Thermosensitive polymeric nanoparticles for drug co-encapsulation and intraductal delivery into the mammary tissue

Abstract

The high incidence of breast tumors and the lack of strategies for local management of non-invasive, low grade ductal carcinoma in situ (DCIS) and other pre-tumor and atypical lesions led us to propose the development of nanocarriers for intraductal drug administration, aiming to obtain a prolonged drug retention and localization at the target site, improved efficacy and reduction of systemic adverse effects. More specifically, we propose the development of thermosensitive poly(N-isopropyl acrylamide, pPNIPAM) nanoparticle delivery system for intraductal administration. PNIPAM thermosentitive nanoparticles are water-soluble at temperatures below the lower critical solution temperature (LCST) and undergo hydrophobic collapse at physiological conditions, allowing controlled drug release. We propose to encapsulate the cytotoxic agent piplartine with the peptide KAFAK, an inhibitor of MAPKAP Kinase 2 (MAPK2) to improve the nanocarrier antitumor effect. To target tumor cells, the peptide SILY will be attached to pNIPAM nanoparticles to bind collagen, which are over-expressed in many types of tumors including breast cancer. Nanoparticles diameter, zeta potential, drug loading and release will be characterized. Subsequently, the influence of nanoencapsulation and association of drugs on formulation cytotoxicity effects against breast cancer cells will be assessed in 2D cultures and 3D spheroids.