Abstract 174: Preclinical activity of new liposomal formulation of doxorubicin (TLD-1)

Abstract

Abstract Background: InnoMedica is a young company with focus on clinical translation of nanomedicine. The company employs its own manufacturing technology that gives rise to a novel liposome platform. The platform allows for specific shaping of nanosurfaces. This leads to a myriad of different particle designs with highly distinct biological functions. In a first approach, the lead-formulation TLD-1 (targeted liposomal doxorubicin) was developed in order to ameliorate chemotherapeutic outcome for patients, taking into account the patterns of biodistribution in the entire organism as well as nanoparticle-cell interactions and subcellular localisation. Methods: Pharmacologic properties of TLD-1 were investigated in vitro and in vivo. Human ovarian cancer cells A2780 were cultured in both 2D and 3D settings and antineoplastic activity of different formulations of doxorubicin was measured by quantification of cell viability. The same formulations were also compared in three animal models of cancer including murine breast cancer 4T1, human breast cancer MDA-MB231, and A2780. MDA-MB231 and A2780 cells were grown in vitro and injected subcutaneously (sc) in immunodeficient mice (Athymic Nude-Foxn1nu). 4T1 cells were injected either sc or in the mammary fat pad of immunocompetent mice (BALB/c). The different drug products were injected intravenously twice weekly for a total of three weeks. Activity was determined with caliper measurements of tumor diameters every three days. Animal body weight was recorded as index of toxicity. Doxorubicin was determined in plasma and tissues by HPLC-MS. Results: In 2D and 3D cell culture assays, TLD-1 showed a marked increase in cytotoxicity compared to Caelyx and was close to free drug. In all three animal models, TLD-1 showed activity superior to that of free doxorubicin given at the same dose and compared well to Caelyx both in terms of activity and toxicity. Conclusions: A couple of nanoparticulate features of TLD-1 liposomes are believed to attribute to the difference in antitumor activity. Cytotoxicity data from cell culture experiments indicate that TLD-1 liposomes are readily taken up by cancer cells and release their drug load into the cytoplasm. Commercial liposomes as in Caelyx seem to largely remain outside of cancer cells. In sum, TLD-1 is a novel and highly active antineoplastic nanodrug that has the potential to outperform free drug as well as commercial liposomal formulations of doxorubicin. Citation Format: Massimo Broggini, Federica Guffanti, Roberta Affatato, Lavinia Morosi, Patrick Buschor, Christoph Matthieu, Florian Weiss, Andreas Konig, Peter Halbherr, Stefan Halbherr. Preclinical activity of new liposomal formulation of doxorubicin (TLD-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 174. doi:10.1158/1538-7445.AM2017-174