July 24, 2006
For Anticancer Nanoparticles, Two Targets Are Better than One
One of the advantages of using nanoparticles as delivery devices for therapeutic and imaging agents is the ability to attach a wide variety of tumor-targeting molecules to the nanoparticle surface. Typically, these molecules target cell-surface receptors that tumor cells overexpress, but that are nonetheless present at some level on many healthy cells, too, and thus such targeting strategies can still result in potent drugs reaching non-malignant cells.
To overcome this less-than-perfect tumor targeting, a team of investigators led by Ravi Ballamkonda, Ph.D., decided to take advantage of the fact that tumors usually overexpress more than one cell-surface receptor. By targeting two such receptors simultaneously, using two targeting molecules on the same nanoparticle, the researchers were able to completely spare non-targeted cells while delivering an effective therapeutic dose of doxorubicin to tumor cells. The results of this study appear in the Journal of Controlled Release.
As a proof-of-concept model, the researchers created doxorubicin-loaded nanoparticles targeted with folic acid and a monoclonal antibody that binds to the epidermal growth factor receptor (EGFR); many types of tumor cells overexpress folic acid and EGFR. To determine the optimal ratio of target molecules, the investigators created a series of nanoparticles with a constant number of antibodies but with various amounts of folic acid. The investigators also created identical nanoparticles targeted with only folic acid or the EGFR antibody.
Administering these nanoparticles to tumor cells and healthy cells growing in culture showed that, as expected, the singly targeted nanoparticles killed tumor cells but also a percentage of healthy cells. In contrast, the dual-labeled nanoparticles were at worst, less toxic to healthy cells, and at best non-toxic to healthy cells while retaining full toxicity for tumor cells. The researchers determined that the optimal formulation contained three monoclonal antibodies and an average of 200 folic acid molecules per nanoparticle.
This work is detailed in a paper titled, “A dual ligand approach for enhancing targeting selectivity of therapeutic nanocarriers.” Investigators from Case Western Reserve University and the University of Texas at Houston also participated in this study. This paper was posted online in advance of print publication. An abstract is available at the journal’s website.