Topical dermal delivery of anti-inflammatory drugs with catanionic vesicles for the treatment of psoriasis – TANDANSS

The TANDANSS project proposes to use catanionic vesicles, i.e., mixtures of cationic and anionic amphiphiles, as an innovative candidate to help the anti-inflammatory drugs to go into the deep tissues taking into account that these catanionic systems have shown to be able to interact and fuse with lipid membranes.
In addition to classical steroidal and non-steroidal anti-inflammatory drugs, a new generation of dendritic anti-inflammatory drugs (in preclinical development to treat Chronic Inflammatory Diseases like Rheumatoid Arthritis and Multiple Sclerosis via systemic administration) will also be tested. One of this non-formulated drug candidate has actually shown promising topical efficacy in vivo in an Imiquimod-induced mouse model of psoriasis.Two analogs of this drug candidate will be synthesized and tested in this TANDANSS project.
One of the key concern lies in the comparison of the in vitro anti-inflammatory properties of the formulated drugs with the properties of the non-formulated ones. Another aspect concerns the effect of these formulations on skin and the impact of their physicochemical properties on the drug permeation properties. The TANDANSS project will imply the measurement of skin permeation properties thanks to in vitro assays on human skin models and validated ex vivo on human living cell models. Psoriasis being the relevant skin inflammation pathology targeted by the TANDANSS project, key information will also be gathered by studying in vitro the effect of the formulated drugs on immune-competent skin cells, including keratinocytes. These data will be completed by in vivo studies on the anti-inflammatory and immunomodulatory properties of the formulations on psoriasis mouse models.

- Synthesis of an innovative dendrimer: the G1 (PTPA) ABP dendrimer is a new compound resulting from a new modular synthesis of phosphorus dendrimers with poly-thiophosphoramidate (PTPA).
- Stable formulation with high encapsulation rate: This process involving a water-insoluble dendrimer precursor increases its insertion capacity in the hydrophobic part of the vesicles and thus obtains an encapsulation rate greater than 80%, and to simply separate the non-encapsulated active ingredient by filtration.
- Increased skin penetration using catanionic vesicles: The phase transition temperature of the vesicles being close to the temperature of the skin, these systems become fluid upon contact and are capable of increasing the skin penetration of the active in the deep layers of the skin.
- Confirmation of the therapeutic efficacy of the G1 (PPH) ABP dendrimer for reducing psoriasiform skin inflammation induced by imiquimod in mice.

We will now compare the therapeutic efficacy of the new dendrimers and the different formulations will be compare on the psoriasis-like skin inflammation induced in mice by imiquimod. We aim in particular to characterize the immune infiltrate. The efficacy will be confirmed using human models of the disease. To understand the mechanisms of action underlying the therapeutic efficacy, the penetration and effects of the different dendrimers, formulated or not, on human keratinocytes in 2D or 3D culture (proliferation, differentiation, production of cytokines, etc.) will be analyzed. Their immunomodulatory properties will also be tested on human monocytes.

1. Dendrimères à motifs thiophosphoramidate et dérivés. J. Aujard-Catot, A. Oukhrib, R. Poupot, C.O. Turrin, brevet français n° FR1915518, déposé le 23 décembre 2019
2. Formulation d’un dendrimère anti-inflammatoire pour le traitement de psoriasis. M. Blanzat, R. Jebbawi, R. Poupot, C.O. Turrin, brevet français n° FR1915517, déposé le 23 décembre 2019

The TANDANSS project proposes an innovative and competitive positioning that could bring about decisive advances to extend the knowledge related to acute health and wellness societal issues associated to chronic skin inflammatory diseases, and in particular psoriasis. Currently, treatment of psoriasis includes topical therapy, systemic therapy and phototherapy. The topical administration of anti-inflammatory drugs and steroidal drugs is the first line of treatment and the most practical medication method for psoriasis patients. However, the conventional topical treatments have low efficiency and are replaced, for the most severe forms of the disease, by systemic administration of synthetic drugs with severe side effects or by aggressive phototherapy. In this regard, biologic immunomodulators are often criticized because they are highly expensive (15000 to 20000 €/y/patient) and because they can cause severe (sometimes lethal) side effects, as shown by the withdrawal of several of them by regulatory agencies after the death of patients under treatment. There is undoubtedly an unmet societal need for the development of alternative, non “biologics-like” new drugs that could provide sustainable remissions and life quality improvements for patients, as an alternative to the current strategies.
A promising strategy to overcome these problems includes the development of a suitable drug carrier system to achieve controlled and localized delivery of the anti-inflammatory drugs and to provide penetration enhancement to the drugs deep into the tissue according to the specific therapeutic needs. The challenge of this project is to design nanovectors carrying potent anti-inflammatory compounds to provide deep dermal penetration to the drug. Vesicular systems, and especially fluid and/or deformable vesicles, are of great interest in the dermal delivery field as they offer control on drug bioavailability and skin permeation enhancement, if they can deform or fuse with skin lipids. The TANDANSS project proposes to use catanionic vesicles, i.e., mixtures of cationic and anionic amphiphiles, as an innovative candidate to help the anti-inflammatory drugs to go in the deep tissues taking into account that these catanionic systems have shown to be able to interact and fuse with lipid membranes. It should be emphasized that a proof of concept related to the penetration enhancement potential of such a vesicular system has been patented for cosmetic applications with the Affichem company (Toulouse, France).
In addition to classical steroidal and non-steroidal anti-inflammatory drugs, a new generation of dendritic anti-inflammatory drug (in preclinical development to treat Chronic Inflammatory Diseases (CIDs) like Rheumatoid Arthritis and Multiple Sclerosis via systemic administration) will also be tested. This non-formulated drug candidate has actually shown promising topical efficacy in vivo in an Imiquimob-induced mouse model of psoriasis (unpublished results of the consortium).
One of the key concern lies in the comparison of the in vitro anti-inflammatory properties of the three formulated drugs with the properties of the non-formulated one. Another aspect concerns the effect of these formulations on skin and the impact of the drug physicochemical properties on the formulations permeation properties. The TANDANSS project will imply the measurement of skin permeation properties thanks to in vitro assays on human skin models and validated ex vivo on human living cell models. Psoriasis being the relevant skin inflammation pathology targeted by the TANDANSS project, key information will also be gathered by studying in vitro the effect of the formulated drugs on immune-competent skin cells, and these data will be completed by in vivo studies on the anti-inflammatory and immunomodulatory properties of the formulations on psoriasis mouse models.