Journal articles on the topic 'Trojan Nano Horse'

The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a “Trojan horse” for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.

The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called “Trojan horse”-type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- and intracellular-mediated effects is still missing. Therefore, the impact of the endocytosis inhibitor hydroxy-dynasore (OH-dyn), as well as bafilomycin A1 (bafA1), inhibiting the vacuolar type H+-ATPase (V-ATPase), on the cellular toxicity of nano- and microsized CuO particles, was investigated in BEAS 2 B cells. Selected endpoints were cytotoxicity, copper uptake, glutathione (GSH) levels, and the transcriptional DNA damage and (oxidative) stress response using the high-throughput reverse transcription quantitative polymerase chain reaction (RT-qPCR). OH-dyn markedly reduced intracellular copper accumulation in the cases of CuO NP and CuO MP; the modulation of gene expression, induced by both particle types affecting especially HMOX1, HSPA1A, MT1X, SCL30A1, IL8 and GADD45A, were completely abolished. BafA1 lowered the intracellular copper concentration in case of CuO NP and strongly reduced transcriptional changes, while any CuO MP-mediated effects were not affected by bafA1. In conclusion, the toxicity of CuO NP depended almost exclusively upon dynamin-dependent endocytosis and the intracellular release of redox-active copper ions due to lysosomal acidification, while particle interactions with cellular membranes appeared to be not relevant.

AIM: To demonstrate the feasibility of mesenchymal stem cell (MSC)-mediated nano drug delivery, which was characterized by the “Trojan horse”-like transport of hypoxia-inducible factor-1α small interfering RNA (HIF-1α siRNA) between MSCs and retinal pigment epithelial cells (RPE) under hypoxia environment. METHODS: Plasmid and lentivirus targeting the human HIF-1α gene were designed and constructed. HIF-1α siRNA was encapsulated into poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) through the water-in-oil-in-water (w/o/w) multiple emulsion technique. The effect of PLGA-NPs uptake on the expression of HIF-1α mRNA was tested in RPE cells by real-time quantitative polymerase chain reaction (qPCR) and additional transfected conditions were used as control, including lentivirus group, nude plasmid group and blank PLGA group. MSCs were transfected with the NPs and the transfection efficacy was evaluated by flow cytometry. Transwell co-culture system of transfected MSCs and RPE cells was constructed under hypoxia environment. The effects of MSC-loaded HIF-1α siRNA PLGA-NPs on proliferation, apoptosis, and migration of RPE cells were then evaluated. The effect of transfected MSCs on HIF-1α expression of RPE cells was analyzed by using qPCR at the time points 24h, 3d, and 7d. RESULTS: The average diameter of PLGA-NPs loaded with HIF siRNA was 314.1 nm and the zeta potential was -0.36 mV. The transfection efficiency of PLGA-NPs was 67.3%±5.2% into MSCs by using flow cytometry. Compared with the lentivirus group, the PLGA-NPs loaded with HIF-1α siRNA can effectively reduce the expression of HIF-1α mRNA up to 7d in RPE (0.63±0.05 at 7d, P<0.001). In the Transwell co-culture system of transfected MSCs and RPE, the abilities of proliferation (2.34±0.17, 2.40±0.28, 2.47±0.24 at 48h, F=0.23, P=0.80), apoptosis (14.83%±2.43%, 12.94%±2.19%, 12.39%±3.21%; F=0.70, P=0.53) and migration (124.5±7.78, 119.5±5.32, 130±9.89, F=1.33, P=0.33) of the RPE cells had no differences between MSC-loaded HIF-1α siRNA PLGA-NPs and other groups. The inhibition of PLGA on the HIF-1α mRNA expression in RPE cells could continue until the 7th day, the level of HIF-1α mRNA was lower than that of other groups (F=171.98, P<0.001). CONCLUSION: The delivery of PLGA-NPs loaded with HIF-1α siRNA carried by MSCs is found to be beneficial temporally for HIF-1α mRNA inhibition in RPE cells under hypoxia environment. The MSC-based bio-mimetic delivery of HIF-1α siRNA nanoparticles is a potential method for therapy against choroidal neovascularization.

Aim: The effective application of nanoparticles in cancer theranostics is jeopardized by their aggregation in biological media, rapid degradation and clearance. The design of biomimetic nanoconstructs with enhanced colloidal stability and non-immunogenicity is therefore essential. We propose naturally stable cell-derived extracellular vesicles to encapsulate zinc oxide (ZnO) nanocrystals as efficacious nanodrugs, to obtain highly biomimetic and stable Trojan nano-horses (TNHs). Materials & methods: Coupling efficiency, biostability, cellular cytotoxicity and internalization were tested. Results: In vitro studies showed a high internalization of TNHs into cancer cells and efficient cytotoxic activity thanks to ZnO intracellular release. Conclusion: TNHs represent an efficient biomimetic platform for future nanotheranostic applications, with biomimetic extracellular vesicle-lipid envelope, facilitated ZnO cellular uptake and potential therapeutic implications.

Background: Current cerebral drug delivery to the brain and Cerebrospinal Fluid (CSF) is limited by the Blood-Brain Barrier (BBB) or the blood-blood Cerebrospinal Fluid (CSF) barrier. The popular, non-invasive, intranasal delivery provides an exciting route for topical and systemic applications. For example, intranasal drug delivery of Central Nervous System (CNS) drugs can be designed to pass the BBB barrier via the nose-to-brain pathways. Recent nanotechnology research and patenting focus mainly on overcoming typical limitations including bioavailability, transport, BBB penetration, targeted delivery, controlled release rate and controlled degradation. Objective: The aim of the present study was to assess the state-of-the-art of nose-to-brain drug delivery systems and the role of nanotechnology in targeted delivery for the treatment of CNS and related therapeutic conditions. Methods: Patent and related searches were made with analytics to explore and organize nanotech work in intranasal drug delivery to the brain. Technical advancements were mapped by API, formulation and performance criteria. Patents and published patent applications were searched with concept tables of keywords, metadata (e.g., assignee) and patent classes (e.g., International Patent Classes and Cooperative Patent Classes). Results: The reviewed patents and published applications show a focus on formulations and therapeutic indications related to the nano-based nose-to-brain drug delivery. The main patented materials were surface modifiers, delivery systems and excipients. Conclusion: Surface modified nanoparticles can greatly improve drug transport and bioavailability of drugs, particularly higher molecular weight drugs. The most commonly used surface modifiers were chitosan, lectin and cyclodextrin-cross-linker complex. Nanoformulations of herbal drugs could increase drug bioavailability and reduce toxicity. Biotechnology-related drug delivery approaches such as monoclonal antibodies and genetically engineered proteins (molecular Trojan horses) deliver large molecule therapeutics.

AbstractIt is well known that copper oxide nanoparticles (CuO NPs) are heavily toxic on in vitro systems. In human alveolar epithelial cells, the mechanism of toxicity is mostly related to oxidative insults, coming from intracellularly dissolved copper ions, finally leading to apoptotic or autophagic cell death. Our hypothesis is based on possible early oxidative events coming from specific NP surface reactivity able to undermine the cell integrity and to drive cell to death, independently from Lysosomal-Enhanced Trojan Horse mechanism. Two types of CuO NPs, with different oxidative potential, were selected and tested on A549 cells for 1 h and 3 h at 10, 25, 50 and 100 µg/ml. Cells were then analyzed for viability and oxidative change of the proteome. Oxidative by-products were localized by immunocytochemistry and cell-NP interactions characterized by confocal and electron microscopy techniques. The results show that CuO NPs induced oxidative changes soon after 1 h exposure as revealed by the increase in protein carbonylation and reduced-protein-thiol oxidation. In parallel, cell viability significantly decreased, as shown by MTT assay. Such effects were higher for CuO NPs with more crystalline defects and with higher ROS production than for fully crystalline NPs. At these exposure times, although NPs efficiently interacted with cell surface and were taken up by small endocytic vesicles, no ion dissolution was visible inside the lysosomal compartment and no effects were produced by extracellularly dissolved copper ions. In conclusion, a specific NP surface-dependent oxidative cell injury was demonstrated. More detailed studies are required to understand which targets precociously react with CuO NPs, but these results introduce new paradigms for the toxicity of the metal-based NPs, beyond the Lysosomal-Enhanced Trojan horse-related mechanism, and open-up new opportunities to investigate the interactions and effects at the bio-interface for designing safer as well as more effective CuO-based biocides.

Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life—and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood–brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB.

Among the sub-genres of science fiction, one of the most traditional and most machine-laden is space opera. The name is dismissive and was coined in parallel with the now little recognised 'horse opera' (for westerns) in the wake of the success of the term 'soap opera' (for romantic serials). Space operas were adventure sagas across the galaxies with space ships carrying intrepid crews on voyages of discovery, into glorious battles and terrifying encounters with aliens. The 'opera' part presumably refers to their seriality and overstated melodrama. At various times during the last fifty years space opera has seemed as doomed as the horse type, but sufficient examples were published to keep the sub-genre puttering along until new authors could invigorate it. This has now happened and I want in this brief note to see the change, through looking at one current writer's series to see what has been done, how it has been received and how observing the role of a particular novum (Darko Suvin's term for the imaginative invention that characterises sf) -- a machine in this case, of course -- illuminates what has happened. Because this begins with a consideration of sf history, I want to start with one of the key distinctions that has long operated in both popular and academic analysis of science fiction (though admittedly it has more currency now in the popular); that between hard and soft sf. Unsurprisingly, given how loaded those terms are, it is a gendered distinction. Hard sf is the boys' playground; technologically driven, its allegiances are to physics and engineering. From nano-widgets to space ships as big as planets, it loves machines. The boysiness of hard sf was sedimented in popular sf through the generic hegemony achieved by Hugo Gernsback in his US pulp magazine empire starting with Astounding in 1926. Space opera was the quintessential type of hard sf in the early years, though it came to be challenged if not displaced by colonisation narratives that concentrated on engineering. Soft sf, of necessity the girly stuff, has the squishy bits -- biology certainly, but also the social sciences. Both New Wave and feminist sf, the innovative sub-genres of sf in the 60s and 70s, used soft rather than hard tropes in their subsequently incorporated revisions of the genre. In the 80s, cyberpunk presented itself as the hard stuff, but this was pretty disingenuous (all that voodoo, those drugs, the excursions into various social sciences), not to mention, as Samuel Delany among others has pointed out, the way this could only be managed by denying its feminist foremothers. These days, the traces of space opera's pulp-laden past are there to be read in the way that the more serious American writers like Kim Stanley Robinson prefer sober space colonisation narratives while the truly innovative work (as well as the quality writing) is done outside the US, by a Scot -- Iain M. Banks. In addition to Banks's wondrous novels of the Culture, the revivified field includes more traditional series like Lois McMaster Bujold's Vorkosigan saga, David Weber's Honor Harrington sequence and Colin Greenland's tracing of the career of Tabitha Jute. It would not be possible to examine how Banks has remapped the field in a note such as this, but dealing with some of the more traditional examples can provide an interesting case study in the hardness of the sub-genre, as well as pointing to wider movements in the sf world. It is the latter that is evident in the way in which the male writers produce female lead and the female the male (by and large, Bujold does occasional female leads). Not that Weber makes any attempt to make Honor credible as a female, she's laughably improbable and only needs to be placed near Greenland's Tabitha Jute for the disparity to become evident. (I'm using this comparison not just for its power but also because it stops the suggestion that male writers can't produce decent female action heroes.) For the more detailled part of this I want to concentrate on Bujold's series in part to mull over why it might be that her books are dismissed as too soft and 'girly' to be good space opera. There is something of a problem in that I find the whole hard:soft distinction more than a bit juvenile and value it primarily for its power in understanding sf history. The moves to broaden the field beyond what it was so artificially limited to in early to mid-twentieth century America seem to me to be a move to a more integrated adulthood rather than the imposition of a line of squishy feminine referents to be denied or repelled. I don't see 'softness' as a negative quality (nor 'hardness' for that matter), but I am interested in why and how a space opera series with space ships, space weaponry, gadgets galore and large quantities of prime quality derring-do should be deemed soft. Bujold has written a long series of space operas set in an Earth-colonised far-future that centre on the deformed figure of Lord Miles Vorkosigan. A few other fictions are set in the same universe and link in various ways to the core texts. Not all are set on spaceships though the majority require their presence as significant features of the plot while others rely on such standards of space narrative as space stations, terra-forming and the hardware of space warfare. To dismiss Bujold's world as one where the hardness of space opera technology is subsumed in girliness, it is necessary to overlook not just great passages of certain texts, but to dismiss whole novels. The Vor Game for instance follows a long sequence at an arctic weather station which culminates in the necessary destruction of outdated toxic weaponry with an escapade across great reaches of space in a whole range of ships displaying, selling and eventually using all manner of wonderful weaponry climaxing in a battle for control of a wormhole nexus. The only woman of any narrative prominence is a evil mercenary leader ("face of an angel, mind of a rabid mongoose"). One would think that it all sounds rather a sitter as a hard piece of space opera fare written for a readership of boys of all ages. My description though so far fails to convey where it is that Bujold has updated the sub-genre. It could be that the problem lies in the same place as the updating -- in the nuancing of the character of the hero Miles Vorkosigan and the continuing delineation of the interweaving of his double life as mercenary Admiral and loyal Imperial lieutenant. Traditionally the space opera hero comes into the world if not fully formed, then at least ready for a coming-of-age tale. Bujold shows us the formation of the hero, ensuring that he remains located within his extended family. It could be that complaints come from those who would prefer their heroes not to have mothers. But then again it could be about the humour. Bujold doesn't see earnestness as desirable and writes a fantastical adventure romp. It seems to me that this is one core difference between her and fellow Baen writer David Weber. There is no predicting what a descriptive passage about technology will lead to in Bujold; it could be a novel way to win hand to hand combat or a comic sequence making a moral point about abuse of power. For Weber, a sequence of space ships and weaponry is sufficient in itself, being an opportunity to talk of model numbers and ballistic capabilities with all the narrative brio of Tom Clancy (i.e. none), but at least Clancy is usually talking about something that has an existence in the real world. When both the machine and the science it operates by are more than speculative, labouring the trainspotters'-guide-to-hyperspace-technology talk can only delight anoraks. Machines are ends in themselves for Weber, means to a narrative or characterological point in Bujold. As well as why the machine is mentioned, there is also the question of what kind of machines are favoured. Maybe over the whole sequence, Bujold pays more attention to biologically-based technologies; when she focusses on engineering it is more often as a means to a biological end (usually terraforming), though in Falling Free, the least closely linked of the novels, the biology which enables the creation of the 'quads' -- freefall workers with four arms rather than arms and legs -- is in the service of engineering advantage. The passion in her work, and despite the humour and invention, there is considerable ideologically driven passion, is reserved for her biologically based beliefs -- that physical difference should be no barrier to achievement. As is common in sf, race is incidental and not part of the argument (it is rare for any but black writers of sf to see race as a meaningful issue for the future), but sex and ability are primary. Thus Miles, whose bones were damaged while a foetus and who is short and hunched, Bel Thorne, the hermaphrodite, Taura, the genetically engineered 'perfect soldier' eight foot tall with claws and fangs, Mark, Miles's clone brother and many others who appear less frequently carry the story of difference that must not be allowed to make a difference. Where gender is concerned, the popular spread of feminism means that forceful statements of position are read as political, not as some more woolly bit of being 'nice to the afflicted'. Bujold's feminism may be old-fashioned liberal rather than radical or post-modern, but it doesn't operate by parachuting women in to narratively significant positions of power. You buy the book and you get the argument and with Cordelia, Miles's mother, inscribed as the figure of rationality, the bases are loaded. The machine around which the discourse of liberation is organised, Bujold's novum and the machine which is the focus of complaint, is the uterine replicator -- an artificial womb. In the Bujold universe this is the ultimate good machine. It was a replicator that enabled Miles to survive after teratogenic damage in utero; his first love and his mother both issued from them; and it seems like the key test of a man is his willingness or otherwise to have his wife reproduce in vitro. I suppose I can see why this offends those wedded to old-fashioned hard space opera. Traditionally, the machines that tell the men from the girls/boys/lesser beings are the ships and their weaponry, but here the machines that count replicate the uterus (ultimate squishiness) and so, far from delivering death, deliver babies. Furthermore, their entry into the narrative is almost always the cue for a disquisition on the inequities of the patriarchal society within which Bujold sets almost all her action. InMirror Dance Miles's clone brother Mark finally meets the senior Vorkosigans. He is taken to a court ball by his 'mother' who explains the dynamics of the evening in terms of the political agenda of the old men and the genetic one of the old women. The men imagine theirs is the only one but that's just an ego-serving self-delusion. ... The old men in government councils spend their lives arguing against or scheming to fund this or that piece of off-planet military hardware. Meanwhile the uterine replicator is creeping in past their guard. (296) In the most recent book,Komarr, the main female character is an abused wife with a young son and the fact that her husband required her to bear the child herself is presented as just one of the many abuses he subjects her to. When you read the various passages which discuss the uterine replicators across the books, it can be surprising to discover the insistence with which barbarity and male oppression are figured in the refusal to countenance the machine and good men are revealed by their regarding it as a valuable device. It seems almost to verge on the excessive (but then this is not how such ephemeral texts as popular space opera are read, and if one put together a collection of the passages of 'best bits of weapons admiration' that would look a bit strange too). One could, if so minded, easily dismiss the Vorkosigan adventures as a bit girly on the basis of their enjoyment of interpersonal relations, character development, or romance. If, though, one were willing to admit that only certain pieces of hardware had generically usable hardness, it might rather be possible to observe that the carping at the centrality of the wrong kind of machine identifies much more accurately what is really worrying about the whole popularity of the series -- that this machine is a Trojan Horse for the incorporation through hard technology of 'hard' feminist politics. References Bujold, Lois McMaster. Komarr. Earthlight, 1998. ---. Mirror Dance Riverdale: Baen, 1994. ---. The Vor Game. Riverdale: Baen, 1990. Delany, Samuel R. Silent Interviews: On Language, Race, Sex, Science Fiction and Some Comics. Hanover: Wesleyan UP, 1994. Suvin, Darko. Metamorphoses of Science Fiction. New Haven: Yale UP, 1979. Citation reference for this article MLA style: Frances Bonner. "The Hard Question of Squishy Machines." M/C: A Journal of Media and Culture 2.6 (1999). [your date of access] <http://www.uq.edu.au/mc/9909/bujold.php>. Chicago style: Frances Bonner, "The Hard Question of Squishy Machines," M/C: A Journal of Media and Culture 2, no. 6 (1999), <http://www.uq.edu.au/mc/9909/bujold.php> ([your date of access]). APA style: Frances Bonner. (1999) The hard question of squishy machines. M/C: A Journal of Media and Culture 2(6). <http://www.uq.edu.au/mc/9909/bujold.php> ([your date of access]).