zhu Et Almentioning

confidence: 99%

“…The mean particle size and polydispersity index (PDI) of LDL were 24.36±0.62 nm and 0.173, respectively ( Figure S1), and the zeta potential was −1.34±0.11 mV, which is consistent with the literature. 41 Free siRNA was rapidly degraded by the nucleases in blood or body fluids; thus, siRNA should be protected from nucleases. Figure 3A shows that after incubation with RNase A (20 µg⋅mL −1 ) for 0.5 h, free chol-siRNA was almost completely degraded, whereas the chol-siRNA encapsulated in LDL was protected from degradation for up to 2 h. The serum stability of the siRNA/LDL complex was evaluated through turbidity changes during incubation with 50% FBS.…”

Section: Evaluation Of the Sirna/ldl Complexmentioning

confidence: 99%

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Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

Zhu¹,

Yang²,

Qu³

et al. 2017

IJN

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Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein– N -succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.

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Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy

Cited by 98 publications

References 29 publications

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

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Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy

Cited by 98 publications

References 29 publications

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel&ndash;cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor

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Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines