Receptor-specific targeting with highly functional polymer nanocontainers in cell culture and animal experiment

Medicine needs novel strategies to carry advanced functionality to diseased cells and organs for first world killer diseases like cardiovascular disease and cancer as well as for third world killer disease, namely infections. Nanotechnology-based targeting strategies appear highly promising, although the feasibility of this approach is not proven, the interaction of synthetic nanostructures with the living cell and the whole organism is not well studied, and the concern of potential toxicity of new approaches in medicine needs careful attention.
The aim of this project is to develop and to study a generic platform for disease targeting, combining advanced biological functionality, namely

• immunologic stealth properties (evasion of the immune system to avoid undesired degradation of the system in the organism)
• highly specific molecular /cellular targeting suited for diagnostic purposes (“molecular imaging” applications) as well as
• tailorable behaviour at the target (controlled degradation and controlled drug release), and
• proof of biocompatibility and absence of toxicity in cell culture and in vivo.

The interdisciplinary approach chosen includes:

1. Nanomaterial design and synthesis (synthetic block-copolymer nanocontainers built by molecular self-assembly)
2. Integration of functional biomolecules into synthetic nanocontainers (target-receptor specific ligands)
3. Receptor-specific targeting in cell culture and animal experiments (fluorescence, confocal and electron microscopy)
4. Thorough assessment of toxicity in cell culture and animal experiments

Using activated macrophages as a model cell and their scavenger-receptor A1 (which is involved in the development of arteriosclerosis) as molecular target, the poly-G quadruplex structure was chosen as targeting ligand and linked to a ABA block-copolymer nanocontainer carrier loaded with substance (here fluorescent dyes for proof of concept). In multiple cell lines, receptor-and cell specificity for nanocontainer binding was tested, uptake kinetics of the nanocontainers by the cells were studied, the capability of immune system evasion by nanocontainers built for that purpose was analyzed and cellular toxicity was assessed.
The findings of strong molecular specificity for receptor binding (Figure 2), the ability to selectively target specific cell types in mixed culture combined with impressive “stealth” features of the containers, and the observed uptake of the nanocontainers into the cell without observable cellular toxicity (Figure 3) strongly underline the potential of such a generic carrier system for medical applications, as evidenced by peer recognition of the project by several peer groups including physical chemists, cardiologists, pharmacologists, and oncologists. Ongoing work focuses on further expansion of the functionality toolbox deployable at the target and on in-depth animal experience of efficacy and toxicity.

Cell targeting by a generic receptor-targeted polymer nanocontainer platform
Pavel Brož, Samantha M. Benito, CheeLoong Saw, Peter Burger, Harald Heider, Matthias Pfisterer, Stephan Marsch, Wolfgang Meier and Patrick Hunziker
Journal of Controlled Release, Volume 102, Issue 2, 2 February 2005, Pages 475-488

Figure 1: The vision: cell- and receptor-specific medical targeting for medical diagnosis and treatment.		Figure 2: A macrophage (blue) exposed to red-tagged nanocontainers cannot scavenge them (upper left; “immunologic stealth properties”) while receptor-specific targeting leads to strong binding (lower left) and uptake (right panel)
Figure 3: No cellular toxicity (here measured by adenine release) observable in nanocontainer-targeted cells (red) compared to various controls (blue, green), while adenine release is markedly increased in the positive control experiment (pink).

Contact:

Patrick Hunziker
Department of Internal Medicine and Cardiology Kantonsspital Basel Switzerland

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