Lipids, curvature, and nano‐medicine

Abstract

The physical properties of the lamellar lipid-bilayer component of biological membranes are controlled by a host of thermodynamic forces leading to overall tensionless bilayers with a conspicuous lateral pressure profile and build-in curvature-stress instabilities that may be released locally or globally in terms of morphological changes. In particular, the average molecular shape and the propensity of the different lipid and protein species for forming non-lamellar and curved structures are a source of structural transitions and control of biological function. The effects of different lipids, sterols, and proteins on membrane structure are discussed and it is shown how one can take advantage of the curvature-stress modulations brought about by specific molecular agents, such as fatty acids, lysolipids, and other amphiphilic solutes, to construct intelligent drug-delivery systems that function by enzymatic triggering via curvature.Practical applications: The simple concept of lipid molecular shape and how it impacts on the structure of lipid aggregates, in particular the curvature and curvature stress in lipid bilayers and liposomes, can be exploited to construct liposome-based drug-delivery systems, e.g., for use as nano-medicine in cancer therapy. Non-lamellar-forming lysolipids and fatty acids, some of which may be designed to be prodrugs, can be created by phospholipase action in diseased tissues thereby providing for targeted drug release and proliferation of molecular entities with conical shape that break down the permeability barrier of the target cells and may hence enhance efficacy.

Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape

“…Since first being described by English hematologist Alec Bangham in 1961 (Bangham et al, 1965), artificial lipid vesicles (also called liposomes) have been recognized and extensively used as delivery vehicles for pharmaceuticals (Karmali & Chaudhuri, 2007), as chemical microreactors (Deepthi & Kavitha,, 2014;Lemière et al, 2015;Sercombe et al, 2015), and as model biomembrane systems (Mouritsen, 2011). The phospholipid bilayer envelope is a cell-like boundary appropriate for cellular investigations and affords liposomes a functional scaffold suitable for fundamental cellular functions such as motility and shape change , not to mention the ability to mimic the biophysical properties of living cells (Hua & Wu, 2013).…”

“…New approaches to construct improved liposomes for therapeutic delivery have addressed, on one end, biophysical parameters (one common example is charge (Sercombe et al, 2015)) which can be manipulated by altering the constituent bilayer phospholipids to better tailor the liposome to the required application. Other parameters that can and have been manipulated include lamellarity (Deepthi & Kavitha,, 2014), bilayer curvature (Mouritsen, 2011), bilayer fluidity , as well as surface modification for active or passive targeting approaches (Hua & Wu, 2013). Assembly methods play a key role in defining final liposome characteristics, including encapsulation efficiency and drug release profiles.…”

Cell Membrane Fluid–Mosaic Structure and Cancer Metastasis

“…If the hydrophobic portions of this structure are mismatched, an elastic distortion of the lipid matrix around the integral membrane protein occurs (15,29,37). This can produce protein conformational changes, potentially effecting protein function and protein-protein interactions, such as protein aggregation into membrane super-structures (37,39). In addition, there are other physical forces, such as lateral pressure forces, lateral phase changes, membrane curvature, ionic interactions, among other forces, that must be considered to produce an overall tensionless membrane structure (11,39).…”

How synthetic membrane systems contribute to the understanding of lipid-driven endocytosis

“…The molecular packing considerations, in combination with thermodynamics and molecular geometry of lipids, are taken into account in these calculations and allow for the study of membrane curvature [53][54][55][56]. Based on these shapes, self-assembly into complex supramolecular structures such as micelles, cubic structures and bilayers can be explained and described as a function of intrinsic membrane curvature properties for a particular lipid geometry [57]. The physiological relevance of such lipid shapes could be exposed in a study investigating the exosome formation and intraendosomal membrane transport.…”