The specific activity carried out by the Laboratory of Biocompatible Polymers of the Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) of the University of Palermo, focused on the development of new therapeutic strategies for hepatocellular carcinoma, setting as key objectives the improvement of the bioavailability and therapeutic index of anticancer active ingredients, as well as their controlled and targeted release that would allow a selective efficacy accompanied by a reduction of the most disabling side effects.
Three approaches have been developed:
1. Production and characterization of nano-sized targeted drug delivery systems (TDDSs) with the aim of efficiently and selectively conveying the most used and/or most promising anticancer drugs for the treatment of hepatocarcinoma, such as Sorafenib and Lenvatinib. For the production of these nanosystems, a patented polymer was used as the starting material (Pitarresi G, Cervello M, Azzolina A, Puleio R, Loria GR, Puleo S, Giammona G. Nanoparticles for controlled release of sorafenib and sorafenib derivatives, WO 2018/150302 A1) and pubblishing (Cervello M, Pitarresi G, Volpe AB, Porsio B, Balasus D, Emma MR, Azzolina A, Puleio R, Loria GR, Puleo S, Giammona G., Nanoparticles of a polyaspartamide-based brush copolymer for modified release of sorafenib: In vitro and in vivo evaluation, J. Control. Release 266 (2017) 47-56) which has already been found to be very beneficial for the preparation of nanoparticles for the modified release of Sorafenib in the treatment of hepatocarcinoma. PBBD has been used for the formulation of nanosystems resulting in nanometer size particles (NPBBDs), with a good polydispersity index and negative surface potential.
The NPBBD systems obtained were further characterized by evaluating the amount of directing agent on the surface of the nanoaggregates, available for possible recognition by the target cells. The values obtained were adequate to obtain an active direction, suggesting that the NPBBD nanosystem may be able to reach the target site both by passive direction, due to nanometric dimensions, and active direction, by recognition between the directing agent and the target site. In light of these encouraging results, experimental conditions were subsequently developed to obtain PBB and PBBD-based nanoparticles containing adequate amounts of Sorafenib or Lenvatinib. In vitro release studies under simulated physiological conditions have shown the ability of these nanosystems to release selected drugs in a controlled manner.
2. Production and characterization of polymeric nanoparticles functionalized with directing agent and containing gold nanorods in order to selectively release an anticancer drug (Sorafenib or Lenvatinib) and generate heat (hyperthermic effect) in a controlled manner. in particular, the excellent near-infrared photothermic (NIR) conversion capacity of gold nanorods (AuRNs) with the capacity of the galactose-derived PBB polymer (GAL), a directing agent for hepatocarcinoma cells that overexpress receptors for asialoglicoproteins, were combined in a single nanosystem.
Therefore, the experimental conditions were developed to adequately derivatize PBB with galactose and to incorporate within the nanoparticles of PBB-GAL, AuNRs in turn coated with a thiolate fatty acid that allows an adequate internalization in the core of the nanoparticles.
The latter were prepared by a nanoprecipitation process that allowed the obtaining of hybrid nanosystems with a diameter of about 200 nm and an efficient amount of incorporated drug (9% of Sorafenib and 5.4% of Lenvatinib). Thanks to the presence of AuNRs, these nanosystems have shown the ability to convert NIR radiation into heat and release the embedded drugs remotely-controlled. Both the biocompatibility and synergistic effects of the combination of chemotherapy and phototherapy were evaluated in vitro, as well as the internalization of receptor-mediated nanosystems was evaluated in vitro, using model cell lines.
3. Production and characterization of nanogels for theranostics in which in addition to the polymeric component there are elements that allow both diagnostic imaging and hyperthermia and the localized release of Sorafenib and Lenvatinib. In particular, starting from an appropriate biocompatible polymer functionalized with a directing agent, nanogels containing in addition to the selected anticancer drugs, also nanocarbon dots and graphene oxide were prepared and characterized.
The presence of nanocarbon dots allows to obtain information on the tumor mass through fluorescence imaging while graphene oxide allows to obtain a NIR-induced photothermal therapy thanks to the generation of heat following short irradiation with low-power radiation (physiotherapy laser; λ = 810 nm) which combines with the cytotoxic effect on cancer cells due to the release of the anticancer drug from the nanogel.
