Multivalent networks for drug delivery and DNA transfection: the classical use of the designed platforms for DNA will be replaced by a constitutional strategy: the dynamic self-organization of molecular components within constitutional systems will be used for exploring their adaptive behaviors and their structural evolution toward the fittest binding structure to the target molecules like DNA, lectins etc., and to control accurately their chemical/biological responses. Numerous artificial gene delivery systems utilizing designed molecular or nanocarrier systems have been developed in the last decades. Non-exhaustive cell penetrating examples of cationic lipids, peptides, calixarenes, polymeric structures and fullerenes have all been used in this context by using design approaches.

         Concurrently, the design of multivalent systems containing DNA coordination, membrane penetration and anti-opsonisation functions has attracted a great deal of interest. Convergent self-assembly strategies have been used for the synthesis of multivalent supramolecular nanodevices, designed to mimic natural delivery functions. Despite such impressive progress, important application problems, deriving from the enormous variability of both DNA targets and nature of the transfected cells, the rational design became limited to the introduction of a reduced number of components and should be completed by combinatorial approaches. Within this context, the Dynamic Combinatorial Strategy,38 appeared one of the most attractive screening method for the rapid access to the active systems from large and complex libraries. By virtue of the reversible interchanges between the hydrophilic heads and hydrophobic tails, the fittest Dynamic transfector can adapt simultaneously to the DNA biotarget and cell membrane barrier. As for the Design approaches, a future alternative Constitutional Selection strategy which may embody the flow of structural information from molecular level to dynamic multivalent devices that bind DNA on their nanosurfaces. This concerns the use of Dynamic Constitutional Frameworks –DCFs composed by combinations of linear and/or cross-linked arrays of components reversibly interconnected via core connectors and containing functional groups synergistically interacting with DNA and bilayer membrane components

         With all these in mind, the simplicity of the synthetic strategy and of their binding properties analysis can be easily led to highly functional Dynamic Interactive Frameworks presenting relative DNA/cell membrane synergistic affinities, toward the systematic rationalization and prediction of active delivery systems. We now intend to reach the next goal of making more selective DCFs carriers and to transport them across the cell membranes and to delivery those directly toward nucleus with controlled properties. In this project, novel compounds will be used as molecular scaffolds to conceive more competitive channels. The objective of this task is to synthesize novel DCFs combining a particularly broad range of features: 1) a) The functional charged/DNA binding heads will be decorated with various functionalities in order to enhance their binding; b) specific recognizing markers (folic acid for cancer cells, specific peptides for the cell nucleus binding) or c) drug molecules (doxorubicine, methotrexate, AZT etc.). 2) The DIFs core and segment components will be varied in order to modulate self-assembly: a) the supramolecular or nano-assembled platforms (i.e. cyclodextrines, fullerenes, polyxomoybdates POMs capsules, nanoparticles-NPs etc.) will be used for a specific spatial distribution of hydrophobic tails, including novel geometries of the channels; 3) The hydrophobic tail will be varied in order to have: rigid or flexible elements, chiral elements, post-synthetic grafting groups, compatible compounds with the bilayer membrane more (cholesterol, squalene, etc.) or F-backbones. Within this context, self-assembled supramolecular DIFs for precise selective delivery can be rationally designed and synthesized. From the mechanistic point of view, we start with molecular components which can self-assemble into nanometric species, presenting potential membrane-spanning and adaptive DNA/drug binding-behaviors at nanoscale level.