Trojan Horse Approach Research Articles

Versatile quarto stimuli nanostructure based on Trojan Horse approach for cancer therapy: Synthesis, characterization, in vitro and in vivo studies

Nanostructured delivery and diagnostic systems that induces specific targeting properties by exploiting the local physicochemical tumour characteristics will be evaluated is the present work. It is well known that cancer cells have specific physicochemical characteristics, which can be taken into consideration for the design of a broad spectrum of drug delivery systems (DDS). Some of those characteristics including the different temperature environment their susceptibility when temperature ranges between 40 and 43°C where cell apoptosis is induced, the intra- and extra-cellular pH which varies from 6.0 to 6.8, for cancer cells, and 6.5 to 7.4 for normal cells respectively, (lysosomes acidic pH ranges 4–5). Additional significant factors are the overexpressed receptors on the tumour surface. Loading and release studies were carried out by using the anthracycline drug Doxorubicin and their cytotoxicity was evaluated by using the MTT assay in healthy and diseased cell lines. The highlight of this work is the in vitro and in vivo studies which were performed in order to evaluate different nanostructures as for their biodistribution, pharmacokinetic and toxicity per se.

The Trojan horse approach for managing invasive ants: a study with Asian needle ants, Pachycondyla chinensis

Ants are among the most ecologically and economically significant biological invaders and are notoriously difficult to eradicate once established. Invasive ants are typically managed with toxic baits which are often unattractive to the target species, toxic to non-targets, and environmentally persistent. The current study evaluated a novel Trojan horse approach for managing invasive ants in natural habitats based on the use of poisoned prey. Eastern subterranean termites (Reticulitermes flavipes) were topically exposed to fipronil and presented to Asian needle ants (Pachycondyla chinensis) which are a significant invader in natural and disturbed habitats in the eastern United States. In laboratory assays, P. chinensis colonies were offered fipronil-treated termites within experimental arenas. The termites were readily attacked and consumed and results demonstrate that a single termite exposed to 25 ppm fipronil for 1 h is capable of killing 100 P. chinensis workers in 9 h. To evaluate population effects, field studies were conducted in forested areas invaded by P. chinensis. Fipronil-treated termites scattered on the forest floor provided rapid control of P. chinensis and ant densities throughout the treated plots declined by 98 ± 5 % within 28 days. I demonstrate that the poison baiting approach based on fipronil-treated termite prey is highly effective against P. chinensis and may offer an effective alternative to traditional bait treatments against other invasive ants, especially those with predatory and generalist feeding habits. Furthermore, I demonstrate that the poison baiting approach offers environmental benefits by delivering substantially less toxicant to the environment relative to current control methods which rely on commercial bait formulations. In summary, the poison baiting approach evaluated in this study appears highly suitable for controlling invasive ants and should be further tested against other invasive ants.

Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain.

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by 'infecting' neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS.

Siderophores as "Trojan Horses": tackling multidrug resistance?

Siderophores as "Trojan Horses": tackling multidrug resistance?

Capsules containing entomopathogenic nematodes as a Trojan horse approach to control the western corn rootworm

The use of entomopathogenic nematodes in the biological control of soil insect pests is hampered by the costly and inadequate application techniques. As a possible solution we evaluated a nematode encapsulation approach that offers effective application and may possibly attract the pest by adding attractants to the capsule shell. Heterorhabditis bacteriophora nematodes, which show high virulence against the maize root pest Diabrotica virgifera virgifera, were encapsulated in a polysaccharide shell derived from the algae Laminaria ssp. Shells of varying thickness and composition were evaluated. Nematodes readily survived the encapsulation process and were able, varying with shell thickness and temperature, to break through the shell and subsequently infect hosts. The added attractants and feeding stimulants to the shell attracted the pest larvae as much as maize roots. In field trials, encapsulated H. bacteriophora nematodes were more effective in controlling D. v. virgifera than those sprayed in water over the soil surface, but in these trials the addition of stimulants did not increase the control efficiency. The study demonstrates that nematodes can be successfully applied in capsules in the field. Further improvements are needed to make the capsules a cost effective alternative to conventional field application of nematodes.

Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers

Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC50 values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction.

RETRACTED ARTICLE: Targeted suicide gene therapy for glioma using human embryonic stem cell-derived neural stem cells genetically modified by baculoviral vectors

Tumor-tropic neural stem cells (NSCs) can be used in the Trojan horse approach as cellular vehicles for targeted delivery of therapeutic agents to distant tumor sites. To realize this cancer therapy potential, it is important to have a renewable source to generate large quantities of uniform human NSCs. Here, we reported that NSCs derived from HES1 human embryonic stem cell line were capable of migrating into intracranial glioma xenografts after systemic injection or after intracranial injection at a site distant from the tumor. To test whether the HES1-derived NSCs can be used for cancer gene therapy, we used a baculoviral vector to introduce the herpes simplex virus thymidine kinase suicide gene into the cells and demonstrated that baculovirus-mediated transgene expression may last for at least 3 weeks in NSCs. After being injected into the cerebral hemisphere opposite the tumor site and in the presence of ganciclovir, NSCs expressing the suicide gene were able to inhibit the growth of human glioma xenografts and prolong survival of tumor-bearing mice. Our findings suggest that human embryonic stem cells could potentially serve as a clinically viable source for production of cellular vehicles suitable for targeted anticancer gene therapy.

Social evolution in micro-organisms and a Trojan horse approach to medical intervention strategies.

Medical science is typically pitted against the evolutionary forces acting upon infective populations of bacteria. As an alternative strategy, we could exploit our growing understanding of population dynamics of social traits in bacteria to help treat bacterial disease. In particular, population dynamics of social traits could be exploited to introduce less virulent strains of bacteria, or medically beneficial alleles into infective populations. We discuss how bacterial strains adopting different social strategies can invade a population of cooperative wild-type, considering public good cheats, cheats carrying medically beneficial alleles (Trojan horses) and cheats carrying allelopathic traits (anti-competitor chemical bacteriocins or temperate bacteriophage viruses). We suggest that exploitation of the ability of cheats to invade cooperative, wild-type populations is a potential new strategy for treating bacterial disease.

Metastasis Research Society–American Association for Cancer Research Joint Conference on Metastasis

By analogy, the study of metastasis is like a group of blind people studying an elephant. Each describes the pachyderm based on the part (s)he touches, but none comprehends the whole elephant because his/her exposure is limited. Likewise, the complexity of metastasis can only be appreciated when one

Nuclear gene delivery: the Trojan horse approach

The nuclear envelope represents a formidable barrier to the transfer of plasmids to the cell nucleus, particularly in nondividing cells. The probability of intact plasmids arriving in the nucleus by a passive process is extremely low. There is substantial evidence in the literature that describes the transport of macromolecules, including plasmids, to the nucleus as a very inefficient process, and so far attempts to affect the active transport through the nuclear pores have achieved limited success. Several approaches have been attempted to improve nuclear transport of plasmids, including the condensation of plasmids to unimolecular complexes of minimal hydrodynamic diameter to favour passive transport through the nuclear pore complex, and the incorporation of nuclear localisation signals in the plasmid or in the delivery system to enhance the active transport of plasmids through the nuclear pores.

Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents.

Siderophores (microbial iron chelators) play an extremely important role in microbial pathogenicity. Microbial uptake of siderophore-iron complexes through active transport systems allow microbes to survive and proliferate even under iron deficient environments during invasion of a host. Due to their structural complexity, unique iron (III) chelation, acquisition properties, and their therapeutic potential, siderophores have attracted much attention in a broad range of disciplines. Tremendous progress has been made in siderophore syntheses, in determination of the structures and functions of outer membrane receptors (e.g. FhuA and FepA), and in the mechanistic insight into siderophore-iron-mediated active transport processes. One of the important practical applications of this active transport system is development of species-selective active drug transport (the Trojan Horse approach) to potentially treat infections due to drug resistant strains of microbes. Siderophore-drug conjugates have shown great potential in active drug delivery to target pathogenic microbes.

Feedback regulation of collagen gene expression: a Trojan horse approach.

The mechanisms involved in feedback regulation of type I procollagen synthesis by the N-terminal propeptide of the pro alpha 1(I) chain, termed Col 1, are poorly understood. We have constructed a metallothionein-human collagen chimeric minigene (pMTCol) that codes for a Col 1 fusion protein but lacks a signal peptide sequence and, therefore, would be expected to direct the synthesis of the fusion protein to the cytosol. Baby hamster kidney cells and fetal calf ligament cells, transfected with pMTCol, transcribed the gene and synthesized an intracellular antigen that was identified as the fusion protein with a monospecific antibody. Transfected fetal calf ligament fibroblasts showed significantly reduced levels of endogenously produced type I collagen, as determined by imaging and digital quantitation of immunofluorescence by confocal microscopy; synthesis of fibronectin, thrombospondin, and SPARC (secreted protein, acidic and rich in cysteine) was unchanged or increased in these cells. This recombinant approach offers the potential for a systematic analysis of feedback regulation of collagen synthesis.