Delivery of the vitamin E compound tocotrienol to cancer cells

Tocotrienol, a member of the vitamin E family of compounds, is currently receiving increased attention because of its highly promising anti-cancer effects. However, its potential in cancer therapy is limited by its poor bioavailability and its inability to specifically reach tumors at therapeutic concentrations after intravenous administration. In order to remediate to these problems, various delivery strategies have been proposed, such as the inclusion of tocotrienol in γ-cyclodextrins, prodrugs and emulsions, entrapment in lipid nanoparticles and vesicles. Among these approaches, we demonstrated that the entrapment of tocotrienol within vesicles bearing transferrin, whose receptors are overexpressed on numerous cancer cells, significantly improved the uptake by cancer cells overexpressing transferrin receptors. Consequently, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles led to tumor regression and even complete tumor suppression in some cases in a murine tumor model, as well as improvement of animal survival. Transferrin-bearing vesicles are therefore highly promising for the delivery of tocotrienol to cancer cells in vitro and in vivo and should be further investigated to optimize the anti-cancer therapeutic effect of tocotrienol

Liposomes encapsulating polymeric chitosan based vesicles - a vesicle in vesicle system for drug delivery

Drug delivery systems comprising vesicles prepared from one amphiphile encapsulating vesicles prepared from a second amphiphile have not been prepared previously due to a tendency of the bilayer components of the different vesicles to mix during preparation. Recently we have developed polymeric vesicles using the new polymer-palmitoyl glycol chitosan and cholesterol in a 2:1 weight ratio. These polymeric vesicles have now been encapsulated within egg phosphatidylcholine (egg PC), cholesterol (2:1 weight ratio) liposomes yielding a vesicle in vesicle system. The vesicle in vesicle system was visualised by freeze fracture electron microscopy. The mixing of the different bilayer components was studied by monitoring the excimer fluorescence of pyrene-labelled polymeric vesicles after their encapsulation within egg PC liposomes or hexadecyl diglycerol ether niosomes. A minimum degree of lipid mixing was observed with the polymeric vesicle-egg PC liposome system when compared to the polymeric vesicle-hexadecyl diglycerol ether niosome system. The polymeric vesicle-egg PC vesicle in vesicle system was shown to retard the release of encapsulated solutes. 28% of 5(6)-carboxyfluorescein (CF) encapsulated in the polymeric vesicle compartment of the vesicle in vesicle system was released after 4 h compared to the release of 62% of encapsulated CF from plain polymeric vesicles within the same time period

Dendrimers in gene delivery

Dendrimers have unique molecular architectures and properties that make them attractive materials for the development of nanomedicines. Key properties such as defined architecture and a high ratio of multivalent surface moieties to molecular volume also make these nanoscaled materials highly interesting for the development of synthetic (non-viral) vectors for therapeutic nucleic acids. Rational development of such vectors requires the link to be made between dendrimer structure and the morphology and physicochemistry of the respective nucleic acid complexes and, furthermore, to the biological performance of these systems at the cellular and systemic level. The review focuses on the current understanding of the role of dendrimers in those aspects of synthetic vector development. Dendrimer-based transfection agents have become routine tools for many molecular and cell biologists but therapeutic delivery of nucleic acids remains a challenge

Effects of the vasoactive intestinal peptide (VIP) and related peptides on glioblastoma cell growth in vitro

The growth rate of numerous cancer cell lines is regulated in part by actions of neuropeptides of the vasoactive intestinal peptide (VIP) family, which also includes pituitary adenylate cyclase-activating peptide (PACAP), glucagon, and peptide histidine/isoleucine (PHI). The aim of this work was to investigate the effect of these peptides on the growth of the rat glioblastoma cell line C6 in vitro. We also sought to determine which binding sites were correlated with the effects observed. Proliferation studies performed by means of a CyQuant trade mark assay showed that VIP and PACAP strongly stimulated C6 cell proliferation at most of the concentrations tested, whereas PHI increased cell proliferation only when associated with VIP. Two growth hormone-releasing factor (GRF) derivatives and the VIP antagonist hybrid peptide neurotensin-VIP were able to inhibit VIP-induced cell growth stimulation, even at very low concentrations. Binding experiments carried out on intact cultured C6 cells, using 125I-labeled VIP and PACAP as tracers, revealed that the effects of the peptides on cell growth were correlated with the expression on C6 cells of polyvalent high-affinity VIP-PACAP binding sites and of a second subtype corresponding to very high-affinity VIP-selective binding species. The latter subtype, which interacted poorly with PACAP with a 10,000-fold lower affinity than VIP, might mediate the antagonist effects of neurotensin- VIP and of both GRF derivatives on VIP-induced cell growth stimulation

Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats

The aim of this work was to study in rats the nasal route for the brain delivery of the vasoactive intestinal peptide (VIP) neuropeptide. After evaluating VIP stability in solutions obtained from nasal washes, the effect of formulation parameters (pH 4-9, 0-1% (w/v) lauroylcarnitine (LC), hypo- or isoosmolality) on the brain uptake of intranasally administered VIP (10(-8)M)/125I-VIP (300,000 cpm/ml) was studied, using an in situ perfusion technique. Brain radioactivity distribution was assessed by quantitative autoradiographic analysis. Results were compared to intravenously administered VIP. With a hypotonic formulation at pH 4 containing 0.1% LC and 1% bovine serum albumin, VIP stability was satisfactory and loss by adsorption was minimal. Using this formulation, around 0.11% of initial radioactivity was found in the brain after 30 min perfusion and was located in the olfactory bulbs, the midbrain and the cerebellum. HPLC analysis of brain and blood extracts demonstrated the presence of intact VIP in brain and its complete degradation in the blood compartment. By intravenous administration, no intact VIP was found either in brain or in blood. In conclusion, intact VIP could be delivered successfully to the brain using the intranasal route for administration

Emergence of cationic polyamine dendrimersomes : design, stimuli sensitivity and potential biomedical applications

For decades, self-assembled lipid vesicles have been widely used in clinics as nanoscale delivery systems for various biomedical applications, including treatment of various diseases. Due to their core-shell architecture and versatile nature, they have been successfully used as carriers for the delivery of a wide range of therapeutic cargos, including drugs and nucleic acids, in cancer treatment. Recently, surface-modified polyamine dendrimer-based vesicles, or dendrimersomes, have emerged as promising alternatives to lipid vesicles for various biomedical applications, due to their ease of synthesis, non-immunogenicity, stability in circulation and lower size polydispersity. This mini-review provides an overview of the recent advances resulting from the use of biomimetic hydrophobically-modified polyamine-based dendrimersomes towards biomedical applications, focusing mainly on the two most widely used polyamine dendrimers, namely polyamidoamine (PAMAM) and poly(propylene imine) (PPI) dendrimers

Niosomes and polymeric chitosan based vesicles bearing transferrin and glucose ligands for drug targeting

PURPOSE: To prepare polymeric vesicles and niosomes bearing glucose or transferrin ligands for drug targeting. METHODS: A glucose-palmitoyl glycol chitosan (PGC) conjugate was synthesised and glucose-PGC polymeric vesicles prepared by sonication of glucose-PGC/cholesterol. N-palmitoylglucosamine (NPG) was synthesised and NPG niosomes also prepared by sonication of NPG/ sorbitan monostearate/ cholesterol/ cholesteryl poly-24-oxyethylene ether. These 2 glucose vesicles were incubated with colloidal concanavalin A gold (Con-A gold), washed and visualised by transmission electron microscopy (TEM). Transferrin was also conjugated to the surface of PGC vesicles and the uptake of these vesicles investigated in the A431 cell line (over expressing the transferrin receptor) by fluorescent activated cell sorter analysis. RESULTS: TEM imaging confirmed the presence of glucose units on the surface of PGC polymeric vesicles and NPG niosomes. Transferrin was coupled to PGC vesicles at a level of 0.60+/-0.18 g of transferrin per g polymer. The proportion of FITC-dextran positive A431 cells was 42% (FITC-dextran solution), 74% (plain vesicles) and 90% (transferrin vesicles). CONCLUSIONS: Glucose and transferrin bearing chitosan based vesicles and glucose niosomes have been prepared. Glucose bearing vesicles bind Con-A to their surface. Chitosan based vesicles are taken up by A431 cells and transferrin enhances this uptake

Development of transferrin-bearing vesicles encapsulating aspirin for cancer therapy

Originally developed for the treatment of inflammatory disorders, the non-steroidal antiinflammatory drug aspirin was shown to have a preventive effect against cancer in the past decades. Most importantly, recent studies suggested that it might also provide a therapeutic benefit in the treatment of cancer in vitro. However, this drug failed to specifically reach tumors at a therapeutic concentration following intravenous administration, thus resulting in lack of efficacy on tumors. In this work, we demonstrated that aspirin could be formulated in transferrin-bearing vesicles and that this tumor-targeted formulation could lead to an increase in the anti-proliferative efficacy of the drug in three cancer cell lines in vitro. The in vitro therapeutic efficacy of aspirin was significantly improved when formulated in transferrin-bearing vesicles, by about 2-fold compared to that of drug solution. These results are promising and support the optimization of this delivery system to further improve its potential as a therapeutic tool in combination with other anti-cancer therapies

Anticancer drug delivery with transferrin targeted polymeric chitosan vesicles

The study reports the initial biological evaluation of targeted polymeric glycol chitosan vesicles as carrier systems for doxorubicin (Dox). Transferrin (Tf) was covalently bound to the Dox-loaded palmitoylated glycol chitosan (GCP) vesicles using dimethylsuberimidate (DMSI). For comparison, glucose targeted niosomes were prepared using N-palmitoyl glucosamine. Biological properties were studied using confocal microscopy, flow cytometry, and cytotoxicity assays as well as a mouse xenograft model. Tf vesicles were taken up rapidly with a plateau after 1-2 h and Dox reached the nucleus after 60-90 min. Uptake was not increased with the use of glucose ligands, but higher uptake and increased cytotoxicity were observed for Tf targeted as compared to GCP Dox alone. In the drug-resistant A2780AD cells and in A431 cells, the relative increase in activity was significantly higher for the Tf-GCP vesicles than would have been expected from the uptake studies. All vesicle formulations had a superior in vivo safety profile compared to the free drug. The in vitro advantage of targeted Tf vesicles did not translate into a therapeutic advantage in vivo. All vesicles reduced tumor size on day 2 but were overall less active than the free drug

Transferrin-bearing liposomes entrapping plumbagin for targeted cancer therapy

The therapeutic potential of plumbagin, a naphthoquinone extracted from the officinal leadwort with anticancer properties, is hampered by its failure to specifically reach tumours at a therapeutic concentration after intravenous administration, without secondary effects on normal tissues. Its use in clinic is further limited by its poor aqueous solubility, its spontaneous sublimation, and its rapid elimination in vivo. We hypothesize that the entrapment of plumbagin within liposomes grafted with transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumours after intravenous administration. The objectives of this study were therefore to prepare and characterize transferrin-targeted liposomes entrapping plumbagin and to evaluate their therapeutic efficacy in vitro and in vivo. The entrapment of plumbagin in transferrin-bearing liposomes led to an increase in plumbagin uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity in B16-F10, A431, and T98G cell lines compared with that observed with the drug solution. In vivo, the intravenous injection of transferrin-bearing liposomes entrapping plumbagin led to tumour suppression for 10% of B16-F10 tumours and tumour regression for a further 10% of the tumours. By contrast, all the tumours treated with plumbagin solution or left untreated were progressive. The animals did not show any signs of toxicity. Transferrin-bearing liposomes entrapping plumbagin are therefore highly promising therapeutic systems that should be further optimized as a therapeutic tool for cancer treatment