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Bioactive block copolymer vesicles as pH-triggerable, nano particulate carriers for cancer vaccination

Final Report Summary - POLYTRIGG (Bioactive block copolymer vesicles as pH-triggerable, nano particulate carriers for cancer vaccination)

Many anticancer drugs require intracellular delivery to be effective. The agents such as nucleic acids, therapeutic enzymes, proteins and certain antibiotics cannot cross the cell membrane and, therefore such problems can be overcome by using nano delivery systems. Investigation of nanocarriers for biomedical purposes is dominating the field and is especially pronounced in cancer related research. Both the size of nanoparticles and the additional ability of drug delivery systems to release the active compound in a controlled manner play key roles in successful medical treatment. For instance, pathological vasculature is more permeable in comparison to healthy tissue, thus an accumulation of high molecular weight molecules and nanoparticles is possible in the interstitial space of tumours. Since the molecular weight of conventional drugs is only a few hundred Daltons, they easily escape from tumours. However, when encapsulated in a nanocarrier, the increased size allows entrance into the tumour vasculature but inhibits escape, leading to accumulation in the tumour tissue. Hence, the development of different stimuli-responsive platforms to control the release of drugs upon applying external stimuli has attracted a lot of interest. In particular, a response to pH change is desirable, since defined pH gradients exist in biological systems, e.g. between the extracellular medium at pH 7.4 endosomes at pH 6.0-6.5 and lysosomes at pH 4.5-5.0. Also, the more acidic environment in cancer cells compared to healthy cells make pH responsive systems a good supplement to the permeation retention effect (EPR) effect when targeting cancerous tissues.
Most of reported nanocarries used polyethylene glycol (PEG) or polyethylene oxide (PEO)-based block copolymers. Therefore, it is important to develop a new “smart” generation of supramolecular structures. Experiments have shown that the behaviour of the polyoxazoline (POXA) based delivery platforms is similar to that of the corresponding PEG-based materials. Furthermore, POXA can be easily tuned by the variation of side chains that provide variable hydrophilic and hydrophobic properties, leading to a variety of synthetic possibilities.
In PolyTRIGG project we developed nanocarriers based on amphiphilic poly(2-methyloxazoline) (PMOXA) and polydimethysiloxane (PDMS) blocks in combination with stimulus-responsive acrylate copolymers blocks. A series of block copolymers were synthesized with controlled radical polymerizations (e.g. dual initiator route combining cationic ring-opening (CROP) and Atom Transfer Radical Polymerization (ATRP)). Hierarchical self-assembly studies were performed under physiological conditions. Nanoparticulates based on short acrylate blocks displayed excellent cell viability, while self-assemblies with longer blocks were cytotoxic. However, the cytotoxicity of these polymers was drastically reduced by modification of tertiary amino group present in the block copolymers. The platforms were able to released anticancer drug doxorubicin (DOX) in response to an ambient pH drop from 7.4 to 5.5. Furthermore, delivery systems exhibit intracellular pH-response (demonstrating endosomal escape), as changes in cell morphology and drug release was observed within 24 h. Additional experiments involving DNA release studies, surface modification with targeting ligand and immune activation studies are currently under detailed investigation. The information obtained within these methods will lead to better understanding of formulations, designed for peptide, DNA and anti-cancer drugs delivery.