Novel stimuli-responsive protein nanocapsules for targeted drug delivery in breast cancer therapy

The main aim of the project is the development of pH-responsive MTX loaded mAb surface functionalized HSA-SF nanocapsules for targeted breast cancer therapy. Breast cancer is the most common cancer type diagnosed in women and has the highest mortality rate among women aged over 50. Commonly used endocrine therapies are targeting estrogen receptor positive and progesterone receptor positive breast cancers. HER2/neu positive cancer types can be targeted using the humanized monoclonal antibody Trastuzumab, which was approved by the FDA in 1998. Nevertheless, HER2 overexpression is directly related with more aggressive tumor phenotypes and greater likelihood of lymph node involvement. Concerning triple negative breast cancer, folate receptor alpha (FR{alpha}) was identified as overexpressed protein receptor and can be targeted with the monoclonal antibody Farletuzumab. Strategies developed in the NOVICAPS consortium using the novel system of pH-responsive HSA-SF nanocapsules for MTX release at the target side will be firstly combined with mAb as a dual-stimuli targeted delivery system. Therefore, enzymatic and chemical surface functionalization of protein nanocapsules with monoclonal antibodies are seen as promising for the functionalization of sonochemically produced HSA-SF nanocapsules, with Farletuzumab and Trastuzumab in a novel combination to target both HER2 positive and triple negative breast cancer types in a highly specific way. Therefore, the project will be divided in six work packages (WP). Project management is situated in WP1. WP2 will focus on the production and optimization of MTX loaded pH-responsive HSA-SF nanocapsules and their surface functionalization with mAbs, e.g. either humanized Farletuzumab or a humanized biosimilar to Trastuzumab and as well as their combination. WP3 aims at the full characterization of the produced nanocapsules involving analytical tools such as ATR-FTIR, SEM, CLSM or LC-ESI-TOF. In WP4 in vitro cell studies will be performed to determine cell uptake, cell toxicity and in-cell distribution of the produced nanocapsules in cell monolayers as well as in innovative 3D cell models. After successful completion of in vitro studies, WP5 will focus onto further characterization of nanocapsule specificity in vivo using xenograft mice models. Dissemination and reporting is covered by WP6.