Peptides for targeted delivery of Pt(IV) pro-drugs in the treatment of rare cancers Jevon Marsh, Nicola Farrer University of Oxford, UK Despite the advancements in medicine, many cancers remain untreatable leaving patients with little to no options to help manage or treat their illness. This is the case with Diffuse Intrinsic Pontine Gliomas (DIPG), an incurable and highly aggressive pediatric brain tumor with a prognosis of only 1-2 years. [1] Treatment of DIPG with radiation provides no long-term benefits to patients and surgery is not possible due to the location of the tumor; additionally, the use of current clinically approved chemotherapies is ineffective due to complications in bypassing the Blood Brain Barrier (BBB). [1] The chemotherapies used in treating cancers usually involve Platinum (Pt) – a metal at the crux of various Food and Drug Administration (FDA) approved chemotherapeutics including Pt(II) complexes cis-platin, oxaliplatin and carboplatin. However, Pt(II) complexes have an array of complications including poor solubility and low specificity for cancer cells, and often demonstrate high off-target effects which result in detrimental side effects in patients. [2] Our aim is to overcome these limitations of Pt(II) complexes by synthesizing Pt(IV) ‘pro-drugs’, with a particular interest in pro-drugs specific for DIPG. By oxidizing a Pt(II) complex into a Pt(IV) complex, an improved solubility, cellular uptake profile and even specificity towards tumor cells can be achieved. [2] Furthermore, the additional substituents in the axial positions of Pt(IV) complexes allows for further functionalization with other components; these may include other cytotoxic agents that can increase the potency of pro-drugs towards cancer cells and/or peptides for targeted delivery towards the tumor site. The aim of our research is to synthesize multi-modal pro-drugs involving (i) a Pt(IV) complex, (ii) one or more cytotoxic agents (e.g. Histone Deacetylase (HDAC) Inhibitors) and (iii) peptides for specific delivery to cancer cells in DIPG, and explore methods to bypass the BBB; these pro-drugs may reduce off-target effects and improve the prognosis for DIPG patients. References 1. Srikanthan, D., Taccone, M.S., Van Ommeren, R.et al.Diffuse intrinsic pontine glioma: current insights and future directions. Chin. Neurosurg. J., 2021,7,6. 2. Gibson, D.Platinum(iv) anticancer prodrugs – hypotheses and facts. Dalton Trans., 2016, 45, 12983-12991.
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