Multifunctional Polymers for the Targeted Treatment of Breast Cancer via RNA Interference

The use of RNA interference in gene therapy has recently shown great potential in cancer treatment. Using nanomedicines to deliver siRNA to cancer cells is an excellent solution to delivery problems encountered in previous experiments. These nanoparticles must contain a specific siRNA sequence, ligands able to target only cancer cells, and imaging abilities.

To produce an efficient nanomedicine, there are several important components that must be considered. The most important requirement for a nanomedicine is stability and biocompatibility. All components must not be unexpectedly degraded by different environments in the body or toxic to unexpected parts of the body. The nanomedicine must have some type of imaging, targeting, and treatment capabilities. The nanomedicine in my research was composed of gadolinium nanoparticles with biocompatible polymers attached to the outside of the nanoparticle. Gadolinium was used because it is an effective imaging agent for MRIs. This allows for the nanomedicines to be tracked and make sure they are concentrated near the cancer cells. The biocompatible polymers can be modified with targeting ligands, siRNA, or a chemotherapeutic. I used folic acid to target breast cancer cells and siRNA for treatment.

The nanomedicine is administered to patients intravenously, travels throughout the body, and attaches to cancer cell surface receptors. Once the targeting ligand attaches to over expressed cell surface receptors, the nanomedicine is endocytosed into the cell. When in the cell enzymes or changes in pH can activate the release of siRNA from the nanomedicine and RNA interference (RNAi) can commence.

The process of RNA interference to silence specific oncogenes has incredible possibilities. RNAi makes use of small interfering RNA (siRNA) molecules to regulate gene expression by the inhibition or degradation of existing genetic material. This prevents transcription of mature messenger RNA (mRNA) into phenotypic expression. RNAi is a natural self-defense mechanism present in all eukaryotic cells and requires small amounts of siRNA to completely silence a specific gene.

RNAi is initiated when double stranded RNA (dsRNA) molecules enter the cell. A protein complex called Dicer cleaves the dsRNA into smaller fragments, siRNA, about twenty nucleotides in length. A new protein called the RNA induced silencing complex (RISC) attaches to a siRNA molecule and uses its helicase activity to separate the two strands. The RISC protein and an associated single stranded siRNA attach to complementary nucleotides on mRNA in the cytoplasm. The RISC protein cleaves the mRNA into fragments and these “fragments are recognized by the cell as being aberrant and are destroyed” by other proteins.^[1]

Though there is a lot of research that needs to be done, multifunctional nanomedicines and the use of RNAi for the treatment of cancer shows great potential.

[1] Nature Reviews. RNA Interference (Video).

http://www.nature.com/focus/rnai/animations/animation/animation.htm.

[2] N. Durcan, C. Murphy, and S. Cryan. Inhalable siRNA: Potential as a Therapeutic Agent in the Lungs. Molecular Pharmaceutics. 2008. Vol. 5, No. 4, 559-566.

[3] P. Low, W. Henne, and D. Doorneweerd. Discover and Development of Folic-Acid-Based Receptor Targeting for Imaging and Therapy of Cancer and Inflammatory Diseases. Accounts of Chemical Research. 2007. Vol. 41, No. 1, 120-129.