This project aims to develop a Theranostic Nanosystem allowing selective co-delivery of therapeutic agents with distinct physical chemical properties to target diseased cells in vivo. Besides good on-shelf and in vivo stability and low toxicity, the system must enable ratiometric control of cargo loading, avoid premature release of transported agents, allow controlled drug release at targeted locations, and its real-time, non-invasive, monitorization in vivo. Although adaptable to other applications, the system here will transport two chemotherapeutic drugs (Doxorubicin and Cisplatin), one RNA (antagomir-10b) and one peptide (H5WYG), coated with PEG-folate conjugate to confer both stealthness and cell specific tropism to the whole. The nanosystem will be fabricated, characterized in vitro and optimized, and the function of each component will be examined in cultured murine Metastatic Breast Cancer 4T1 cells. The latter forms highly aggressive metastatic tumors in immune competent BALB/c mice that recapitulate the human disease. 4T1 overexpresses folate receptor, which will interact with the system and induce its internalization through the endosomal pathway. These cells are sensitive to doxorubicin and cisplatin, and their metastatic character is inhibited by antagomir-10b. Whilst chemotherapeutic drugs escape the endosome by simple diffusion, escape of antagomir-10b from will be facilitated by an endosomolytic peptide co-transported by the system. Acidification of the endosome will trigger drug release and endosomo-lysis. The correct functioning of the system should inhibit metastatic spreading of 4T1 cells in mice and kill primary and secondary tumors, offering an ideal model to optimize performance. A Superparamagnetic Iron Oxide core will allow in vivo monitorization of distribution and therapeutic response using Magnetic Resonance Imaging. This methodology will pave the way for additional strategies that could be applied to other cancer types.
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