Liposomes for Use in Gene Delivery

Liposomes have a wide array of uses that have been continuously expanded and improved upon since first being observed to self-assemble into vesicular structures. These arrangements can be found in many shapes and sizes depending on lipid composition. Liposomes are often used to deliver a molecular cargo such as DNA for therapeutic benefit. The lipids used to form such lipoplexes can be cationic, anionic, neutral, or a mixture thereof. Herein physical packing parameters and specific lipids used for gene delivery will be discussed, with lipids classified according to overall charge

Chitosan-Graft-Branched Polyethylenimine Copolymers: Influence of Degree of Grafting on Transfection Behavior

BACKGROUND: Successful non-viral gene delivery currently requires compromises to achieve useful transfection levels while minimizing toxicity. Despite high molecular weight (MW) branched polyethylenimine (bPEI) is considered the gold standard polymeric transfectant, it suffers from high cytotoxicity. Inversely, its low MW counterpart is less toxic and effective in transfection. Moreover, chitosan is a highly biocompatible and biodegradable polymer but characterized by very low transfection efficiency. In this scenario, a straightforward approach widely exploited to develop effective transfectants relies on the synthesis of chitosan-graft-low MW bPEIs (Chi-g-bPEI(x)) but, despite the vast amount of work that has been done in developing promising polymeric assemblies, the possible influence of the degree of grafting on the overall behavior of copolymers for gene delivery has been largely overlooked. METHODOLOGY/PRINCIPAL FINDINGS: With the aim of providing a comprehensive evaluation of the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of copolymeric vectors, we have synthesized seven Chi-g-bPEI(x) derivatives with a variable amount of bPEI grafts (minimum: 0.6%; maximum: 8.8%). Along the Chi-g-bPEI(x) series, the higher the degree of grafting, the greater the ζ-potential and the cytotoxicity of the resulting polyplexes. Most important, in all cell lines tested the intermediate degree of grafting of 2.7% conferred low cytotoxicity and higher transfection efficiency compared to other Chi-g-bPEI(x) copolymers. We emphasize that, in transfection experiments carried out in primary articular chondrocytes, Chi-g-bPEI(2.7%) was as effective as and less cytotoxic than the gold standard 25 kDa bPEI. CONCLUSIONS/SIGNIFICANCE: This work underlines for the first time the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of Chi-g-bPEI(x) copolymers. Crucially, we have demonstrated that, along the copolymer series, the fine tuning of the degree of grafting directly affected the overall charge of polyplexes and, altogether, had a direct effect on cytotoxicity

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

Introducing small DNA molecules (Dbait) impairs the repair of damaged chromosomes and provides a new method for enhancing the efficiency of radiotherapy in radio-resistant tumors. The radiosensitizing activity is dependent upon the efficient delivery of Dbait molecules into the tumor cells. Different strategies have been compared, to improve this key step. We developed a pipeline of assays to select the most efficient nanoparticles and administration protocols before preclinical assays: (i) molecular analyses of complexes formed with Dbait molecules, (ii) cellular tests for Dbait uptake and activity, (iii) live zebrafish embryo confocal microscopy monitoring for in vivo distribution and biological activity of the nanoparticles and (iv) tumor growth and survival measurement on mice with xenografted tumors. Two classes of nanoparticles were compared, polycationic polymers with linear or branched polyethylenimine (PEI) and covalently attached cholesterol (coDbait). The most efficient Dbait transfection was observed with linear PEI complexes, in vitro and in vivo. Doses of coDbait ten-fold higher than PEI/Dbait nanoparticles, and pretreatment with chloroquine, were required to obtain the same antitumoral effect on xenografted melanoma. However, with a 22-fold lower ‘efficacy dose/toxicity dose' ratio as compared with Dbait/PEI, coDbait was selected for clinical trials

DNA vaccination for prostate cancer: key concepts and considerations

While locally confined prostate cancer is associated with a low five year mortality rate, advanced or metastatic disease remains a major challenge for healthcare professionals to treat and is usually terminal. As such, there is a need for the development of new, efficacious therapies for prostate cancer. Immunotherapy represents a promising approach where the host’s immune system is harnessed to mount an anti-tumour effect, and the licensing of the first prostate cancer specific immunotherapy in 2010 has opened the door for other immunotherapies to gain regulatory approval. Among these strategies DNA vaccines are an attractive option in terms of their ability to elicit a highly specific, potent and wide-sweeping immune response. Several DNA vaccines have been tested for prostate cancer and while they have demonstrated a good safety profile they have faced problems with low efficacy and immunogenicity compared to other immunotherapeutic approaches. This review focuses on the positive aspects of DNA vaccines for prostate cancer that have been assessed in preclinical and clinical trials thus far and examines the key considerations that must be employed to improve the efficacy and immunogenicity of these vaccines

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Περιέχει την περίληψηΜέσα στα πλαίσια της Κοινωνίας της Πληροφορίας οι βιβλιοθηκονόμοι διεκδικούν, άλλοτε πετυχημένα, άλλοτε όχι και τόσο, ένα πιο ενεργό και απαιτητικό ρόλο, προβάλλοντας το επιχείρημα πώς όσο μεγαλύτερη είναι η παραγωγή πληροφορίας και γνώσης και η παροχή πληροφόρησης τόσο mo απαιτητική είναι και η διαδικασία που αναγκάζεται να ακολουθήσει ο χρήστης ώστε να ικανοποιήσει τις ανάγκες του. Αλλά, η αναγκαιότητα του βιβλιοθηκονόμου (ως επιστήμονα της πληροφόρησης πλέον), του διαμεσολαβητή, δηλαδή, ανάμεσα στην πληροφορία και στον χρήστη, δικαιολογεί απαραιτήτως και την αναγκαιότητα για την ίδια τη Βιβλιοθήκη; Τεκμηριώνεται, δηλαδή, η ύπαρξη αυτού του οργανισμού ως μη κερδοσκοπικού, πολιτιστικού ιδρύματος που εξυπηρετεί όχι μόνο πληροφοριακές αλλά και ψυχαγωγικές, εκπαιδευτικές, κοινωνικοοικονομικές ανάγκες των επισκεπτών του; Και τότε, το έργο του βιβλιοθηκονόμου πώς προδιαγράφεται; Ποιο το περιεχόμενο και ο τρόπος της διαμεσολάβησης; Πρόκειται για σύνθεση ή μηχανιστική διάδοση της πληροφορίας; Αν η Πληροφορία διακινείται, στις μέρες μας κυρίως και πρωτίστως, με ηλεκτρονικά μέσα, τότε το αυτονόητο της ύπαρξης ενός απτού οικοδομήματος που στεγάζει την πληροφορία παύει να ισχύει και είτε πρέπει να καταλυθεί, είτε να εφευρεθεί από την αρχή, προσδίδοντας νέα επίκαιρα χαρακτηριστικά σε ένα αρχαιότατο κατασκεύασμα