Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles

Choi, Chung Hang Jonathan; Alabi, Christopher A.; Webster, Paul; Davis, Mark E.

doi:10.1073/pnas.0914140107

Cited by 624 publications

(466 citation statements)

References 25 publications

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“…However, if the receptor density is such that multiple targeting ligands on the nanoparticle can bind to the receptors simultaneously, then the targeted nanoparticle avidity (9) and selectivity (8) can be increased. These effects have been illustrated in several investigations; for example, Choi et al (9) reported the interactions of Tf-containing gold nanoparticles on both cancer cells in vitro and tumors in vivo in mice. These authors showed that the animal whole-body biodistribution of Tf-containing gold nanoparticles of ∼70 nm in diameter was independent of the Tf content, but that the amount of nanoparticles localizing in the cancer cells of solid tumors at 24 h after injection increased with increasing Tf content.…”

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confidence: 99%

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

Wiley

Webster

Gale

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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407

348

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Receptor-mediated transcytosis across the blood-brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR.E ffective delivery of therapeutics to the brain has remained elusive owing to many factors, including inadequate transport across the blood-brain barrier (BBB). Numerous multidisciplinary-based strategies for transporting therapeutic agents from the blood into the brain have been proposed (1), including the use of receptor-mediated transcytosis. Recently, Yu et al. (2) reported increased accumulation of antibodies to transferrin (Tf) receptor (TfR) in the brain parenchyma when the antibody affinity was reduced. In that work, antibodies with high TfR affinity bound strongly to and remained associated with TfRs in the BBB, whereas antibodies with lower TfR affinity allowed for their detachment from TfRs and subsequent release into the brain parenchyma. These results are consistent with a previous report of a low-affinity (nearly identical to Tf-TfR interaction strength) antibody that significantly accumulated in the brain parenchyma (3).Targeted nanoparticles are finding applications for the delivery of a wide variety of therapeutic agents, and several have already reached the clinical testing stage in humans (4, 5). For example, in a Phase I clinical trial, a Tf-containing nanoparticle was used to deliver siRNA to cancer patients and shown to deliver functional siRNA to melanoma tumors in a dose-dependent manner (6). The results demonstrate that Tf-containing nanoparticles can be administered safely to humans.It is well known that the avidity and receptor selectivity of targeted nanoparticles can be tuned by the choice of targeting ligand and its number density; multivalent nanoparticles can engage multiple cell surface receptors simultaneously (7,8). When an individual targeting ligand is conjugated to a nanoparticle, the affinity of the ligand to the receptor is reduced. However, if the receptor density is such that multiple targeting ligands on...

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confidence: 99%

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

Wiley

Webster

Gale

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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407

348

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“…In order to avoid the rapid removal of these nanoparticles from systemic circulation after intravenous administration, due to rapid uptake by reticular endothelial system (RES), pegylated PPSu nanoparticles based on PEG-PPSu copolymers have been developed [11][12][13][14][15][16][17][18]. Although pegylation of nanoparticles surface can lead to their preferential accumulation in tumor tissue due to the enhanced permeability and retention (EPR) phenomenon, it does not appear to increase the uptake of nanoparticles, and consequently of their drug load, by cancer cells [19]. In order to enhance nanoparticles uptake by tumor cells, targeting moieties, e.g.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of folate- pegylated polyester nanoparticles encapsulating ixabepilone for targeting folate receptor overexpressing breast cancer cells

Sıafaka

Betsiou

Tsolou

et al. 2015

J Mater Sci: Mater Med

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The aim of this study was the preparation of novel polyester nanoparticles based on folic acid (FA)-functionalized poly(ethylene glycol)-poly(propylene succinate) (PEG-PPSu) copolymer and loaded with the new anticancer drug ixabepilone (IXA). These nanoparticles may serve as a more selective (targeted) treatment of breast cancer tumors overexpressing the folate receptor. The synthesized materials were characterized by 1 H-NMR, FTIR, XRD and DSC. The nanoparticles were prepared by a double emulsification and solvent evaporation method and characterized with regard to their morphology by scanning electron microscopy, drug loading with HPLC-UV and size by dynamic light scattering. An average size of 195 nm and satisfactory drug loading efficiency (3.5 %) were observed. XRD data indicated that IXA was incorporated into nanoparticles in amorphous form. The nanoparticles exhibited sustained drug release properties in vitro. Based on in vitro cytotoxicity studies, the blank FA-PEG-PPSu nanoparticles were found to be non-toxic to the cells. Fluorescent nanoparticles were prepared by conjugating Rhodanine B to PEG-PPSu, and live cell, fluorescence, confocal microscopy was applied in order to demonstrate the ability of FA-PEG-PPSu nanoparticles to enter into human breast cancer cells expressing the folate receptor. Graphical Abstract 1 Introduction

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“…nanoliposomes | PLK-1 inhibitor | MEK-1 inhibitor T here is currently wide interest in the development of nanoparticles for drug delivery (1)(2)(3)(4)(5)(6)(7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low.…”

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confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

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Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles

Cited by 624 publications

References 25 publications

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

Synthesis of folate- pegylated polyester nanoparticles encapsulating ixabepilone for targeting folate receptor overexpressing breast cancer cells

Remote loading of preencapsulated drugs into stealth liposomes

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