Periodic Reporting for period 1 - SQUALAC (Preclinical development of squalenic acid and gemcitabine squalene nanomedicine)
Periodo di rendicontazione: 2015-03-01 al 2016-08-31
We have discovered that the linkage of squalene (a natural lipid) to drugs, confers to the resulting bioconjugates the remarkable property to self-assemble as nanoparticles, due to the folded molecular conformation of squalene. This approach is unique and has never been used before. The so called "squalenoylation" technology may be considered as a generic platform to construct nanomedicines. Remarkably, it was shown that these nanomedicines were more efficient and less toxic than the parent drugs. The gemcitabine-squalene (Gem-SQ) nanomedicine, our first candidate for further pharmaceutical developments, was shown not only to display an impressive anticancer activity in experimental tumors but also to overcome drug resistance, thus addressing a major challenge in tumor therapy. These pre-clinical data deserve further development towards translation into the clinic for the treatment of the pancreatic cancer, a devastating disease. However, the squalenic acid (SQCO2H), the chemical template essential for the synthesis of the Gem-SQ bioconjugate, was obtained through the Van Tamelen reaction which cannot be employed for the preparation of a clinical sample of Gem-SQ, because of the use of CrO3 (a toxic compound) and the poor yield of the reaction. Therefore, the synthesis of SQCO2H represents a lock for further clinical development of our Gem-SQ nanomedicine. The goals of the SQUALAC PoC are : (i) to perform the synthesis of SQCO2H avoiding the use of CrO3 and (ii) further scaling-up and acceptable preparation of Gem-SQ nanoparticles.
In the course of this project, we looked for alternative oxidizing agents. After many attempts, we discovered that the required oxidation steps could be efficiently performed using a Sulfur (VI) oxidizing agent and that the trisnor-squalenic acid could be obtained through this chemical pathway with a 60-65% yield. With the help of a patent attorney, the patentability of this important finding was investigated and it was, however, concluded that the synthesis pathway was new, but that the step of inventiveness was not sufficient for patenting. The scaling-up of the preparation of Gem-SQ nanoparticles has been further investigated through microfluidics experiments to identify the key parameters and the nanoparticles were successfully freeze-dryed in order to provide stable conservation of the nanoparticle sample. Finally, the added value and market positioning of Gemcitabine-Squalene nanoparticles has been investigated by Efficient Innovation as subcontractor and it was concluded that the Gem-SQ nanomedicine represents an interesting improved delivery formulation of Gemcitabine but that a very limited number of pharmaceutical companies are still currently interested in the development of small molecules as cytostatics. In addition, preclinical deal value seems very limited to an up-front of around $1M (based on comparative deals).
In the course of this project, we looked for alternative oxidizing agents. After many attempts, we discovered that the required oxidation steps could be efficiently performed using a Sulfur (VI) oxidizing agent and that the trisnor-squalenic acid could be obtained through this chemical pathway with a 60-65% yield. With the help of a patent attorney, the patentability of this important finding was investigated and it was, however, concluded that the synthesis pathway was new, but that the step of inventiveness was not sufficient for patenting. The scaling-up of the preparation of Gem-SQ nanoparticles has been further investigated through microfluidics experiments to identify the key parameters and the nanoparticles were successfully freeze-dryed in order to provide stable conservation of the nanoparticle sample. Finally, the added value and market positioning of Gemcitabine-Squalene nanoparticles has been investigated by Efficient Innovation as subcontractor and it was concluded that the Gem-SQ nanomedicine represents an interesting improved delivery formulation of Gemcitabine but that a very limited number of pharmaceutical companies are still currently interested in the development of small molecules as cytostatics. In addition, preclinical deal value seems very limited to an up-front of around $1M (based on comparative deals).