Self-assembled iron(III) hosts for MRI-guided delivery of chemotherapeutics

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Abstract Image-guided drug delivery is a promising approach to improve tumor uptake and to prevent the accumulation of toxic chemotherapeutic agents in healthy tissue. The imaging agent serves to provide information about biodistribution and drug delivery to better inform treatment. Most examples of image guided drug delivery have liposomes or nanoparticles as drug and imaging carriers. Our approach involves innovative Fe(III) self- assembled cages that are effective T1 MRI contrast agents. The four Fe(III) ions are tightly connected in a tetrahedral shape to form a robust complex that is highly soluble in water and has an interior cavity for encapsulation of metal ion complexes. One of our Fe(III) cages binds to serum albumin and accumulates in murine tumor models as shown by MRI studies. Such tumor uptake and accumulation suggests that the cage will be an effective agent for MRI guided drug delivery. Our overall goals are to develop methods for the delivery of Pt(II) and Pt(IV) anti-cancer agents to murine tumor models to determine the feasibility of this approach. Specific aims include the preparation of different Fe(III) cage derivatives that have varying overall charge and binding affinity to serum albumin. This aim will test our hypothesis that albumin binding is key to tumor uptake of the cages. The Fe(III) cage biodistribution and pharmacokinetic clearance will be studied in healthy mice and, subsequently in mice containing subcutaneous tumors from patient derived xenografts (PDX). The second aim involves the encapsulation of Pt(II) or Pt(IV) drugs, primarily carboplatin derivatives, in the Fe(III) cages. Release of the Pt drugs from the cages will be studied in solution and will be tested for cytotoxicity in cancer cell lines in order to gain insight into cellular uptake and release of the Pt drug. The third aim entails study of the uptake of the Fe(III) caged Pt drugs in NSG (NOD scid gamma) mice with subcutaneous PDX models. A PDX from squamous non-small cell lung cancer that is carboplatin responsive is chosen for study. Tumor size will be monitored with a three-week dosing schedule, and the amount of Pt and Fe in tumors will be measured by mass spectrometry. Fe(III) cage carriers of Pt will be compared to the Pt drug administered without cage.