Oxygen depleted hypoxic regions in the tumour are generally resistant to therapies1. Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour2 of magnetotactic bacteria3, Magnetococcus marinus strain MC-14, can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals5, tend to swim along local magnetic field lines and towards low oxygen concentrations6 based on a two-state aerotactic sensing system2. We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in SCID Beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.

A new method has been developed to determine the complete orientational order profile of lipid bilayers using 2H-NMR. The profile is obtained from a single powder spectrum of a lipid which has a saturated chain fully deuteriated. The smoothed order profile is determined directly from the normalized dePaked spectrum assuming a monotonic decrease of the order along the acyl chain. The oscillatory variations of the order at the beginning of the chain are not described by this method. However the smoothed order profile reveals in a straightforward way the crucial features of the anisotropic order of the bilayer.

Fourier-transform infrared-spectroscopic and fluorescence measurements have been combined to examine the effect of cholesterol on the intermixing of short-chain dilauroyl phosphatidylcholine (DLPC) and its bromo-substituted derivative (12BrPC) with longer-chain (C16- or C18-) phosphatidylcholines (PCs) in hydrated lipid bilayers. Infrared spectroscopy of mixtures combining protonated DLPC or 12BrPC with chain-perdeuterated dipalmitoyl PC reveals that cholesterol at lower concentrations in the bilayer modifies the resolved thermal melting profiles for both phospholipid components and, at high bilayer concentrations, produces a convergence of the thermal transitions for the two PC species. Fluorescence-quenching measurements using a short-chain fluorescent PC (1-dodecanoyl-2-[8-[N-indolyl]octanoyl] PC) in ternary mixtures combining 12BrPC, dipalmitoyl or distearoyl PC, and cholesterol confirm that very high cholesterol levels (50 mol %) abolish the lateral segregation of the PC components at 25 degrees C, a temperature where the phospholipids extensively phase-separate in the absence of sterol. By contrast, under these same conditions cholesterol at lower concentrations in the bilayer is found to enhance the tendency of the PC components to exhibit lateral segregation. We show that these seemingly contradictory effects of cholesterol can be readily explained in the light of a ternary phase diagram that is fully consistent with out current understanding of the nature of cholesterol-phospholipid interactions in binary mixtures.

The leakage induced by melittin, a membrane-perturbing amphipathic peptide, from large unilamellar 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) vesicles was studied using calcein as fluorescent marker. The extent of leakage has been found to be regulated by the melittin/lipid molar ratio. Melittin leads to the complete release of trapped calcein from some vesicles. This all-or-none mechanism leads to the co-existence of two different vesicle populations: the 'empty' and the intact one. Intervesicular migration of melittin was not observed. The results reveal a specific targeting of the lysed vesicles by melittin. The presence of negatively charged lipids (unprotonated palmitic acid or 1-palmitoyl-2-oleoylphosphatidylglycerol) in the neutral POPC matrix inhibits the lytic power of melittin; this inhibition increases with increasing surface charge density. It is proposed that the anchorage of the peptide on the charged surface prevents the formation of defects allowing leakage. A statistical model based on a random distribution of the peptide molecules on the vesicles is proposed to describe the release induced by melittin. It is proposed that about 250 melittin molecules per vesicle are required to affect the bilayer permeability and to empty a vesicle of its content. This large number suggests that leakage is more likely due to collective membrane perturbation by the peptide rather than to the formation of a well-defined pore.