siRNA nanoformulation against the Ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma

Delivery is a very important concern for therapeutic applications of siRNA. In this study, we have used chitosan-coated poly(isobutylcyanoacrylate) nanoparticles to deliver siRNA with a complementary sequence to the fusion oncogene ret/PTC1. By screening the mRNA junction we have selected a potent siRNA sequence able to inhibit this oncogene in a model of Papillary Thyroid Carcinoma cells. This siRNA sequence has then been validated by a shRNA approach using the same sequence. Furthermore, the high ret/PTC1 inhibition has triggered a phenotypic reversion of the transformed cells. We have designed well-defined chitosan decorated nanoparticles and succeeded to reduce their size. They have allowed to protect ret/PTC1 siRNA from in vivo degradation and leading to significant tumour growth inhibition after intratumoral administration

Nanodiamond as a vector for siRNA delivery to Ewing sarcoma cells

We investigated the ability of diamond nanoparticles (nanodiamonds, NDs) to deliver small interfering RNA (siRNA) in Ewing sarcoma cells, in the perspective of in vivo anti-cancer nucleic acid drug delivery. siRNA was adsorbed onto NDs previously coated with cationic polymer. Cell uptake of NDs has been demonstrated by taking advantage of NDs intrinsic fluorescence coming from embedded color center defects. Cell toxicity of these coated NDs was shown to be low. Consistent with the internalization efficacy, we have shown a specific inhibition of EWS/Fli-1 gene expression at the mRNA and protein level by the ND vectorized siRNA in a serum containing medium

Chitosan and its derivatives as nanocarriers for siRNA delivery

The ability to specifically silence genes using siRNA has enormous potential for treating genetic diseases. However, siRNA instability and biodistribution issues still need to be overcome, and adequate delivery vehicles have proven indispensable in conveying siRNA to its target. Chitosan is a promising biopolymer for siRNA delivery, its interest stemming from its safety, biodegradability, mucoadhesivity, permeation enhancing effect and cationic charge, as well as amenability to undergo chemical modifications. Chitosan and its derivatives can be readily arranged into complexes or nanoparticles able to entrap and carry siRNA. Specific strategies have been adopted to improve chitosan-based vectors with regard to transfectability. However, further efforts are required to verify their value and adapt them to enhance therapeutic output prior to clinical application. This review emphasizes the potential of chitosan and its derivatives to develop nanocarriers for siRNA delivery. The properties of chitosan that are significant for transfectability and the most relevant findings are assessed

Nanotechnology and the Treatment of HIV Infection

Suboptimal adherence, toxicity, drug resistance and viral reservoirs make the lifelong treatment of HIV infection challenging. The emerging field of nanotechnology may play an important role in addressing these challenges by creating drugs that possess pharmacological advantages arising out of unique phenomena that occur at the “nano” scale. At these dimensions, particles have physicochemical properties that are distinct from those of bulk materials or single molecules or atoms. In this review, basic concepts and terms in nanotechnology are defined, and examples are provided of how nanopharmaceuticals such as nanocrystals, nanocapsules, nanoparticles, solid lipid nanoparticles, nanocarriers, micelles, liposomes and dendrimers have been investigated as potential anti-HIV therapies. Such drugs may, for example, be used to optimize the pharmacological characteristics of known antiretrovirals, deliver anti-HIV nucleic acids into infected cells or achieve targeted delivery of antivirals to the immune system, brain or latent reservoirs. Also, nanopharmaceuticals themselves may possess anti-HIV activity. However several hurdles remain, including toxicity, unwanted biological interactions and the difficulty and cost of large-scale synthesis of nanopharmaceuticals

Développement d'une formulation à base de nanoparticules pour la libération de siRNA dans un modèle de carcinome papillaire de la thyroïde

L intérêt d utiliser des nanoparticules en tant que vecteurs de siRNAs est leur capacité à protéger ces derniers de la dégradation par les nucléases et également de leur permettre d être délivrés au niveau de leur cible thérapeutique. Afin d appuyer cette théorie, ce travail s est concentré sur le modèle du carcinome papillaire de la thyroïde. Dans le but de mettre en place une formulation médicamenteuse, une séquence de siRNA ciblant spécifiquement l oncogène ret/PTC1 impliqué dans le développement de ce cancer a été identifiée. Sous forme de siRNA et également de shRNA, cette séquence a montré une efficacité à inhiber l expression du gène ret/PTC1 in vitro et in vivo chez la souris. Pour permettre une administration intraveineuse du siRNA actif, ce dernier a été associé à un vecteur constitué par des nanoparticules de type cœur-couronne. Ces nanoparticles à cœur de poly(cyanoacrylates) d alkyles sont recouvertes par du chitosan qui permet d adsorber le siRNA. Certaines formulations du siRNA vectorisé ont montré une très bonne efficacité antitumorale après avoir été injectées chez la souris par voie intratumorale et également par voie intraveineuse. Enfin, un modèle d étude de la fonctionnalisation de la surface des nanoparticules a été proposé en vue d apporter une spécificité de ciblage des cellules tumorales au vecteur développé.At first, the aim of this work was to identify an efficient sequence of siRNA against the ret/PTC1 oncogene involved in the development of papillary thyroid carcinoma. This sequence was shown to down-regulate the expression of ret/PTC1 oncogene in vitro and in vivo in mice after administration as a siRNA and after integration in a shRNA. As a second goal of this work, the active siRNA was formulated in nanoparticulate formulations to allow in vivo administration in mice bearing model ret/PTC1 tumor by intratumoral and intravenous routes. Some formulations of the vectorized siRNA were found efficient to reduce tumor growth including after intravenous administration. In the last part of this work, a methodology was developed to add cell recognition properties to the nanoparticles to further improve their targeting specificity toward the tumor cells.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

siRNA nanoformulation against the ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma.

In this study, we have used chitosan-coated poly(isobutylcyanoacrylate) nanoparticles to deliver siRNA with a complementary sequence to the fusion oncogene ret/PTC1. By screening the mRNA junction we have selected a potent siRNA sequence able to inhibit this oncogene in a model of Papillary Thyroid Carcinoma cells. This siRNA sequence has then been validated by a shRNA approach using the same sequence. Furthermore, the high ret/PTC1 inhibition has triggered a phenotypic reversion of the transformed cells. We have designed well-defined chitosan decorated nanoparticles and succeeded to reduce their size. They have allowed to protect ret/PTC1 siRNA from in vivo degradation and leading to significant tumour growth inhibition after intratumoral administration