Multitasking hybrid scaffolds

 

Multitasking hybrid scaffolds

Figure 1. Boc-protected octaaminooxy-COSS used as scaffold for orthogonal bioconjugations
Figure 1. Boc-protected octaaminooxy-COSS used as scaffold for orthogonal bioconjugations

Cube-octameric silsesquioxanes (COSS) widely used in fine-tuned polymeric compositions, have recently found biochemical application in their monomeric form. A broad range of COSS-based hybrid systems has been developed, which are used in drug development, delivery, and diagnostics. Currently, bio-inspired research taking advantage of these versatile scaffolds is a fast-growing field, and it seems like the era of COSS has just begun.

COSS belong to the group of silica nanoparticles and are highly symmetric hybrid molecules comprising an inorganic core composed of silicon and oxygen. Every silicon atom is linked to an organic residue allowing for further modifications. The molecular composition of silsesquioxanes, first reported in 1874, is given by the empirical formula (RSiO1,5)2n where n is an integer and R substitutes hydrogen or aliphatic organic groups. Improvements of synthetic strategies allowing for the manipulation of pendant organic groups, as well as recent commercial availability of a wide range of silsesquioxane monomers have contributed to the rapid development of COSS chemistry within the last decades. These small, compact, and highly symmetric molecules have recently attracted increased attention as scaffolds for tailor-made bioconjugates. The expanded arsenal of effective conjugation methods (CuAAC, TEC, oxime ligation) allow one to decorate these nanoparticles bearing up to eight addressable organic substituents, with a wide range of biorelevant ligands.

 

In our group, we develop COSS-based bioconjugates bearing bioactive peptides, among them miniproteins (Fig. 1), reporter molecules, and cell-penetrating units. Low toxicity of COSS-based molecules combined with solubility in aqueous systems and half-life sufficient for in-vivo studies make these structures attractive targets for a number of applications, among them drug delivery, tumor diagnostics and therapy.

To develop novel cell-penetrating modules for the targeted delivery of active components inside the cell, we decorated COSS cages with a releasable peptide able to address intracellular targets, and equipped the resulting construct with a fluorescent marker to visualize the cell events. This architecture allowed for the penetration of human cells and peptide accumulation in the cell nucleus via selective binding to PCNA, a protein involved in DNA replication and repair (Fig.2).

Figure 2. Cell uptake of fluorescently-labeled novel COSS-based delivery modules. Microscopic image ( left: transmitted light channel, right: flourescent channel)
Figure 2. Cell uptake of fluorescently-labeled novel COSS-based delivery modules. Microscopic image ( left: transmitted light channel, right: flourescent channel)
 
 

Related Publications

  • 1. S. Fabritz, S. Hörner, O. Avrutina, H. Kolmar. Bioconjugation on cube-octameric silsesquioxanes, Org. Biomol. Chem., 2013, 11, 2224-2236.
  • 2. S. Fabritz, S. Hörner, D. Könning, M. Empting, M. Reinwarth, C. Dietz, B. Glotzbach, H. Frauendorf, H. Kolmar, O. Avrutina. From pico to nano: biofunctionalization of cube-octameric silsesquioxanes by peptides and miniproteins, Org. Biomol. Chem, 2012, 10, 6287-6293.
  • 3. S. Hörner, S. Fabritz, H. H. Herce, O. Avrutina, C. Dietz, R.W. Stark, M.C. Cardoso, H. Kolmar, Cube-octameric silsesquioxane-mediated cargo peptide delivery into living cancer cells, Org. Biomol. Chem., 2013, 11, 2258-2265.
  • 4. S. Fabritz, D. Heyl, V. Bagutski, M. Empting, E. Rickowski, H. Frauendorf, I. Balog, W.-D. Fessner, J. J. Schneider, O. Avrutina, H. Kolmar. Towards click bioconjugations on cube-octameric silsesquioxane scaffolds, Org. Biomol. Chem, 2010, 8, 2212-2218.