Loujin Houdaihed
University of Toronto
Loujin Houdaihed is a PhD Candidate in Christine Allen lab at the department of Pharmaceutical Sciences, University of Toronto. She received a B.Sc. degree in Pharmacy and Pharmaceutical Chemistry from Damascus University, Syria in 2011. She started her M.Sc. degree at Univeristy of Toronto in 2014 and successfully transferred to the PhD program in 2016. Loujin is developing actively targeted-nano drug formulations of combination therapies for breast cancer. She is the recipient of the CIHR Doctoral Research Award and the Centre for Pharmaceutical Oncology Scholarship (CPO) 2015-2016.
Introduction: The combination of paclitaxel (PTX) and trastuzumab (TmAb) has been the first line therapy for metastatic HER2+ breast cancer (BC) for nearly two decades. However, the majority of patients develop TmAb resistance and the conventional PTX currently used (Taxol®) has been associated with dose-limiting toxicities. mTOR inhibitors, such as everolimus (EVER), were found to overcome TmAb resistance and increase sensitivity to PTX. Importantly, administering PTX and EVER at a synergistic ratio could allow for reducing the dose and toxicities of PTX. This research aims to develop a HER2-targeted polymeric nanoparticle (NP) formulation encapsulating PTX and EVER to improve tumor growth inhibition and reduce PTX-induced toxicities in TmAb sensitive/resistant HER2+ metastatic breast cancer in vivo.
Methods: The combination of PTX and EVER was evaluated in BC cell lines. PTX+EVER-NPs were prepared and characterized for physicochemical properties. HER2-targeted Fab fragments were obtained by digestion of TmAb and conjugated to NPs by Amine Coupling. Internalization of FITC-labeled TmAb(Fab)-NPs vs untargeted-NPs were studied in the SKBR3 BC cell line (HER2+) using flow cytometry after 24 h exposure.
Results: The synergistic ratio of PTX: EVER combination was defined at 1:0.5 in all BC cell lines tested. PTX+EVER-NPs were spherical, ~55nm in diameter, had a total drug loading of 9% (wt%), and exhibited sustained drug release in vitro under physiological conditions for 168 h. A significant shift in FITC fluorescence intensity for TmAb(Fab)-NPs was observed in comparison to untargeted-NPs, indicating a significant increase in cellular uptake (3.3 fold) for TmAb(Fab)-NPs relative to untargeted-NPs in SKBR3 cell line (HER2+).
Discussion: The combination of PTX and EVER increased the growth inhibition of BC in vitro, including a TmAb resistant cell line, compared with PTX alone, and was encapsulated in polymeric NPs at the synergistic ratio. TmAb(Fab) fragments were prepared, characterized and conjugated to the NPs. From flow cytometry data, the amount of TmAb(Fab)-NPs internalized in SKBR3 BC cells (HER2+) was significantly increased relative to that of untargeted NPs. These data show high potential for a HER2-targeted formulation of PTX and EVER combination to improve tumor growth inhibition and reduce PTX toxicities in TmAb sensitive/resistant BC in vivo.
Targeted drug delivery and nanocarriers , Nanomedicine for cancer diagnosis & therapy
