Heterogeneous Domains and Membrane Permeability in Phosphatidylcholine−Phosphatidic Acid Rigid Vesicles As a Function of pH and Lipid Chain Mismatch

Abstract

Heterogeneous lipid membranes tuned by pH were evaluated at 37 degrees C in the form of PEGylated vesicles composed of lipid pairs with dipalmitoyl ( n = 16) and distearoyl ( n = 18) chain lengths. One lipid type was chosen to have the titratable moiety phosphatidic acid on its headgroup, and the other lipid type was chosen to have a phosphatidylcholine headgroup. The effect of pH on the formation of lipid heterogeneities and on membrane permeability was studied on vesicles composed of lipid pairs with matching and nonmatching chain lengths. The formation of lipid heterogeneities increases with decreasing pH in membranes composed of lipid pairs with either matching or nonmatching chain lengths. Increased permeability with decreasing pH was exhibited only by membranes composed of lipid pairs with nonmatching chain lengths. Permeability rates correlate strongly with the predicted extent of interfacial boundaries of heterogeneities, suggesting defective packing among nonmatching acyl chains of lipids. In heterogeneous mixtures with one lipid type in the fluid state ( n = 12), the dependence of membrane permeability on pH is weaker. In the presence of serum proteins, PEGylated gel-phase vesicles containing lipid pairs with nonmatching chain lengths exhibit faster release rates with decreasing pH compared to measured release rates in phosphate buffer, suggesting a second mechanism of formation of separated phases. PEGylated vesicles composed of lipid pairs with nonmatching chain lengths labeled with internalizing anti-HER2/neu antibodies that target overexpressed antigens on the surface of SKOV3-NMP2 ovarian cancer cells exhibit specific cancer cell targeting, followed by extensive internalization (more than 84% of bound vesicles) and fast release of contents intracellularly. These PEGylated vesicles composed of rigid membranes for long blood circulation times that exhibit pH-dependent release of contents intracellularly could become potent drug delivery carriers for the targeted therapy of solid tumors.

Recent Trends in Multifunctional Liposomal Nanocarriers for Enhanced Tumor Targeting

“…Third, ligand unmasking by acidic pH-induced membrane reorganization has been introduced as a reversible ligand-masking strategy. Sofou and coworkers developed a new platform for pH-triggered liposomal drug delivery [287, 288]. The rationale for their design involves the increased permeability at the boundaries between lipid domains [289].…”

“…The rationale for their design involves the increased permeability at the boundaries between lipid domains [289]. Using lipid pairs of phosphatidic acid as a titrable headgroup and phosphatidylcholine as the colipid headgroup with mismatched hydrophobic chain lengths (dipalmitoyl and distearoyl) they demonstrated that formation of heterogeneous domains in PEGylated liposomes containing 5% of cholesterol allowed faster pH-dependent content release than liposomes with matched chains [288]. They showed a pH-dependent membrane transition due to the protonation of phosphatidylserine at lower pH in cholesterol-rich membranes, with protonation favoring their homologous interaction, leading to the formation of DSPS (1,2-distearoyl-sn-glycero-3[phosphor-L-serine]) lipid domains.…”

“…The presence of cholesterol or rigid saturated lipids (DSPC, HSPC) stabilizes the liposomal membrane against liposomal dissociation by plasma proteins and limits drug leakage, and thus most drug-loaded liposomes include cholesterol in the lipid bilayer [45, 288, 301]. These lipids have high gel-to-liquid crystalline phase transition temperatures (55–58°C) compared to physiological temperature (37°C) which prevents coexistence of the two phases and contributes to improved drug pharmacokinetics [13, 45, 302].…”

Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

“…The addition of folate-PEG 3350 -CHEMS made the lipid membranes more heterogeneous due to the poor lipid packing, and thus increased membrane permeability. 45 Pharmacokinetic tests in vivo echoed the results of the drug release in vitro. Only when the drug release is slower than the liposome clearance will the liposome control the drug pharmacokinetics and bio-distribution and express the EPR effect for passive targeting.…”

Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting

“…Additionally, in the slightly acidic tumor interstitium (7.4 > pH > 6.0) [14,15] a pHresponsive mechanism on the liposome membrane results in release of these chelated forms of encapsulated radioactivity [16].…”