Designing nanocomplexes to deliver therapies to cancer cells [with video]

Small interfering RNAs (siRNAs) are used to decrease the production of specific proteins in cells and promise new types of therapies to treat tumors. The challenge is to design drug-delivery tools capable of specifically transporting siRNAs to cancer cells. This paper systematically explores a variety of nanocomplex designs and identifies key criteria that allow them to enter cells and release siRNA cargo.

HFSP Cross-Disciplinary Fellow Sabine Hauert and colleagues
authored on Thu, 13 December 2012

Cancer is caused by an accumulation of genetic mutations in cells that lead them to replicate uncontrollably. These mutations cause changes in the expression of proteins that the altered genes produce. While most traditional drugs target these proteins directly, many proteins are deemed undruggable because of their hard-to-access structure. Instead, small interfering RNAs are able to prevent the production of proteins in the first place by specifically intercepting and destroying messenger RNA, which represents an intermediate step between genes and proteins. Ultimately, the use of siRNA helps to explain aspects of basic cell biology by specifically reducing the production of proteins of interest and promises to improve treatment of undruggable targets.

Artist's rendition of a nanocomplex

However, siRNA-based therapeutics is a challenge because of the inability to deliver naked siRNA to the inside of cancer cells due to their size, charge and degradability in the body. To address this challenge, we propose a new type of nanocomplex that encapsulates siRNA for delivery to the inside of cancer cells. The nanocomplex features a tumor penetrating domain that binds to receptors that are over-expressed on the surface of certain cancer cells. Upon binding, a mechanism is activated that drives the nanocomplex deep into tumor tissue and allows it to internalize in cells (see video below for a general overview of nanoparticle transport). When the nanocomplex enters a cell, it is encapsulated in a membrane known as the endosome. A cell penetrating domain on the nanocomplex helps it cross the endosomal membrane, allowing the siRNA to reach the cell’s main compartment where it can start interfering with protein production.

We systematically screened through a library of nanocomplexes with different cell penetrating domains to identify those that are able to deliver siRNA to cancer cells while sparing healthy cells. For each nanocomplex, we measured its ability to bind to receptors on cancer cells,to internalize in the cells, to escape from the endosome, and ultimately, to deliver the siRNA. Computational analysis is used to further understand what structural properties were important in making a good nanocomplex. Important factors included the charge of the nanocomplex and the number of tumor penetrating domains that were visible on its surface. The best nanocomplex identified in this study was then used in a follow-up preclinical study to treat ovarian tumors in mice [Ref 1].

 

 

Reference

Identification and Characterization of Receptor-Specific Peptides for siRNA Delivery.  Yin Ren, Sabine Hauert, Justin H. Lo, and Sangeeta N. Bhatia.  ACS Nano 2012 6 (10), 8620-8631.

Other References

Ref [1]. Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.  Yin Ren, Hiu Wing Cheung, Geoffrey von Maltzhan, Amit Agrawal, Glenn S. Cowley, Barbara A. Weir, Jesse S. Boehm, Pablo Tamayo, Alison M. Karst, Joyce F. Liu, Michelle S. Hirsch, Jill P. Mesirov, Ronny Drapkin, David E. Root, Justin Lo, Valentina Fogal, Erkki Ruoslahti, William C. Hahn and Sangeeta N. Bhatia .  Science Translational Medicine 2012 4(147): 147ra112.

Pubmed link