Preclinical antitumor efficacy evaluation of dendrimer-based methotrexate conjugates

Although a variety of nanoparticles continue to show promise for improving cancer imaging and therapy, regulators and drug developers are concerned that these delivery systems may prove difficult to manufacture on a consistent basis, which is key for any agent designed for use in humans.

A new study from James Baker, Jr., M.D., PI, Cancer Nanotechnology Platform Partnership at the University of Michigan, and colleagues provides data showing that such concerns can be overcome.

Writing in the journal Anti-Cancer Drugs, the investigators present the results of studies designed to show that they could achieve consistent and specific targeting and cell-killing activity across multiple manufacturing batches of a dendrimer-based therapeutic agent. To assess targeting and cytotoxicity simultaneously, the investigators developed a novel system for growing in the same culture dish both targeted and nontargeted cells and distinguishing between the two by a difference in color. This “coculture” system comprises tumor cells that express a high-affinity folic acid receptor (FA+) and a similar tumor cell line that does not (FA-). The researchers modified the FA+ cells to also express a red fluorescent protein and the FA- cells to express a green fluorescent protein.

The investigators prepared one batch of a dendrimer-folic acid-methotrexate formulation for testing, and a contract manufacturer prepared three additional batches. Chemical analysis showed that the four lots were comparable. The researchers then treated cocultured cells with each of the four batches or with free methotrexate as a control. These assays produced consistent results across all four batches and demonstrated that the dendrimer was toxic only to targeted cells. In contrast, methotrexate alone was toxic to both FA+ and FA- cells.

This work is detailed in the paper “Preclinical antitumor efficacy evaluation of dendrimer-based methotrexate conjugates.” This work was supported by the NCI’s Alliance for Nanotechnology in Cancer. An abstract of this paper is available through PubMed.

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http://nano.cancer.gov