Traditional chemotherapy in the form of cytotoxic drugs is one of the standards in cancer treatment, but it is hindered by various barriers to drug delivery throughout the cancer microenvironment. Recently, nanoparticles have been of great interest as drug delivery vectors because they can be tailored for specific functions to increase the amount of administered drug in solid tumors. In particular, biocompatible C₆₀ fullerene has potential as a drug delivery scaffold since it has been shown to penetrate very restrictive physiological membranes (e.g. blood-brain-barrier and nuclear membrane)¹. In addition, radiofrequency (RF) irradiation can also be combined with C₆₀ fullerene-based drug delivery to increase the permeability of solid tumors to improve material uptake in cancerous tissue². Our long-term goal is to determine the biodistribution of a biocompatible C₆₀ material, as well as other pharmacokinetic data in both small and large animal models in order to evaluate its potential as a clinical drug vector for anti-cancer drugs. In this work, we have synthesized a C₆₀ derivative with a metal chelating agent covalently bound to the C₆₀ cage (Figure 1). The chelating agent of this material can be easily radiolabeled with ⁶⁴Cu²⁺ (β⁺ emitter; t_1/2 = 12 h) and tracked in vivo using positron emission tomography (PET) imaging. Because of its extreme sensitivity and routine clinical use, PET is an ideal imaging technique for studying pharmacokinetic properties and tumor accumulation of a C₆₀ fullerene delivery vector, for both preclinical and possible future clinical studies. The material has been synthesized following an optimized six-step synthesis and the stability of the ⁶⁴Cu²⁺ ion in the chelate has been evaluated by challenge with biological media. Animal biodistribution data will be determined using PET imaging in tumor- and non-tumor-bearing murine models and possibly porcine models as well. Our primary focus is on pancreatic cancer, since clinical treatment of this disease is presently ineffective³. Future studies include examining changes in biodistribution and exploring the potential to achieve increased selectivity for cancerous tissue with RF irradiation, as well as expanding to other tumor models.

Acknowledgements:  

We gratefully acknowledge The Welch Foundation (C-0627) and the Kanzius Cancer Research Foundation for support of this work, as well as the Department of Chemistry and the Smalley-Curl Institute at Rice University and the Department of Surgery at Baylor College of Medicine. Additionally, the work is supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 1450681 (N.G.Z.).

References:

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(2)       Corr, S. J.; Shamsudeen, S.; Vergara, L. A.; Ho, J. C.-S.; Ware, M. J.; Keshishian, V.; Yokoi, K.; Savage, D. J.; Meraz, I. M.; Kaluarachchi, W.; Cisneros, B. T.; Raoof, M.; Nguyen, D. T.; Zhang, Y.; Wilson, L. J.; Summers, H.; Rees, P.; Curley, S. A.; Serda, R. E. PLoS ONE 2015, 10(8), e0136382.

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