Self-Assembled Nano-Liposomes as Diagnostic/Therapeutic Carriers

Unilamellar liposomes have been commercialized as carriers for pharmaceuticals and imaging contrast agents. Traditional manufacturing methods of small uniform (~50 nm) unilamellar liposomes usually involves labour-intensive multi-stage extrusion, where filter rupture and fouling can be problematic, resulting in production delays and elevated monetary costs. Our recent research on spontaneously formed unilamellar liposomes from lipid mixtures composed of a short-chain and a long-chain phospholipid, and slightly doped with a charged lipid has resolved many of the issues associated with extruded liposomes. Firstly, these liposomes consistently self-assembly and are extremely stable. Moreover, the average diameter of the self-assembled liposomes can be as small as 20 nm with a narrow size distribution (i.e., polydispersity ~ 20%). These liposomes have also been shown to release their contents as a function of temperature, a useful characteristic when it comes to the delivery of therapeutics. One of our preliminary in vivo studies has shown that such functionalized liposomes preferentially targeted tumours in an animal model. Using small angle neutron scattering, we have successfully investigated the formation mechanism of self-assembled liposomes not only to gain a deeper understanding of colloidal systems in general, but also to better control their final size, which can be altered depending on their applications

Effect of drug-to-lipid ratio on nanodisc-based tenofovir drug delivery to the brain for HIV-1 infection

Background: Combination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood–brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge. Methods: This study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo. Result: The nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models. Conclusion: The study provides potential applications of nanodiscs for HIV-1 therapy development

Deformation and orientation of dissolved polymer chains in an elongational flow

The addition of a low concentration of dissolved high molecular weight polymer can greatly modify the rheological properties of a simple. Many of the modification can be attributed to flow-induced departures of the average chain conformation from its isotropic value at quiescence. The statistical deformation and orientation of polymer chains in flow has been predicted by various molecular models, but these predictions have not been adequately tested. This research provides an important molecular-level understanding of chain conformation in dilute solutions undergoing elongational flow; the work applies light scattering and birefringence techniques to probe chain conformation in situ. We have investigated the influences of chain stiffness and solvent quality on the chain conformations produced in and around the stagnation point of opposed jet flow. By light scattering, the average radius of gyration of the examined polymers has been probed both parallel and perpendicular to the stretching axis for flows of various strength. Flexible polymers are not deformed affinely under any circumstances, with statistical coil deformation falling much below this limit. Although solvent quality has little impact, slightly more coil deformation is observed in a theta solvent than in a good one. For a relatively stiff polymer of approximately 15 persistence lengths, the behavior of chain deformation/orientation in opposed jet flow is different; Because less strain is required to orient a stiff polymer than to deform an analogous flexible polymer, conformation changes are less localized, extending outside the region between the jets. Nevertheless, the overall conformational changes remain less than that predicted by a rod model

Facile self-assembly of porphyrin-embedded polymeric vesicles for theranostic applications

A robust and uniform porphysome, which reveals an efficient photodynamic therapy and contrast-enhanced ultrasonic imaging for theranostic applications, can be fabricated from a 4-armed porphyrin–polylactide conjugate

Decorating Nanoparticle Surface for Targeted Drug Delivery: Opportunities and Challenges

The size, shape, stiffness (composition) and surface properties of nanoparticles (NPs) have been recognized as key design parameters for NP-mediated drug delivery platforms. Among them, the surface functionalization of NPs is of great significance for targeted drug delivery. For instance, targeting moieties are covalently coated on the surface of NPs to improve their selectively and affinity to cancer cells. However, due to a broad range of possible choices of surface decorating molecules, it is difficult to choose the proper one for targeted functions. In this work, we will review several representative experimental and computational studies in selecting the proper surface functional groups. Experimental studies reveal that: (1) the NPs with surface decorated amphiphilic polymers can enter the cell interior through penetrating pathway; (2) the NPs with tunable stiffness and identical surface chemistry can be selectively accepted by the diseased cells according to their stiffness; and (3) the NPs grafted with pH-responsive polymers can be accepted or rejected by the cells due to the local pH environment. In addition, we show that computer simulations could be useful to understand the detailed physical mechanisms behind these phenomena and guide the design of next-generation NP-based drug carriers with high selectivity, affinity, and low toxicity. For example, the detailed free energy analysis and molecular dynamics simulation reveals that amphiphilic polymer-decorated NPs can penetrate into the cell membrane through the “snorkeling” mechanism, by maximizing the interaction energy between the hydrophobic ligands and lipid tails. We anticipate that this work will inspire future studies in the design of environment-responsive NPs for targeted drug delivery

Fluid phase lipid areas and bilayer thicknesses of commonly used phosphatidylcholines as a function of temperature

The structural parameters of fluid phase bilayers composed of phosphatidylcholines with fully saturated, mixed, and branched fatty acid chains, at several temperatures, have been determined by simultaneously analyzing small-angle neutron and X-ray scattering data. Bilayer parameters, such as area per lipid and overall bilayer thickness have been obtained in conjunction with intrabilayer structural parameters (e.g. hydrocarbon region thickness). The results have allowed us to assess the effect of temperature and hydrocarbon chain composition on bilayer structure. For example, we found that for all lipids there is, not surprisingly, an increase in fatty acid chain trans\u2013gauche isomerization with increasing temperature. Moreover, this increase in trans\u2013gauche isomerization scales with fatty acid chain length in mixed chain lipids. However, in the case of lipids with saturated fatty acid chains, trans\u2013gauche isomerization is increasingly tempered by attractive chain\u2013chain van der Waals interactions with increasing chain length. Finally, our results confirm a strong dependence of lipid chain dynamics as a function of double bond position along fatty acid chains.Peer reviewed: YesNRC publication: Ye

Formation mechanism of self-assembled unilamellar vesicles

Uniform size self-assembled unilamellar vesicles (ULVs) can be produced from mixtures of weakly charged short- and long-chain phospholipids. These lipid mixtures self-assemble into bilayered micelles (so-called bicelles), and a bicelle to ULV transition has been previously reported. Here, we discuss the effect of various parameters (i.e., lipid concentration, charge density, membrane rigidity, lipid composition, and lipid hydrocarbon chain length) on ULV radius as determined by small angle neutron scattering (SANS). SANS data were best fit using a core-shell disk and a spherical-shell model to obtain the size of bicelles and ULVs, respectively. From the present experiments we conclude that a previously proposed mechanism of ULV formation, where bicelles coalesce into large precursor and self-fold into ULVs, is able to explain the present SANS data.Il est possible de produire des v\ue9sicules \ue0 une couche auto-assembl\ue9es et de grosseur uniforme (ULVs), \ue0 partir de m\ue9langes de cha\ueenes de phospholipides courtes et longues faiblement charg\ue9es. Ces m\ue9langes de lipides s\u2019auto-assemblent en micelles bicouches (parfois appel\ue9es bicelles) et une transition de bicelle \ue0 ULV a d\ue9j\ue0 \ue9t\ue9 d\ue9crite. Nous discutons ici l\u2019effet de diff\ue9rents param\ue9tres (la concentration lipidique, la densit\ue9 de charge, la rigidit\ue9 de membrane, la composition lipidique et la longueur des cha\ueenes lipidiques) sur le rayon des ULV qui est d\ue9termin\ue9 par diffusion de neutrons aux petits angles (SANS). Nous ajustons la courbe des donne\ub4es SANS \ue0 l\u2019aide d\u2019un mod\ue8le en couches sph\ue9riques pour obtenir la grosseur des bicelles et des ULV respectivement. \uc0 partir des pr\ue9sentes exp\ue9riences, nous concluons qu\u2019un m\ue9canisme pr\ue9alablement rapport\ue9 sur la formation des ULV, o\uf9 les bicelles coalescent en un gros pr\ue9curseur et s\u2019auto-replient en ULV, est capable d\u2019expliquer les pr\ue9sentes donn\ue9es SANS.Peer reviewed: YesNRC publication: Ye

Spontaneously forming ellipsoidal phospholipid unilamellar vesicles and their interactions with helical domains of saposin C

We have observed a bimodal distribution of ellipsoidal unilamellar vesicles (ULVs) in a phospholipid mixture composed of dioleoyl phosphatidylserine (DOPS) and dipalmitoyl and dihexanoyl phosphatidylcholine, DPPC and DHPC, respectively. Dynamic light scattering and transmission electron microscopy data indicate a bimodal size distribution of these nanoparticles with hydrodynamic radii of approximately 200 and >500 nm, while small-angle neutron scattering data were fit using a model of coexisting monodisperse morphologies, namely, oblate and triaxial ellipsoidal vesicles. Unlike DOPS ULV formed by sonication, which can fuse days after being formed, these ULVs are stable over a period of 12 months at 4 degrees C. We also report on the structure of these ULVs associated with the two helical peptide domains (H1 and H2) of a glucosylprotein, namely, Saposin C, to gain some insight into protein-membrane interactions.NRC publication: Ye

Influence of cholesterol on the bilayer properties of monounsaturated phosphatidylcholine unilamellar vesicles

The influence of cholesterol on the structure of unilamellar-vesicle (ULV) phospholipid bilayers is studied using small-angle neutron scattering. ULVs made up of short-, mid- and long-chain monounsaturated phospholipids (diCn :1PC, n = 14 , 18, 22, respectively) are examined over a range (0-45mol %) of cholesterol concentrations. Cholesterol's effect on bilayer structure is characterized through changes to the lipid's transmembrane thickness, lateral area and headgroup hydration. For all three lipids, analysis of the experimental data shows that the addition of cholesterol results in a monotonic increase of these parameters. In the case of the short- and mid-chain lipids, this is an expected result, however, such a finding was unexpected for the long-chain lipid. This implies that cholesterol has a pronounced effect on the lipid's hydrocarbon chain organization.NRC publication: Ye