Ability of co-administered peptide liposome nanoparticles to exploit tumour acidity for drug delivery

Abstract

Using a previously-characterised solid tumour model we demonstrate that a mixture of pH sensitive peptide and liposome nanoparticles (PLNs) can be used to induce payload release in response to small changes in tumour acidity. The classical pH sensitive GALA peptide was modified at two different positions to help tether with preformed liposomes and cause release of calcein marker in response to a less than 1.0 unit drop in pH from the physiological value. The circular dichroic spectra of the peptide showed that, unlike the GALA sequence, its helical structure was unusually independent of pH suggesting a different mechanism of action for calcein release. Intravenously-administered PLNs accumulated in tumour tissue in mice, and subjecting the excised tumour tissue slices to low pH buffer confirmed that these nanoparticles remained pH responsive. Quantitative in vivo imaging of tumours implanted in mouse dorsal skin allowed real time measurements of nanoparticle accumulation, monitored through DiI labelling of the liposome membrane, and intra-tumour pH dependent release, monitored by calcein release, to be followed. The release of calcein in the live tumours at their natural acidity of pH 6.8 was further enhanced with MIBG glucose treatment to induce tumour acidification to approximately pH 6.5. Following accumulation a substantially greater and more rapid calcein release was observed in tumours administered with PLNs and subjected to pH-lowering using MIBG treatment, compared to control tumours administered with liposomes lacking the peptide or tumours not treated with MIBG. This work highlights that while PLNs were relatively unresponsive to intrinsic tumour pH, they did have the ability to respond rapidly to extrinsically-induced small changes in pH near the patho-physiological range.