A Clinically Relevant Case Study: the Development of Livatag® for the Treatment of Advanced Hepatocellular Carcinoma

A journey through the emergence of nanomedicines with poly(alkylcyanoacrylate) based nanoparticles

“…Very first biodistribution studies of early liposomes and PACA nanoparticles have revealed that intravenously injected man-made nano-objects were sequestrated by the immune system of the host [Gregoriadis, 1977, Couvreur et al, 1980a, Kante et al, 1980, Oppenheim, 1981. This found interest for targeting drugs to intracellularly infected macrophages [Fattal et al 1989, Abed and Couvreur, 2014, Abeb et al, 2015, Jiang et al, 2018 and to other liver disease such as liver cancer [Chiannilkulchai et al 1989, Reddy and Couvreur, 2011, Soma et al, 2012, Merle et al 2015, Lu et al, 2018. However, sequestration of nanoparticles by the immune system is a considerable obstacle to achieve drug delivery to disease tissues localized in organs that are not the main seats of the immune system.…”

“…Today, we know that these side effects were the consequence of a complement activation-related pseudoallergy [CARPA] reaction that may occur with some patients following injections of nanomedicines and were later understood from the work of Szebeni and his coworkers [Szebeni et al, 1999, Szebeni, 2014. The reaction can be managed but it was responsible for a few dramatic accidents in the course of several early clinical trials conducted on nanomedicines [Szebeni et al, 1999, Barrenholz, 2012, Soma et al,2012, Szebeni 2014, Merle et al, 2017, Moghimi, 2018. Regarding the pharmacological activity of the polymer nanoparticle formulation of doxorubicin, this clinical study has revealed a superior therapeutic index of doxorubicin administered with the nanoparticles compared to that of the free drug with no cardiotoxicity.…”

“…Despite promising results, the clinical evaluation of the dox-PIHCA nanoparticles was not continued due to major changes in the organization of the sponsors' company. Search for sponsors to support clinical translation of the first nanomedicines was tedious for pioneers [Kreuter, 2007, Barrenholz, 2012 [Soma et al, 2012, Merle et al, 2017 [Later named Livatag®] and was proposed as a treatment of advanced HCC. This deadly drug resistant cancer of the liver remained without therapeutic option at the time of the start of the clinical trial in 2004 [EU/3/04/229 EUDRACT 2006-004088-77] [Keating and Santoro, 2009, Giglia et al, 2010, Cucchetti et al, 2017, Desai et al, 2017, Lu et al, 2018, Raoul et al, 2018.…”

“…This work marked a milestone. It immediately raised a growing interest to polymer nanoparticles as potential drug delivery system and, later, have paved the way for clinical trials [Oppenheim, 1981, Couvreur, 1984, Kreuter, 1983, Douglas et al, 1987, Kattan et al 1992, Soma et al, 2012, Zhou et al, 2009. The context in which this initial work was completed was favourable for the development of polymer-based drug carriers.…”

Radical Polymerization of Alkyl 2-Cyanoacrylates

“…Nanoparticles based on CAs are considered promising polymer colloidal drug delivery systems, and have been significantly studied for cancer therapy with certain formulations reaching Phases III in clinical trials [100]. …”