Transferrin and the Transferrin Receptor for the Targeted Delivery of Therapeutic Agents to the Brain and Cancer Cells

Dufès, Christine; Robaian, Majed Mansour Madi Al; Somani, Sukrut

doi:10.4155/tde.13.21

Cited by 83 publications

(61 citation statements)

References 74 publications

(93 reference statements)

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“…Among the various formulations investigated, multilamellar vesicles conjugated to 12 mg Tf and entrapping 2 mg of -T3 were found to give the highest efficacy against A431 cell viability. These vesicles had a size lower than the cut-off size required for extravasation (which has been found to be 400 nm for most tumors [17,18]) and therefore have the required properties to access the transferrin receptor-expressing cancer cells and specifically deliver tocotrienol. In addition, their net negative charges would limit the risk of having electrostatic interactions between the vesicles and negatively charged cell membrane, therefore reducing any non-specific uptake of the vesicles by non-cancerous cells [19].…”

Section: Discussionmentioning

confidence: 99%

Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

Karim

Somani

Robaian

et al. 2017

Journal of Controlled Release

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The therapeutic potential of tocotrienol, a member of the vitamin E family of compounds with potent in vitro anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a novel tumor-targeted vesicular formulation of tocotrienol would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo.In this work, we demonstrated that novel transferrin-bearing multilamellar vesicles entrapping -T3 resulted in a dramatically improved (by at least 52-fold) therapeutic efficacy in vitro on A431 cell line, compared to the free drug. In addition, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles resulted in tumor suppression for 30% of A431 and 60% of B16-F10 tumors, without visible toxicity. Mouse survival was enhanced by more than 13 days compared to controls administered with the drug solution only. This tumor-targeted, tocotrienol-based nanomedicine therefore significantly improved the therapeutic response in cancer treatment. KEYWORDSTocotrienol; transferrin; tumor targeting; delivery system; cancer therapy 2 1. Introduction Tocotrienol, a member of the vitamin E family of compounds, is currently receiving increased attention because of its promising anti-tumor activity [1,2]. It has been reported to exert its anti-cancer effects through various mechanisms, such as activation of p53, modulation of Bax/Bcl-2 ratio, decrease of oxidative stress and induction of apoptosis [1][2][3][4]. It can also inhibit angiogenesis by downregulating the expression of the vascular endothelial growth factor (VEGF) receptor and blocking intracellular VEGF signaling. In addition, it is able to potentiate apoptosis through inhibition of DNA polymerase and telomerase and of NF-B activation pathway [1][2][3][4]. This wide range of anti-cancer effects therefore makes tocotrienol a very promising therapeutic molecule. However, its efficacy against cancer cells in vivo is hindered by its inability to specifically reach cancer cells at a therapeutic concentration, without affecting normal cells. Given its anti-proliferative properties, it is of the utmost importance to find a strategy to deliver this therapeutic drug specifically to its site of action. On the basis that iron is essential for tumor cell growth and can be effectively carried to tumors by using transferrin receptors overexpressed on cancer cells [5,6], we recently demonstrated that the conjugation of transferrin (Tf) to vesicles entrapping tocotrienol-rich fraction (TRF) extracted from palm oil could lead to tumor regression, and even tumor suppression, on both the tested cancer cell lines, following intravenous injection to a murine model [7][8][9]. It resulted in complete tumor eradication for 50% of B16-F10 tumors and 20% of A431 tumors [7]. The treatments were well tolerated by the animals, without weight loss or apparent signs of toxicity. These previous studies, however, used TRF but did not ev...

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Section: Discussionmentioning

confidence: 99%

Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

Karim

Somani

Robaian

et al. 2017

Journal of Controlled Release

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“…Despite acting as an entrance gateway to the brain, the BBB does possess specific receptor-mediated transport mechanisms that can potentially be exploited as a means to target drugs and genes to the brain. As iron can reach the brain by using transferrin (Tf) receptors overexpressed on the blood-brain barrier [6], targeting the transferrin receptor (TfR) strategy has been widely investigated for the delivery of drugs and genes to the brain [7][8]. Among the non-viral gene delivery systems currently under development, generation 3 diaminobutyric polypropylenimine dendrimer (DAB) appears to be particularly promising.…”

Section: Introductionmentioning

confidence: 99%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body. Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain. KEYWORDSBrain delivery; blood-brain barrier; gene expression; dendrimer; lactoferrin 2 1. Introduction Brain diseases, including glioma, Alzheimer's and Parkinson's diseases, currently represent one of the largest and fastest growing area of unmet clinical need. Brain cancer is the leading cause of cancer death in young people and accounts for more than one third of cancer deaths in children aged under 10. Alzheimer's disease is the most common type of dementia, affecting almost 500 000 people in the UK. The symptoms of this disease develop gradually and become more severe over the course of several years. In addition, there is currently no cure for Parkinson's disease, which affects 127 000 people in the UK [1][2][3][4]. Gene therapy has emerged as a promising therapeutic strategy, as the genetic basis for many of these diseases is known. However, the possibility of using genes as medicines to treat brain pathologies is limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier (BBB) and to deliver DNA to the brain after intravenous administration, without secondary effects to healthy tissues. In addition, locally administered treatments fail to achieve a widespread gene expression in the target cells throughout the entire brain, which is necessary for a successful treatment of most brain pathologies [2-3, 5]. There is therefore an urgent need to develop safe and efficacious non-viral gene-based nanomedicines able to cross the BBB after intravenous administration, in order to ultimately provide better treatment options for brain diseases than currently available. Despite acting as an entrance gateway to the brain, the BBB does...

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“…It has been widely proved that TfRs are overexpressed on various types of malignant cells, including the MCF-7/Adr cells used in this study. 21,23 Here, we investigated the TfR expression on MCF-7/Adr cells by immunofluorescence (as shown in Figure 5A). The large amount of FITC-labeled secondary antibody (green) on MCF-7/Adr cells confirmed the TfR expression.…”

Section: Cellular Uptake Of 7pep-targeted Micellesmentioning

confidence: 99%

“…21 Recently, it has been demonstrated that the emergence of drug resistance is partially associated with further overproduction of TfR, which therefore could render it a potential target for MDR tumors. 22 Sheng et al 23 have demonstrated that TfR ligand and doxorubicin (DOX) conjugate exhibited the ability to target drug-resistant tumors.…”

Section: Introductionmentioning

confidence: 99%

Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

Gao

Duan

et al. 2017

IJN

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The emergence of drug resistance is partially associated with overproduction of transferrin receptor (TfR). To overcome multidrug resistance (MDR) and achieve tumor target delivery, we designed a novel biodegradable pH-sensitive micellar system modified with HAIYPRH, a TfR ligand (7pep). First, the polymers poly( l -histidine)-coupled polyethylene glycol-2000 (PHIS-PEG 2000 ) and 7pep-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (7pep-DSPE-PEG 2000 ) were synthesized, and the mixed micelles were prepared by blending of PHIS-PEG 2000 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG 2000 ) or 7pep-DSPE-PEG 2000 (7-pep HD micelles). The micelles exhibited good size uniformity, high encapsulation efficiency, and a low critical micelle concentration. By changing the polymer ratio in the micellar formulation, the pH response range was specially tailored to pH ~6.0. When loaded with antitumor drug doxorubicin (DOX), the micelle showed an acid pH-triggering drug release profile. The cellular uptake and cytotoxicity study demonstrated that 7-pep HD micelles could significantly enhance the intracellular level and antitumor efficacy of DOX in multidrug-resistant cells (MCF-7/Adr), which attributed to the synergistic effect of poly( l -histidine)-triggered endolysosom escape and TfR-mediated endocytosis. Most importantly, the in vivo imaging study confirmed the target-ability of 7-pep HD micelles to MDR tumor. These findings indicated that 7-pep HD micelles would be a promising drug delivery system in the treatment of drug-resistant tumors.

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Transferrin and the Transferrin Receptor for the Targeted Delivery of Therapeutic Agents to the Brain and Cancer Cells

Cited by 83 publications

References 74 publications

Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

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