Proceedings Article | 4 March 2019
KEYWORDS: X-rays, Colorectal cancer, Gold, Nanoparticles, Photodynamic therapy, Oxygen, Toxicity, Tissues, Molecules, Sensors
We designed X-ray triggered liposomes by co-embedding photosensitizers and gold nanoparticles (3-5 nm) inside a lipid bilayer. Gold was chosen in this work as, due to its high atomic number it strongly interacts with X-ray radiation as shown, for example, by gold nanoparticle-induced radiation enhancement inside biological tissue. As a photosensitizer we chose verteporfin (VP), clinically approved for photodynamic therapy (PDT) of age-related macular degeneration. 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1, 2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) were chosen as lipid components in the liposome formulation because DOPC can load highly hydrophobic molecules and DOTAP can facilitate cellular uptake due to its positive charge. The singlet oxygen generation from different liposome samples and destabilization of the lipid bilayer under X-ray radiation with different dosage (1, 2 and 4 Gy) were assessed by using the Singlet Oxygen Green Sensor (SOSG) and calcein release assays, respectively. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray triggered liposomes. Importantly, our X-ray mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation.
Additionally, the strategy described here has been designed to be compatible with future clinical translation. The materials and approaches used in this study, such as verteporfin, lipids, Dox and X-rays, are clinically used in treatment of tumours. Although gold nanoparticles used in this study have not yet been approved by the regulatory agencies, their size is compatible with the requirements of renal clearance. In this way, long-term nanoparticle toxicity is likely to be minimized if not eliminated. Moreover, the ease of conjugation of targeting ligands to liposome surface with appropriate linkers, for example, lipid-polyethylene glycol (PEG), would be an added advantage when applied to the targeted therapy, in particular for tumour treatment. From a clinical point of view, it would be beneficial to have access to this multimodality treatment, given our evidence of better therapeutic effect (or, potentially, equal therapeutic effect) at diminished toxicity in the case when single modality treatment options alone can only produce desired therapeutic effects at a significant cost of short and long term toxicity.
