Over the last ten years, we have focussed our attention on a technology that combines two of the most successful nanomedicines: liposomes and polymer nanoparticles. Polymersomes, like liposomes, are vesicles that allow the simultaneous encapsulation of hydrophilic and hydrophobic actives; however, instead of using low molecular weight lipids, polymersomes are made by amphiphilic copolymers.<br/>We start with the careful design of the most appropriate polymersome formulation for the specific application, where we exclusively use materials that are either biodegradable into by-products are exclusively endogenous metabolites and chemicals branded by regulatory agencies (e.g. FDA, EMA, MHRA) as generally recognised as safe materials (GRAS). We combine poly(ethylene oxide) (PEO) (also known as poly(ethylene glycol) (PEG)), approved for several drug and protein conjugates; and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) with biodegradable polyesters and polyamminoacid using Ring-Opening Polymerisation (ROP). The polymersome design is based around the requirements to cross biological barriers. At a physiological level, we have equipped them with the necessary surface chemistry to avoid opsonisation and ensure long circulation time in the blood, and we can conjugate their surface with multiple ligands to target specific receptors and hence physiological sites. At the tissue level, we have designed ultra-deformable polymersomes able to penetrate small interstitial spaces reaching well within the parenchyma even through tight space. At the cellular level, we have developed them to interact with the cell machinery that regulates endocytosis and to escape endolysosomal degradation using pH- driven disassembly. Such an effective delivery approach has already proven to enhance conventional chemotherapy both in vitro and in vivo, by several orders of magnitude. We can deliver anticancer drugs (e.g. doxorubicin) intracellularly, achieving up to 100-fold increase in drug per cell. We are combining intracellular delivery with cancer targeting and implemented polymersomes with ligands to target the brain endothelial cells forming the blood-brain barrier (BBB) demonstrating that using LRP-1 mediated transcytosis we can gain access to the CNS and target its cells delivering large therapeutic cargo within their cytosol.

Polypetptide-based polymersomes for crossing the blood brain barrier

2019 Fall National Meeting

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