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. Author manuscript; available in PMC: 2019 Apr 5.
Published in final edited form as: Nat Biomed Eng. 2018 Jul 2;2(8):589–599. doi: 10.1038/s41551-018-0254-6

Figure 1. Design of a TAM-targeting supramolecular therapeutic.

Figure 1

(a) Schematic shows that cancer cells exploit colony stimulating factor 1 receptor (CSF-1R) signaling to polarize macrophages to immunosuppressive “M2” phenotype, and signal regulatory protein alpha (SIRPα)-CD47 interactions to inhibit phagocytosis. (b) Schematic illustration of efficient repolarization of M2 macrophage to effector “M1” phenotype by dual-function supramolecular therapeutic (anti-SIRPα-AK750)-mediated sustained inhibition of CSF-1R signaling and enhanced phagocytosis of cancer cells following inhibition of SIRPα. (c) Representation of the QM-optimized structure of the molecular subunit of supramolecular nanostructure, AK750. (d) Snapshot of all atomistic simulation of the molecular subunit (in red) interacting with the lipid bilayer at 100ns shows stable supramolecular structure; Lipid (SOPC) hydrophilic heads are shown in orange and blue spheres and lipid tails are shown in grey color. (e) Angle between vector defined on C-C bond on SOPC tail with Z-axis (axis perpendicular to bilayer plane) is depicted as θ. Deuterium order parameter (Scd) is calculated using θ. Scd is calculated on each carbon atom of phospholipid tail. Higher the -Scd, higher is the lipid tail ordering; Deuterium order parameter on each methylene group on saturated tail of co-lipid is depicted. Lipid tail ordering for BLZ945-containing lipid bilayer is the least. Lipid tail ordering of AK750 bilayer is similar to that of the pure lipid bilayer; (f) Tilt angle is the angle between vector joining center of mass of phospholipid tails and Z-axis (axis perpendicular to bilayer plane). Value of tilt angle is positive or negative depending on direction of the ripple. Its value is close to 0° when no ripples form. Distribution of tilt angle averaged over last 5 ns of MD trajectory. Broader the distribution larger is the tilt angle, higher is the extent of bilayer instability. (g) High resolution cryo-TEM image of AK750 showing size of ~100 nm and spherical morphology; (h) Graph shows the size distribution (hydrodynamic diameter) of a representative batch of AK750 as measured by dynamic light scattering. The description of panels c–g is adapted from ref. 19.