February 6, 2006
Novel Polymer Nanoparticles for Targeted Drug Delivery
By combining a nanoparticle made of a polymer produced by a slime mold with a cancer targeting agent and two therapeutic antisense nucleic acids, an international team of researchers has created a new type of nanoparticle that accumulates in brain tumors when injected into mice. Laboratory tests also demonstrated that this multifunctional nanoparticle stops malignant glial cells from producing two proteins that these cells need to grow.
Reporting its work in the journal Bioconjugate Chemistry, a group of investigators led by Eggehard Holler, Ph.D., from Universität Regensburg, Germany, used the biodegradable polymer β-poly(L-malic acid) to create a nontoxic nanoparticle to which they could attach a wide variety of targeting, imaging and therapeutically active molecules. In the work reported in this paper, the researchers used a monoclonal antibody that recognizes a glial cell surface protein known as transferrin receptor as the targeting agent. Transferrin receptor is overexpressed by glial cell tumors in brain tissue, also known as gliobastomas. In order to track the nanoparticles, the investigators attached a fluorescent dye, enabling the investigators to visualize targeting of the nanoparticle using a standard fluorescence microscope. The therapeutic agents they chose were two antisense oligonucleotides that block synthesis of two key components of glioblastoma cell membranes. As a final component, the researchers attached what they termed a “membrane-disrupting unit” molecule containing the amino acid L-valine that helps the nanoparticle deliver its therapeutic payload where it can act inside the cell.
Laboratory tests with glioblastoma cells showed that this complex nanoparticle formulation was taken up readily by the malignant cells though its interaction with the transferrin receptor. The membrane-disrupting element enabled the nanoparticles to break out of the endosomes that normally surround such structures after they enter cells. The two antisense oligonucleotides then shut off synthesis of two of the protein chains needed to make a larger protein known as laminin-8. Tests in mice with human brain tumors showed that this nanoparticle crossed the blood-brain barrier and accumulated preferentially in glioblastomas.
This work is detailed in a paper titled, “Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(β-L-malic acid) for drug delivery.” Investigators from Cedars-Sinai Medical Center in Los Angeles and Arrogene, Inc., in Tarzana, CA, also participated in this study. This paper was published online in advance of print publication. An abstract is available at the journal’s website.