GENERAL OBJECTIVES:

The main objective of the project is to design, synthesize and evaluate new complex materials with ability for self-assembling at nano-metric scale, which can add knowledge to macromolecular and organic chemistry (synthesis), colloidal chemistry (self-assembly of the polymers), biochemistry, biology and medicine (application of the nanoparticulate systems to drug delivery). This study will bring new insights into understanding of block copolymer aggregation, as a function of chemical structure and flexibility of hydrophilic and hydrophobic segments. The synthesis of block copolymers containing hydrophobic blocks based on rigid steroidal cycles (bile acids) have not been reported yet.

The specific objectives are:

1. Synthesis of new amphiphilic diblock copolymers with a polysaccharides as hydrophilic block and a biodegradable (bile acid polyesters) or a thermosensitive polymer as hydrophobic (or with “temperature stimulated” hydrophobicity) blocks. The new polymers will be based exclusively on biocompatible and/or biodegradable components (polysaccharides, bile acids, oligoethyleneglycohols).

2. Study of aspects concerning aggregation process (formation of stable micelles and/or vesicles) and the aggregate characteristics (size, shape, surface characteristics, core and shell compactitity/polarity). Correlation between these properties and polymer architecture (type and length of the blocks), overall molar mass, solubility, concentration, will bring new information about the role of blocks’ architecture, taking into account that both hydrophilic and hydrophobic blocks have cyclic structure, what is expecting to have an important role in chain packing, consequently on nanoparticles properties. The thorough understanding of polymeric micelle and vesicle formation is essential for the design of new materials for further applications.

3. Chemical modification of the outer shell of the preformed micelles or vesicles in order to improve their physico-chemical and biochemical properties (crosslinking, introduction of ionic groups, hydrophobic groups or targeting moieties). Crosslinking can improve the particle stability and help to control the encapsulated drug release. Presence of ionic groups can be favorable for the binding of hydrophilic oppositely charged drugs or can be used for a supplementary stabilization procedure by complexation with oppositely charged surfactants or polyelectrolytes (ionic crosslinking) (in this case, the shell becomes a polyelectrolyte complex). Introduction of some hydrophobic groups to polysaccharide block will help to tune the LCST of Ps-b-PNIPAM polymers at values close to or lower than physiological temperature (about 30 ºC). The presence of a targeting moiety will improve the accumulation of drug carrier at the desired site.

4. In vitro evaluation of the potential of synthesized micelles or vesicles as controlled drug delivery systems, including the study of the in vitro ability to encapsulate (bind) and release model drugs, degradation rate under physiological conditions of the polyesters and their block copolymers, study of the aggregate and aggregate/drug combines’ toxicity, biocompatibility, and biological effect on specific cell lines. A special attention will be paid for a double loading of nanoparticles with two different drugs, which will increase the device complexity but will improve its therapeutic potential. Other applications will be considered: flocculation/dispersion of suspensions and emulsions, rheology modifiers, reaction nanocontainers.