pH-sensitive, serum-stable and long-circulating liposomes as a new drug delivery system

Abstract

The lack of stability in blood and the short blood circulation time of pH-sensitive liposomes are major drawbacks for their application in-vivo. To develop pH-sensitive, serum-stable and longcirculating liposomes as drug delivery systems, the impact of polyethylene glycol-derived phosphatidylethanolamine (DSPE-PEG) on the properties of pH-sensitive liposomes was investigated. pH-sensitive liposomes were prepared with dioleoylphosphatidylethanolamine (DOPE) and oleic acid (DOPE/oleic acid liposome) or DOPE and 1,2-dipalmitoylsuccinylglycerol (DOPE/DPSG liposome). The inclusion of DSPE-PEG enhanced the serum stability of both DOPE/oleic acid and DOPE/DPSG liposomes, but also shifted the pH-response curve of pHsensitive liposomes to more acidic regions and reduced the maximum leakage percentage. The impact of DSPE-PEG, however, was much lower in the DOPE/DPSG liposomes than in the DOPE/oleic acid liposomes. In tumour tissue homogenates, where the pH is lower than normal healthy tissues, the pH-sensitive DOPE/DPSG liposomes released the entrapped markers rapidly, in comparison with pH-insensitive dipalmitoylphosphatidylcholine/cholesterol/DSPE-PEG liposomes. Moreover, the release rate was not affected by the content of DSPE-PEG. The blood circulation time of methotrexate incorporated in DOPE/DPSG liposomes was signi cantly prolonged with increasing content of DSPE-PEG. Taken together, the liposomes composed of DOPE, DPSG and DSPE-PEG (up to 5 %) were pH sensitive, plasma stable and had a long circulation time in the blood. The complete destabilization of the liposomes at tumour tissues suggests that the liposomes might be useful for the targeted delivery of drugs such as anticancer agents.

On the formulation of pH-sensitive liposomes with long circulation times

“…These results were confirmed by Hong et al [40], who showed that liposomes composed of DOPE, DPSG and DSPE -PEG (up to 5%) are pH-sensitive, plasma stable and have a long circulation time in the blood. Furthermore, they are able to release an entrapped marker more rapidly in tumor tissue homogenates (where the pH is lower than normal healthy tissues) in comparison with non-pH-sensitive DPPC/ Chol/DSPE -PEG liposomes.…”

Impact of interfacial cholesterol-anchored polyethylene glycol on sterol-rich non-phospholipid liposomes

“…28,45 In shifted the pH-trigged release curve towards more acidic regions and reduced the extent of the leakage that could be induced. 56 The presence of only 1 mol% PEG-DSPE in the formulation led to a decrease of release from >90% without PEG to ~20%, when the pH was set to 5. Similarly the pH-sensitivity of cholesteryl hemisuccinate/DOPE liposomes was attenuated in the presence of PEG-PE: 58 the nearly complete release of the liposome content could be trigged at pH 5, while the inclusion of 2 mol% PEG-PE reduced the pH-induced leakage to ~20%.…”

Application of liposomes in drug development – focus on gastroenterological targets

“…72 The search for liposomes with increased ability to mediate intracellular delivery of therapeutics resulted in the development of pH sensitive liposomes, which have potential application in treating digestive tract diseases such as some tumors or inflamed tissues that are more acidic than normal tissues. 73,74 Conventional dioleoyl phosphatidylethanolamine (DOPE) based pH sensitive liposomes achieved longer circulation time and tumor targeted delivery by incorporation of PEG. 74 The new generation of pH sensitive liposomes that employ pH sensitive lipids other than DOPE show promise to efficiently deliver anticancer agents to cancer cells.…”

“…73,74 Conventional dioleoyl phosphatidylethanolamine (DOPE) based pH sensitive liposomes achieved longer circulation time and tumor targeted delivery by incorporation of PEG. 74 The new generation of pH sensitive liposomes that employ pH sensitive lipids other than DOPE show promise to efficiently deliver anticancer agents to cancer cells. 75,76 Functionalizing pH sensitive liposomes with overexpressed cancer cell surface receptors further enhanced their ability to target cancer cells in a specific manner.…”