Crystalline liquid geleification systems in situ after subcutaneous and intratumoral administration for sustained siRNA release in skin cancer therapy

The RNA interference mechanism is an event of gene repression through the degradation of messenger RNA. This way, it is possible to eliminate the expression of a certain gene, making siRNA a promising therapy for the treatment of several serious diseases, such as cancer. However, for its effective therapeutic application it is necessary to develop delivery systems capable of releasing siRNA in target cells, promoting their cell internalization and preventing its degradation. For the treatment of cancer, where there is high cell proliferation and the effect of siRNA is for a few days, it is interesting to develop systems that promote sustained release of siRNA. A system that has this characteristic are liquid formulations based on lipids or amphilyls that form liquid crystals that are transformed in situ into liquid crystalline gels by self-assembling mechanisms, in the case caused by the absorption of water from the biological environment of the administration site. (subcutaneous or intratumoral). Preliminary results from our research group using formulations based on structural lipids (monolein) and complexing cationic components of siRNA (oleylamine and polyethyleneimine) showed that they are capable of promoting sustained release after gelation, as well as forming complexes with siRNA, being still biocompatible and biodegradable. In this context, the objective of the present project is to develop a delivery system based on precursor liquid formulations for in situ formation of crystalline liquid phase gels after subcutaneous and intratumoral administration, aiming to make gene therapy viable as a new approach for the treatment of severe skin pathologies, where local drug administration is an advantage. The specific objectives of this project include: Standardization of the process for obtaining sterile precursor formulations capable of gelling in situ for parenteral use.