Research ArticleBIOPHYSICS

On the design of precision nanomedicines

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Science Advances  24 Jan 2020:
Vol. 6, no. 4, eaat0919
DOI: 10.1126/sciadv.aat0919
  • Fig. 1 Examples of polymer brushes.

    Schemes of glycocalyx syndecan 4 LRP1 and SRB1 receptor. Proteins were reconstructed with atomic resolution using computational methods and minimized for a stretched brush conformation. Both insets show the details of the end part of the LRP1 next to the four HS chains and the SRB1 size with respect to the syndecans (A). Scheme of a POEGMA-PDPA polymersome decorated with angiopep peptides. The polymersomes were reconstructed using a minimized atomistic model of the single blocks that, in turn, were assembled into a 50-nm vesicle. The inset details show that the peptide is well embedded in the PEO brush.

  • Fig. 2 Repulsive steric potentials.

    Schematics of the binding of a multivalent POEGMA-PDPA polymersome decorated with angiopep peptide and targeting LRP1 (A) with PMPC chains and targeting SRB1 receptors (B) and with both ligands and targeting both receptors (C). The detail of the interaction between angiopep and LRP1 (D) and PMPC and SRB1 (E) modulated by both the PEO and glycocalyx brushes. The corresponding repulsive steric potentials exerted on the LRP1 insertion in the PEO brush (F) and the polymersome inserting in the glycocalyx brush (G). These are calculated as a function of the polymersome radius, R, and insertion parameter for the PEO chains, δP, and for the glycocalyx HS chains, δG, respectively.

  • Fig. 3 Scaling principles in superselectivity.

    Heat maps showing the fraction of bound particle θ as a function of the numbers of receptors <NR> and number of ligands NL (A), the additive inverse ligand affinity −βΔGij (B) and particle radius, R (C). Each map was analyzed to calculate the selectivity αmax and the corresponding <NR> onset, and the graphs of these as a function of the varying parameter are reported alongside.

  • Fig. 4 Multiplexing.

    Heat maps showing the fraction of bound particle θ calculated for multiplexed multivalent nanoparticles targeting ζ = 2 (A) and ζ = 3 (B) for ζ > 3. The data are shown using a radar plot with a heat map (C) where multiple receptors can be combined in a potentially infinite number of permutations.

  • Fig. 5 Selective cellular uptake.

    Average fluorescence per cell measured after 1-hour incubation of polymersomes with BECs and macrophages as a function of ligand numbers for the angiopep peptides (A) and PMPC chains (B) and angiopep peptides mixed with 200 PMPC chains (C). The blue line shows the selectivity index calculated using the BECs as target and the macrophages as sentinel cells.

  • Fig. 6 Superselectivity validation on BECs.

    Binding of polymersomes to BECs and macrophages decorated with angiopep peptides (A) and PMPC chains (B). The experimental data are fitted assuming the geometries shown in Fig. 2 and using Eq. 16. The two ligands are combined to form multiplexed polymersomes, and their binding is measured in BECs (C). The data are thus fitted using Eq. 19. Fitting parameters for angiopep: δP = 0.25, δG = 0.7, NPEO = 10, aPEO = 0.35 nm, σ0 = 3.14 nm2, R = 50 nm, d = 5 nm, LRP1 tip volume VP = 188.4 nm3, and angiopep KD = 313 nM. Best fit from monovalent: syndecan interchain distance dS = 20 nm, receptor density for BECs <NR>BEC = 18 molecules μm−2, and macrophages <NR>M = 13 molecules μm−2. Fitting parameters for PMPC: δP = 0.1, δG = 0.1, NPEO = 10, aPEO = 0.35 nm, σ0 = 3.14 nm2, R = 50 nm, d = 0 nm, SRB1 volume VP = 68.4 nm3, and syndecan interchain distance dS = 20 nm. Best fit from monovalent: PMPC KD = 350 nM, receptor density for BECs <NR >BEC = 17 molecules μm−2, and macrophages <NR>M = 25 molecules μm−2.

Supplementary Materials

  • Supplementary Materials

    This PDF file includes:

    • Supporting Information
    • Fig. S1. Scaling principles in superselectivity continued.
    • Fig. S2. Polymersome characterization.
    • Fig. S3. Polymersome cellular uptake.

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