Attacking the perennial problem of systemic toxicity from typical chemotherapy treatments, Dartmouth investigators, led by Barjor Gimi, PhD, have engineered therapeutic cells encapsulated in nanoporous capsules to secrete antitumor molecules from within the tumor.
Their findings are reported in, "Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme-prodrug therapy," in Journal of Biotechnology. Co-authors on this paper include first author Krishnamurthy V. Nemani, PhD, Dartmouth College senior Riley Ennis, and Karl Griswold, PhD.
"We have engineered cells that locally convert a nontoxic substance into an antitumor agent," explained Gimi. "We can encapsulate cells in nanoporous capsules, which ensures the cells are localized and immunoisolated. This immunoisolated micro-factory can remain in the tumor, providing a permanent and renewable source of therapeutic molecules for long-term cancer management."
Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of nontoxic prodrugs in their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes.
Gimi's team engineered Escherichia coli (E. coli), which was designed to express cytosine deaminase at elevated temperatures under the transcriptional control of a thermo-regulatory promoter cassette. This constituted the thermal switch to trigger enzyme synthesis. They subsequently co-encapsulated the cells with magnetic iron oxide in immunoprotective alginate microcapsules and then remotely triggered cytosine deaminase expression by alternating magnetic field-induced hyperthermia.
The goal of localizing therapy to avoid systemic toxicity from chemotherapy is the impetus for Gimi's vision to ultimately encapsulate a library of therapeutic cells that will take cues from their microenvironment and secrete appropriate antitumor molecules.
Looking forward, Gimi's work will focus on using these microencapsulated cells to stimulate the immune system to act against tumors, as well as activating drug synthesis.
Technical assistance for this project was provided by Dartmouth's Shared Resources including Molecular Biology for DNA sequencing, Irradiation & Small Animal Imaging for AMF treatment, and the Dartmouth College Electron Microscopy Facility for acquiring SEM and TEM images. The Dartmouth Shared Resources are open to outside investigators by arrangement.
Gimi is Associate Professor of Radiology and of Medicine at Dartmouth's Geisel School of Medicine. His work in cancer is facilitated by Dartmouth's Norris Cotton Cancer Center where is he is a Member of the Cancer Imaging & Radiobiology Research Program.
Support for this project was provided by the National Institutes of Health grant U54 CA151662 DCCNE pilot project grant.