Dendrimer-based targeted delivery of an apoptotic sensor in cancer cells

Taking a critical step toward the development of a multifunctional nanoscale anticancer agent that can detect cancer, treat it, and then report on the success or failure of that treatment, investigators at the University of Michigan have developed a nanoscale sensor of cell death.

This sensor is built on the same biocompatible polymeric dendrimer platform that this research team has already used to image and treat tumors.

Reporting their work in the journal Biomacromolecules, James Baker, Jr., M.D., and his colleagues described a novel approach for using dendrimers to detect apoptosis, programmed cell death triggered by anticancer agents. Baker, who first began developing dendrimers as multifunctional nanoscale imaging and drug delivery platforms as part of the National Cancer Institute’s Unconventional Innovations Program, leads one of the NCI’s Cancer Nanotechnology Platform Partnerships.

Most approaches to detect apoptosis rely on the human protein annexin V, which binds to a hidden cell membrane component revealed in the initial stages of apoptosis. Baker’s group took a different approach, looking for the appearance of a protein called caspase-3, an enzyme activated early in the apoptosis process. This enzyme cleaves the bond between two specific amino acids – valine and aspartic acid – and researchers have capitalized on this specificity to design fluorescence-based assays for caspase-3. These assays use a physical process called flourescence resonance energy transfer, or FRET, that generates a bright fluorescent signal only when a specific chemical bond breaks. In this case, flourescence appears only when caspase-3 breaks a valine-aspartic acid bond in a specially designed substrate for this enzyme.

To create their tumor-specific apoptosis detector, the investigators attached folic acid and the caspase-3 substrate to a so-called PANAM dendrimer. Folic acid acts as a tumor-targeting agent, binding to a folic acid that many types of tumor cells produce in abundance. When the researchers added this dendrimer to apoptotic tumor cells bearing this folic acid receptor, the cells took up the dendrimer and fluoresced brightly. In contrast, apoptotic cells lacking the folic acid receptor did not fluoresce.

The investigators note that they have recently developed an optical fiber device capable of detecting FRET emissions in tumors. They have used this device to quantify apoptosis in live mice with tumors bearing the folic acid receptor.

This work, which was supported by the NCI’s Alliance for Nanotechnology in Cancer, is detailed in a paper titled, “Dendrimer-based targeted delivery of an apoptotic sensor in cancer cells.” An abstract of this paper is available through PubMed. View abstract.


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