Current Research
Active Nanoparticle Targeting for Cancer Research Cancer remains one of the leading causes of death around the world and one of the main problems is that many non-targeted treatments lack of tumour specificity. However, tumour cells present a variety of surface markers which could be targeted for more specific treatment, as they are either not expressed, or expressed to a much lower degree, in healthy cells.1 These cell surface receptors could be selectively targeted using a variety of high affinity ligands identified from libraries of antibodies, phage display peptides,2 or aptamers.3 Antibody drug conjugates such as Trastuzumab emtansine (Kadcyla)4 or the folate-targeted drug conjugate ONX-0801 are widely used in the clinic already.5 The ligands modulate the drug biodistribution towards cancer cells that have the relevant receptor, making these therapies safer and often more effective, allowing higher doses to be administered.6 Nanoparticles (NPs) provide multifunctional ligand platforms as well as diagnostic and therapeutic opportunities for the treatment of a variety of conditions,6 typically encapsulating the active pharmaceutical ingredient within and offering many advantages over the unencapsulated drug. Nanoparticles thus potentially offer additional advantages if actively targeted to tumours, however, realisation of these benefits in the clinic has remained challenging. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) is an amphiphilic chitosan derived polymer that selfassembles into highly stable NPs capable of encapsulating poorly water soluble hydrophobic drugs.7,8 In biological fluids these NPs appear to be stable and sustain long circulation, thus potentially addressing some of the challenges for active NP targeting in cancer.9 Building on the advantages of this platform the current project will aim to explore multiplexed targeting to solid tumours. Multifunctionality of NPs with low CMCs can be achieved either by conjugation of multiple functional moieties at defined stoichiometries, or via assembly of a combination of mono-functional polymers with distinct properties. These strategies can tune the avidity and affinity of a given targeted particle as well as explore combination targeting using a mixture of ligands, resulting in stable and targetable particles with improved binding. The same principle can be extended to include a labelling functionality and/or drug conjugates. Interestingly, it was found that GCPQ NPs modified with a PEG linked folate group to specifically target the folate receptor (FR) appear to induce specific targeting to breast tumours. Hence, GCPQ will be synthesised as previously described,7,10 functionalised with a variety of targeting moieties. Self-assembly of targeted GCPQ will be investigated alongside the effect of the ligands on NP properties in terms of their geometry, steric effects, binding efficiency, targeting ability, affinity, avidity, and stability. Protein corona formation can also be investigated to determine the nature of interactions and effect on receptor binding, to address some of the translational challenges in targeted nanoparticle research. References 1 Kim, W.-T. et al. BMB Rep. 50, 285-298 (2017) 2 Park, H.-Y. et al. Mol. Biotechnol. 51, 212-220 (2012) 3 Li, X. et al. Anal. Chem. 86, 6596-6603 (2014) 4 Verma, S. et al. N. Engl. J. Med. 367, 1783-1791 (2012) 5 Banerji, U. et al. J. Clin. Oncol. 35, 2503 (2017) 6 Shi, J. et al. Nat. Rev. Cancer 17, 20-37 (2017) 7 Chooi, K. W. et al. J. Pharm. Sci. 103, 2296-2306 (2014) 8 Lalatsa, A. et al. Mol. Pharm. 9, 1764-1774 (2012) 9 Siew, A. et al. Mol. Pharm. 9, 14-28 (2012) 10 Uchegbu, I. F. et al. Int. J. Pharm. 224, 185-199 (2001)