An Anti-Inflammatory Poly(PhosphorHydrazone) Dendrimer Capped with AzaBisPhosphonate Groups to Treat Psoriasis

Dendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of acute and chronic inflammatory disorders in animal models. In these models, the active pharmaceutical ingredient was administered systematically (intravenous and oral administrations), but also loco-regionally in the vitreous tissue. Herein, we assessed the therapeutic efficacy of the ABP dendrimer in the preclinical mouse model of psoriasis induced by imiquimod. The ABP dendrimer was administered in phosphate-buffered saline solution via either systemic injection or topical application. We show that the topical application enabled the control of both the clinical and histopathological scores, and the control of the infiltration of macrophages in the skin of treated mice

Assessment and optimization of the therapeutic potential of an anti-inflammatory dendrimer by its formulation in catanionic vesicles for the topical treatment of psoriasis

Le psoriasis est une dermatose inflammatoire chronique. Les lésions psoriasiques sont caractérisées par une prolifération anormale des kératinocytes, une dilatation des vaisseaux sanguins dermiques et une infiltration de cellules inflammatoires dans la peau. Malgré l’efficacité des traitements anti-psoriasiques, leurs effets secondaires limitent leur utilisation à long terme. Plusieurs études réalisées dans nos équipes ont montré qu’un dendrimère de type Poly(PhosphorHydrazone) à terminaisons Azabisphosphonate, nommé ABP, présente des propriétés anti-inflammatoires in vitro et dans des modèles animaux de maladies inflammatoires chroniques. L’objectif de notre étude est d'évaluer et d’optimiser le potentiel thérapeutique de l’ABP comme une nouvelle approche pour le traitement du psoriasis. Nous avons montré que l’administration cutanée de l’ABP dans un tampon physiologique, sans formulation particulière, réduit significativement l’inflammation induite par l’imiquimod chez les souris. Toutefois, l'efficacité thérapeutique du dendrimère ABP pour le traitement topique du psoriasis doit être améliorée. En effet, la structure complexe et les propriétés de barrière du stratum corneum, mais aussi les propriétés physico-chimiques du dendrimère ABP limitent sa pénétration cutanée et donc son efficacité thérapeutique par voie cutanée. Afin de maximiser ses effets thérapeutiques, nous avons donc formulé le dendrimère dans un système de vectorisation innovant, des vésicules catanioniques tricaténaires dérivées de sucre. Ces vésicules catanioniques, développées dans notre équipe, sont formées d’une bicouche de deux tensioactifs de charges opposées. Outre leur biocompatibilité, ces vésicules catanioniques ont déjà démontré leur capacité à promouvoir la pénétration cutanée d’actifs quand leur bicouche est à l’état fluide. Après l’optimisation de la formulation du dendrimère dans les vésicules catanioniques, nous avons obtenu des vésicules stables et capables d’encapsuler environ 80% du dendrimère. Nous avons également montré que l’insertion du dendrimère dans la membrane des vésicules la rend fluide à la température de la peau. Nos études ex vivo, sur différents modèles de peaux, ont montré que la formulation du dendrimère dans les vésicules catanioniques permet une pénétration cutanée profonde du dendrimère. Enfin, des études menées sur le modèle murin de psoriasis induit par l’imiquimod ont démontré l’apport de la formulation TriCat/ABP-A dans l’amélioration des lésions psoriasiques induites par l’IMQ. L’ensemble de nos résultats mettent en avant l’efficacité de la formulation dans l’administration du dendrimère dans les couches cutanées profondes pour le traitement du psoriasis.Psoriasis is a chronic inflammatory skin disease. It is characterized by an abnormal proliferation of keratinocytes, dilation of dermal blood vessels and an infiltration of inflammatory cells into the skin. Although effective, the side effects of anti-psoriatic treatments limit their long-term use. A Poly(PhosphorHydrazone) dendrimer capped with AzaBisPhosphonate groups, called ABP, has previously been shown to have anti-inflammatory properties both in vitro and in animal models of chronic inflammatory diseases. The aim of our study is to assess and optimize the therapeutic potential of ABP dendrimer as a new approach for psoriasis therapy. We have shown that ABP dendrimer applied topically in physiological buffer, without specific formulation, significantly reduced the inflammation induced by imiquimod in mice. However, the therapeutic efficacy of the ABP dendrimer for the topical treatment of psoriasis should be improved. The barrier properties of the stratum corneum and physicochemical properties of the ABP dendrimer both contribute to limit its skin penetration and therefore its therapeutic efficacy by topical route. In order to maximize its therapeutic effects, we have formulated the dendrimer in an innovative delivery system, sugar- derived tricatenar catanionic vesicles. These catanionic vesicles, developed in our team, are formed from a bilayer of two opposite charges surfactants. In addition to their biocompatibility, these catanionic vesicles have previously demonstrated their ability to promote skin penetration of active ingredients when their bilayer is in fluid state. After optimization of dendrimer formulation in catanionic vesicles, we obtained stable vesicles capable of encapsulating approximately 80% of the dendrimer. We have also shown that the insertion of the dendrimer into the vesicular bilayer makes it fluid at skin temperature. Our studies ex vivo have successfully shown that the formulation of dendrimer in catanionic vesicles allows deep skin penetration of the dendrimer into the viable epidermis and dermis. Finally, we have demonstrated that TriCat / ABP-A formulation improves the efficacy of dendrimer in murine model of psoriasis induced by imiquimod. Altogether, our results highlight the potential of this innovative formulation to deliver dendrimer to the deeper skin layers for the treatment of psoriasis

Évaluation et optimisation du potentiel thérapeutique d'un dendrimère anti-inflammatoire par sa formulation dans des vésicules catanioniques pour le traitement topique du psoriasis

Psoriasis is a chronic inflammatory skin disease that affects 2-3% of the world's population. It is characterized by an abnormal proliferation of keratinocytes, dilation of dermal blood vessels and an infiltration of inflammatory cells into the skin. Although effective, the side effects of anti-psoriatic treatments limit their long-term use. A Poly(PhosphorHydrazone) dendrimer capped with AzaBisPhosphonate groups, called ABP, has previously been shown to have anti-inflammatory properties both in vitro and in animal models of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. The aim of our study is to assess and optimize the therapeutic potential of ABP dendrimer as a new approach for psoriasis therapy. We have shown that ABP dendrimer applied topically in physiological buffer, without specific formulation, significantly reduced the inflammation induced by imiquimod in mice. However, the therapeutic efficacy of the ABP dendrimer for the topical treatment of psoriasis should be improved. The barrier properties of the stratum corneum and physicochemical properties of the ABP dendrimer both contribute to limit its skin penetration and therefore its therapeutic efficacy by topical route. In order to maximize its therapeutic effects, we have formulated the dendrimer in an innovative delivery system, sugar-derived tricatenar catanionic vesicles. These catanionic vesicles, developed in our team, are formed from a bilayer of two opposite charges surfactants. In addition to their biocompatibility, these catanionic vesicles have previously demonstrated their ability to promote skin penetration of active ingredients when their bilayer is in fluid state. After optimization of dendrimer formulation in catanionic vesicles, we obtained stable vesicles capable of encapsulating up to 80% of the dendrimer. We have also shown that the insertion of the dendrimer into the vesicular bilayer makes it fluid at skin temperature. Our studies in vitro have successfully shown that the formulation of dendrimer in catanionic vesicles allows deep skin penetration of the dendrimer into the viable epidermis and dermis. Finally, in order to assess the anti-psoriatic efficacy of the formulation in vivo, experiments were conducted on a murine model of psoriasis induced by imiquimod. Altogether, our results highlight the potential of this innovative formulation to deliver dendrimer to the deeper skin layers for the treatment of psoriasis.Le psoriasis est une dermatose inflammatoire chronique qui affecte 2 à 3% de la population mondiale. Les lésions psoriasiques sont caractérisées par une prolifération anormale des kératinocytes, une dilatation des vaisseaux sanguins dermiques et une infiltration de cellules inflammatoires dans la peau. Malgré l’efficacité des traitements anti-psoriasiques, leurs effets secondaires limitent leur utilisation à long terme. Plusieurs études réalisées dans nos équipes ont montré qu’un dendrimère de type Poly(PhosphorHydrazone) à terminaisons AzaBisPhosphonates, nommé ABP, présente des propriétés anti-inflammatoires in vitro et dans des modèles animaux de maladies inflammatoires chroniques, telles que la polyarthrite rhumatoïde et la sclérose en plaque. L’objectif de notre étude est d'évaluer et d’optimiser le potentiel thérapeutique de l’ABP comme une nouvelle approche pour le traitement du psoriasis. Nous avons montré que l’administration topique de l’ABP dans un tampon physiologique, sans formulation particulière, réduit significativement l’inflammation induite par l’imiquimod chez les souris. Toutefois, l'efficacité thérapeutique du dendrimère ABP pour le traitement topique du psoriasis doit être améliorée. En effet, la structure complexe et les propriétés de barrière du stratum corneum, mais aussi les propriétés physico-chimiques du dendrimère ABP limitent sa pénétration cutanée et donc son efficacité thérapeutique par voie topique. Afin de maximiser ses effets thérapeutiques, nous avons formulé le dendrimère dans un système de vectorisation innovant, des vésicules catanioniques tricaténaires dérivées de sucre. Ces vésicules catanioniques, développées dans notre équipe, sont formées d’une bicouche de deux tensioactifs de charges opposées. Outre leur biocompatibilité, ces vésicules catanioniques ont déjà démontré leur capacité à promouvoir la pénétration cutanée d’actifs quand leur bicouche est à l’état fluide. Après l’optimisation de la formulation du dendrimère dans les vésicules catanioniques, nous avons obtenu des vésicules stables et capables d’encapsuler jusqu’à 80 % du dendrimère. Nous avons également montré que l’insertion du dendrimère dans la membrane des vésicules la rend fluide à la température de la peau. Nos études in vitro sur différents modèles de peaux ont montré que la formulation du dendrimère dans les vésicules catanioniques permet une pénétration cutanée profonde du dendrimère. Enfin, afin d’évaluer l’efficacité anti-psoriasique de la formulation in vivo, des expériences ont été menées sur le modèle murin de psoriasis induit par l’imiquimod. L’ensemble de nos résultats mettent en avant l’efficacité de la formulation dans la délivrance du dendrimère dans les couches cutanées profondes pour le traitement du psoriasis

Supramolecular and Macromolecular Matrix Nanocarriers for Drug Delivery in Inflammation-Associated Skin Diseases

International audienceSkin is our biggest organ. It interfaces our body with its environment. It is an efficient barrier to control the loss of water, the regulation of temperature, and infections by skin-resident and environmental pathogens. The barrier function of the skin is played by the stratum corneum (SC). It is a lipid barrier associating corneocytes (the terminally differentiated keratinocytes) and multilamellar lipid bilayers. This intricate association constitutes a very cohesive system, fully adapted to its role. One consequence of this efficient organization is the virtual impossibility for active pharmaceutical ingredients (API) to cross the SC to reach the inner layers of the skin after topical deposition. There are several ways to help a drug to cross the SC. Physical methods and chemical enhancers of permeation are a possibility. These are invasive and irritating methods. Vectorization of the drugs through nanocarriers is another way to circumvent the SC. This mini-review focuses on supramolecular and macromolecular matrices designed and implemented for skin permeation, excluding vesicular nanocarriers. Examples highlight the entrapment of anti-inflammatory API to treat inflammatory disorders of the skin

Evaluation of an anti-inflammatory dendrimer to topically treat psoriasis

International audiencePsoriasis is an auto-immune disease resulting from a chronic and exaggerated inflammation of the skin and hyperproliferation of keratinocytes. Conventional topical treatments for this disease, such as anti-inflammatory drugs, present low efficiency, and systemic administration of synthetic drugs or biologic immunomodulators can present severe side effects and/or are highly expensive. So, there is an unmet need to develop new drugs that could provide sustainable therapeutic effects. In this study, we evaluated the potential efficacy of anti-inflammatory dendrimers for the topical treatment of psoriasis. Dendrimers are hyperbranched and perfectly defined macromolecules of nanometer size, constituted of branches grafted on a central core. IMD-006, a phosphorus-based dendrimer capped with azabisphosphonate groups, has strong immuno-modulatory effects towards different immune cell types. Wetested the effects of IMD-006 in two psoriasis models: the imiquimod- induced murine model and a reconstructed human epidermis (RHE) model, in which cocktails of pro-inflammatory cytokines are used to induce psoriasis-associated changes. IMD-006 presented dose-dependent therapeutic efficacies, significantly reducing lesions and histopathological changes associated with psoriasis. Moreover, we show that IMD-006 is rapidly taken up by kerati-nocytes in 2D culture, decreasing their proliferation and increasing their differentiation. In keratinocytes in 2D culture, IMD-006 associated with mitochondria, increased mitochondrial ROS production and ultimately lysosomal degradation of these organelles. Therefore, the anti-psoriatic effect of dendrimers is, at least in part, the result of a direct effect on keratinocytes. Our results demonstrate that anti-inflammatory dendrimers are good candidates forthe topical treatment of psoriasis with a broad effect on multiple cell types involved in the development and progression of the disease

Evaluation of an anti-inflammatory dendrimer to topically treat psoriasis

International audiencePsoriasis is an auto-immune disease resulting from a chronic and exaggerated inflammation of the skin and hyperproliferation of keratinocytes. Conventional topical treatments for this disease, such as anti-inflammatory drugs, present low efficiency, and systemic administration of synthetic drugs or biologic immunomodulators can present severe side effects and/or are highly expensive. So, there is an unmet need to develop new drugs that could provide sustainable therapeutic effects. In this study, we evaluated the potential efficacy of anti-inflammatory dendrimers for the topical treatment of psoriasis. Dendrimers are hyperbranched and perfectly defined macromolecules of nanometer size, constituted of branches grafted on a central core. IMD-006, a phosphorus-based dendrimer capped with azabisphosphonate groups, has strong immuno-modulatory effects towards different immune cell types. Wetested the effects of IMD-006 in two psoriasis models: the imiquimod- induced murine model and a reconstructed human epidermis (RHE) model, in which cocktails of pro-inflammatory cytokines are used to induce psoriasis-associated changes. IMD-006 presented dose-dependent therapeutic efficacies, significantly reducing lesions and histopathological changes associated with psoriasis. Moreover, we show that IMD-006 is rapidly taken up by kerati-nocytes in 2D culture, decreasing their proliferation and increasing their differentiation. In keratinocytes in 2D culture, IMD-006 associated with mitochondria, increased mitochondrial ROS production and ultimately lysosomal degradation of these organelles. Therefore, the anti-psoriatic effect of dendrimers is, at least in part, the result of a direct effect on keratinocytes. Our results demonstrate that anti-inflammatory dendrimers are good candidates forthe topical treatment of psoriasis with a broad effect on multiple cell types involved in the development and progression of the disease

Evaluation of an anti-inflammatory dendrimer to topically treat psoriasis

International audiencePsoriasis is an auto-immune disease resulting from a chronic and exaggerated inflammation of the skin and hyperproliferation of keratinocytes. Conventional topical treatments for this disease, such as anti-inflammatory drugs, present low efficiency, and systemic administration of synthetic drugs or biologic immunomodulators can present severe side effects and/or are highly expensive. So, there is an unmet need to develop new drugs that could provide sustainable therapeutic effects. In this study, we evaluated the potential efficacy of anti-inflammatory dendrimers for the topical treatment of psoriasis. Dendrimers are hyperbranched and perfectly defined macromolecules of nanometer size, constituted of branches grafted on a central core. IMD-006, a phosphorus-based dendrimer capped with azabisphosphonate groups, has strong immuno-modulatory effects towards different immune cell types. Wetested the effects of IMD-006 in two psoriasis models: the imiquimod- induced murine model and a reconstructed human epidermis (RHE) model, in which cocktails of pro-inflammatory cytokines are used to induce psoriasis-associated changes. IMD-006 presented dose-dependent therapeutic efficacies, significantly reducing lesions and histopathological changes associated with psoriasis. Moreover, we show that IMD-006 is rapidly taken up by kerati-nocytes in 2D culture, decreasing their proliferation and increasing their differentiation. In keratinocytes in 2D culture, IMD-006 associated with mitochondria, increased mitochondrial ROS production and ultimately lysosomal degradation of these organelles. Therefore, the anti-psoriatic effect of dendrimers is, at least in part, the result of a direct effect on keratinocytes. Our results demonstrate that anti-inflammatory dendrimers are good candidates forthe topical treatment of psoriasis with a broad effect on multiple cell types involved in the development and progression of the disease

An Anti-Inflammatory Poly(PhosphorHydrazone) Dendrimer Capped with AzaBisPhosphonate Groups to Treat Psoriasis

International audienceDendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of acute and chronic inflammatory disorders in animal models. In these models, the active pharmaceutical ingredient was administered systematically (intravenous and oral administrations), but also loco-regionally in the vitreous tissue. Herein, we assessed the therapeutic efficacy of the ABP dendrimer in the preclinical mouse model of psoriasis induced by imiquimod. The ABP dendrimer was administered in phosphate-buffered saline solution via either systemic injection or topical application. We show that the topical application enabled the control of both the clinical and histopathological scores, and the control of the infiltration of macrophages in the skin of treated mice