For the first time, two distinct, well-characterized water-soluble chemotherapeutic-C60 conjugates have been constructed for targeted drug delivery of paclitaxel to cancer cells.
In vitro work was carried out in two stages to determine IC50 values of the conjugates. Primarily, work was carried out on A375m melanoma, T-24 bladder carcinoma, and Hep 3B hepatocellular carcinoma cell lines. In these studies, it was revealed that although the first compound, a paclitaxel-2’-succinate-C60 derivative, experienced a dramatic loss of cytotoxicity in comparison to paclitaxel, the second derivative, utilizing a poly(ethylene glycol) linker, demonstrated over 10× better cytotoxicity than paclitaxel itself.
Additional in vitro studies were carried out for the purpose of creating a chemotherapeutic-fullerene-monoclonal antibody immunoconjugate for targeted drug delivery. Building on our previous work, supermolecular forces, instead of covalent chemical bonding were used to associate antibodies with the paclitaxel-2’-succinate-C60 derivative to construct an immunoconjugate. While cytotoxicity was measurable, no discernible advantage was seen by the targeted C60-(ZME-018) immunoconjugate over a MuIgG control, thus leaving room for further refinement of the approach for targeted cancer therapy.
In vivo work, using the potent paclitaxel-poly(ethylene glycol)-C60 derivative in a murine model, demonstrated success by producing a similar capacity for tumor-reduction compared to the FDA-approved drug Abraxane®, without the associated weight-loss in animals seen for Abraxane.
A major contribution of this work is the progress made toward development of Fullerene Immunotherapy (FIT) and the potential translation of FIT into the clinic. Having demonstrated the potent, improved cytotoxicity of a paclitaxel-C60 conjugate, the next step in the development of FIT is the successful construction of a therapeutic fullerene-antibody immunoconjugate. The results documented in this work have now shifted the onus of FIT from a theoretical concept to a realistic goal awaiting final developmental refinement.
| Identifer | oai:union.ndltd.org:RICE/oai:scholarship.rice.edu:1911/71131 |
| Date | 13 May 2013 |
| Creators | Berger, Christopher |
| Contributors | Wilson, Lon J. |
| Source Sets | Rice University |
| Language | English |
| Detected Language | English |
| Type | thesis, text |
| Format | application/pdf |
Page generated in 0.0018 seconds