Development of stimuli deformable lipid/polymer hybrid nano-materials for drug delivery applications

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The main aim of this research is to develop nano-materials that can adequately solubilize drugs, and release them in an appropriate rate/location, and be safe for human use. This NSERC funded project, has previously led to the development and global intellectual protection of a library of safe, and degradable block copolymers based on poly(ethylene oxide) (PEO) and functionalized poly(ester)s such as poly(caprolactone) (PCL). The copolymers within this library were utilized to form core/shell nanocarries, namely polymeric micelles, capable of encapsulating a number of drugs, gene therapeutics and imaging probes through physical or chemical means, stabilizing them in the biological environment, reducing their exposure to healthy tissues while directing them towards target sites. This has enhanced the performance of the incorporated cargo in treating or imaging of cancerous or inflammatory sites. To improve the performance of this novel library for additional roles in drug delivery, we propose development of liposomes enveloping polymeric micelles and nano-gels from this polymer family. This approach is expected to: i) enhance the safety of polycationic or polyanionic PEO-poly(ester)s for gene/drug delivery, ii) expand the application of functionalized PEO-poly(ester)s in the co-delivery of small molecules drugs, proteins and genes of various hydrophilic/hydrophobic profile; and iii) lead to the development of nano-delivery systems that can change their shape and firmness and, as a result, show different cell interaction or drug release profiles in response to stimuli. Our specific goals are: 1. To develop lipid vesicles containing PEG-(functionalized)PCL based polymeric micelles (namely lipocells) or nano-gels (namely lipogels). 2. To investigate the effect of lipid structure, encapsulation method, polymer structure as well as stimuli (temperature, pH, reducing agents) on the characteristics (size, morphology, polymer encapsulation and leakage) of lipocells and lipogels. 3. To assess the capacity of lipocells and lipogels for the co-encapsulation and release of model hydrophilic and hydrophobic molecules in comparison to parent liposomal or polymeric nanocarriers. 4. To assess the in vitro protein adsorption, cell uptake and toxicity of lipocells and lipogels in cancer and normal cells, under physiological conditions and in response to stimuli. 5. To investigate the in vivo biodistribution of lipocells and lipogels compared to their parent liposomal or polymeric nanocarriers in mice bearing orthotropic breast tumors. The results of this research can lead to the development of novel nano-materials with improved safety profile and performance for the solubilisation, controlled and/or targeted (co-)delivery of different drugs, gene therapeutics and diagnostics. The proposed architectures, may be adopted to develop artificial cells, in future, mimicking natural cells in terms of incorporation of different subcellular organelles and elasticity.