Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicin

Jiang, Juan; Yang, Shijin; Wang, Jiancheng; Yang, Lijuan; Xu, Zhen-Zhong; Yang, Ting; Liu, Xiaoyan; Qiang, Zhang

doi:10.1016/j.ejpb.2010.06.011

Cited by 144 publications

(58 citation statements)

References 35 publications

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“…In contrast to that, Jiang et al observed optimal cellular transfection and tumor inhibition in a drug-resistant MCF7/A tumor with 1% RGD-modified liposomes containing small interfering ribonucleic acid, suggesting that the 1% molar ratio of RGD modification might be the best ratio for targeting integrin receptors. 44 Nevertheless, biodistribution studies of 111 In-labeled RLPs did not confirm the in vitro data. In general, the highest uptake of RLPs was in the liver and spleen, which was expected since LNPs accumulate in these organs due to extraction via the mononuclear phagocyte system.…”

Section: Discussionmentioning

confidence: 89%

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

Rangger¹,

Helbok²,

Guggenberg³

et al. 2012

IJN

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Purpose: Liposomes have been proposed to be a means of selectively targeting cancer sites for diagnostic and therapeutic applications. The focus of this work was the evaluation of radiolabeled PEGylated liposomes derivatized with varying amounts of a cyclic arginyl-glycyl-aspartic acid (RGD) peptide. RGD peptides are known to bind to α v β 3 integrin receptors overexpressed during tumor-induced angiogenesis. Methods: Several liposomal nanoparticles carrying the RGD peptide targeting sequence (RLPs) were synthesized using a combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, cholesterol, diethylenetriaminepentaacetic acid-derivatized lipids for radiolabeling, a polyethylene glycol (PEG) building block, and a lipid-based RGD building block. Relative amounts of RGD and PEG building blocks were varied. In vitro binding affinities were determined using isolated α v β 3 integrin receptors incubated with different concentrations of RLPs in competition with iodine-125-labeled cyclo-(-RGDyV-). Binding of the indium-111-labeled RLPs was also evaluated. Biodistribution and micro single photon emission computed tomography/computed tomography imaging studies were performed in nude mice using different tumor xenograft models. Results: RLPs were labeled with indium-111 with high radiochemical yields. In vitro binding studies of RLPs with different RGD/PEG loading revealed good binding to isolated receptors, which was dependent on the extent of RGD and PEG loading. Binding increased with higher RGD loading, whereas reduced binding was found with higher PEG loading. Biodistribution showed increased circulating time for PEGylated RLPs, but no dependence on RGD loading. Both biodistribution and micro single photon emission computed tomography/computed tomography imaging studies revealed low, nonspecific tumor uptake values. Conclusion: In this study, RLPs for targeting angiogenesis were described. Even though good binding to α v β 3 integrin receptors was found in vitro, the balance between PEGylation and RGD loading clearly requires optimization to achieve targeting in vivo. These data form the basis for future development and provide a platform for the investigation of multimodal approaches.

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Section: Discussionmentioning

confidence: 89%

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

Rangger¹,

Helbok²,

Guggenberg³

et al. 2012

IJN

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“…27 It is generally accepted that the density of the targeting ligands on the surface of a nanocarrier plays a vital role in determining the efficiency of drug delivery. 28,29 Assuming that GE11 can specifically bind to EGFR on NSCLC cells and increase the cellular uptake of liposomes, the optimal GE11 density required to achieve the best targeting efficiency needs to be determined. Further, to our knowledge, cellular uptake of ligand-modified nanocarriers is primarily mediated by clathrin-dependent and clathrin-independent pathways.…”

Section: Introductionmentioning

confidence: 99%

GE11-modified liposomes for non-small cell lung cancer targeting: preparation, ex vitro and in vivo evaluation

Cheng¹,

Huang²,

Liu³

et al. 2014

IJN

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Non-small cell lung cancer (NSCLC) is a serious threat to human health, and 40%–80% of NSCLCs express high levels of epidermal growth factor receptor (EGFR). GE11 is a novel peptide and exhibits high affinity for EGFR binding. The aim of this study was to construct and evaluate GE11-modified liposomes for targeted drug delivery to EGFR-positive NSCLC. Doxorubicin, a broad-spectrum antitumor agent, was chosen as the payload. GE11 was conjugated to the distal end of DSPE-PEG 2000 -Mal by an addition reaction with a conjugation efficiency above 90%. Doxorubicin-loaded liposomes containing GE11 (GE11-LP/DOX) at densities ranging from 0% to 15% were prepared by combination of a thin film hydration method and a post insertion method. Irrespective of GE11 density, the physicochemical properties of these targeted liposomes, including particle size, zeta potential, and drug entrapment efficiency, were nearly identical. Interestingly, the cytotoxic effect of the liposomes on A549 tumor cells was closely related to GE11 density, and liposomes with 10% GE11 had the highest tumor cell killing activity and a 2.6-fold lower half maximal inhibitory concentration than that of the nontargeted counterpart (PEG-LP/DOX). Fluorescence microscopy and flow cytometry analysis revealed that GE11 significantly increased cellular uptake of the liposomes, which could be ascribed to specific EGFR-mediated endocytosis. It was found that multiple endocytic pathways were involved in entry of GE11-LP/DOX into cells, but GE11 assisted in cellular internalization mainly via the clathrin-mediated endocytosis pathway. Importantly, the GE11-modified liposomes showed enhanced accumulation and prolonged retention in tumor tissue, as evidenced by a 2.2-fold stronger mean fluorescence intensity in tumor tissue than the unmodified liposomes at 24 hours. In summary, GE11-modified liposomes may be a promising platform for targeted delivery of chemotherapeutic drugs in NSCLC.

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“…For example, liposomes carrying the RGD peptide (an active targeting ligand peptide which has high affinity for ITGAV-ITGB3/integrin avb3 receptors) specifically bind to ITGAV-ITGB3/integrin a v b 3 receptors overexpressed on many tumor cells, whereas liposomes carrying folate bind to folate receptors overexpressed in certain cancers. [34][35][36][37][38] While such ligands often result in highly specific drug delivery, they usually do not enhance endocytosis or solid tumor penetration. 39,40 Therefore liposomes can be modified with cationic cell-penetrating peptides (CPP) such as TAT to improve their internalization by cells.…”

mentioning

confidence: 99%

Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin

et al. 2016

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He (2016) Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin, Autophagy, 12:6, 949-962, DOI: 10.1080/15548627.2016 HCQ/Lip-TR was efficiently internalized as a result of its ability to bind ITGAV-ITGB3/integrin a v b 3 receptors highly expressed on the tumor cell surface and to undergo charge reversal from anionic at pH 7.4 to cationic at pH 6.5. Studies in vitro at pH 6.5 showed that the intracellular HCQ concentration was 35.68-fold higher, and lysosomal HCQ concentration 32.22-fold higher, after treating cultures with HCQ/Lip-TR than after treating them with free HCQ. The corresponding enhancements observed in mice bearing B16F10 tumors were 15.16-fold within tumor cells and 14.10-fold within lysosomes. HCQ/Lip-TR was associated with milder anemia and milder myosuppressive reductions in white blood cell and platelet counts than free HCQ, as well as less accumulation in the small intestine, which may reduce risk of intestinal side effects. In addition, co-delivering HCQ/Lip-TR with either free doxorubicin (DOX) or liposomal DOX improved the ability of DOX to inhibit tumor growth. Biochemical, electron microscopy and immunofluorescence experiments confirmed that HCQ/Lip-TR blocked autophagic flux in tumor cells. Our results suggest that loading HCQ into Lip-TR liposomes may increase the effective concentration of the inhibitor in tumor cells, allowing less toxic doses to be used.

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Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicin

Cited by 144 publications

References 35 publications

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

Influence of PEGylation and RGD loading on the targeting properties of radiolabeled liposomal nanoparticles

GE11-modified liposomes for non-small cell lung cancer targeting: preparation, ex vitro and in vivo evaluation

Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin

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