Targeted gene and drug delivery nanosystems to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the major causes of cancer mortality worldwide, highlighting the urgent need for the development of new therapeutic approaches, such as those involving the combination of gene therapy and chemotherapy, that potentially present higher therapeutic efficacy and lesser side effects than conventional treatments. Therefore, our main goal is to develop nanosystems that have the ability to efficiently and specifically mediate these new therapeutic strategies.

In this regard, we have developed different types of nanosystems, including polymer-based, lipid-based, inorganic-based, and hybrid-based formulations. Regarding the polymer-based systems, we developed a mini-library of well-defined glycopolymers to efficiently deliver nucleic acids into target cells. The generated glycoplexes had suitable physicochemical properties, and showed high specificity for the asialoglycoprotein receptor (ASGPR) and high transfection efficiency. Moreover, we demonstrated their ability to effectively mediate antitumor gene therapy strategies, that resulted in high anticancer activity in 2D and 3D-culture models of HCC, which was significantly enhanced by the combination with small amounts of chemotherapeutic agents. On the other hand, we have been developing new hybrid nanocarriers, both silica-polymer hybrid nanosystems and polymer-lipid hybrid ones, aiming at co-loading and co-deliver chemotherapeutic agents and genetic material in target cells. In the case of the silica-polymer hybrid nanocarriers, they exhibited high ASGPR specificity and high biological activity, showing a much higher transfection activity in liver cancer cells than bare silica nanoparticles. Furthermore, we demonstrated the ability of these nanosystems to efficiently mediate a combined antitumor strategy involving HSV-TK/GCV suicide gene therapy and chemotherapy (epirubicin), in liver cancer cells. Regarding the lipid-polymer hybrid nanosystems, composed of a PLGA core coated with a pH-sensitive lipid bilayer functionalized with the targeting ligand GalNAc, they showed not only a high loading capacity of two drugs (selumetinib and perifosine), but also mediated a substantial expression of the PTEN transgene in the target HCC cells. Our results showed that this innovative formulation exhibited adequate physicochemical properties, revealing high specificity to HCC cells, and presented a high antitumor effect, demonstrated not only by the enhancement on the programmed cell death, but also by the reduction in cell proliferation capacity.

Overall, our data show that our nanosystems present a noticeable ability to efficiently and specifically deliver genetic material and drug into HCC cells, thus potentially constituting new platforms to successfully mediate novel antitumor strategies against this disease.

Henrique Faneca holds a PhD in Biochemistry from University of Coimbra. He is Principal Investigator at Center for Neuroscience and Cell Biology, University of Coimbra (CNC-UC), leading the research group Nanosystems and Targeted Antitumor Strategies. His research activity is focused on the development of different types of nanosystems that allow an efficient and specific delivery of therapeutic agents in target cells, and in the generation of new multitarget antitumor strategies, such as those involving the combination of gene therapy and chemotherapy.