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. 2020 Oct 19;59(43):19136-19142.
doi: 10.1002/anie.202006385. Epub 2020 Aug 26.

Proapoptotic Peptide Brush Polymer Nanoparticles via Photoinitiated Polymerization-Induced Self-Assembly

Hao Sun  1 , Wei Cao  1 , Nanzhi Zang  1 , Tristan D Clemons  1   2 , Georg M Scheutz  3 , Ziying Hu  1 , Matthew P Thompson  1 , Yifei Liang  1 , Maria Vratsanos  1 , Xuhao Zhou  1 , Wonmin Choi  1 , Brent S Sumerlin  3 , Samuel I Stupp  1   2   4 , Nathan C Gianneschi  1   5   2
Affiliations

Proapoptotic Peptide Brush Polymer Nanoparticles via Photoinitiated Polymerization-Induced Self-Assembly

Hao Sun et al. Angew Chem Int Ed Engl. .

Abstract

Herein, we report the photoinitiated polymerization-induced self-assembly (photo-PISA) of spherical micelles consisting of proapoptotic peptide-polymer amphiphiles. The one-pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150 mg mL-1 ) with tunable peptide loadings up to 48 wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide-functionalized nanoparticles imbued the proapoptotic "KLA" peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1) proteolytic resistance compared to the oligopeptide alone; 2) significantly enhanced cell uptake by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo-PISA in the large-scale synthesis of functional, proteolytically resistant peptide-polymer conjugates for intracellular delivery.

Keywords: nanoparticles; peptide delivery; peptide-polymer conjugates; polymerization; scaled synthesis.

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Figures

Figure 1.
Figure 1.
Schematic illustration of the one-pot photo-PISA approach to proapoptotic peptide brush polymer nanoparticles.
Figure 2.
Figure 2.
Synthesis and characterization of KLA peptide brush polymer nanoparticles. (a) Synthesis of peptide brush polymer nanoparticles by photo-PISA; (b) GPC analysis of peptide brush polymer macroCTA and resulting amphiphilic block copolymers (NP1-NP3); (c) DLS traces of peptide brush polymer nanoparticles (NP1-NP3); (d-h) TEM images of peptide brush polymer nanoparticles (NP1-NP5) with low and high magnifications.
Figure 3.
Figure 3.
Proteolytic cleavage of KLA peptide monomer, KLA brush polymer (poly(KLAAm10-co-DMA10)), and KLA peptide brush polymer nanoparticles (NPs 1–5) in the presence of trypsin (0.1μM) at 37 °C. All the peptide containing materials had a concentration of 200 μM with respect to peptide in PBS buffer (pH = 7.4). Data displayed as mean ± standard deviation of three independent experiments.
Figure 4.
Figure 4.
Cytotoxicity of free KLA peptide, poly[(KLAAm10-co-DMA30)-b-(DAAm280-co-DMA120)] (NP3), and poly[(KLAAm10-co-DMA10)-b-(DAAm280-co-DMA120)] (NP5) using a CellTiter-Blue cell viability assay. Concentrations were calculated with respect to the total KLA peptide content. HeLa cells were treated with peptide-containing materials and incubated for 72 h at 37 °C. Data displayed as mean ± standard deviation of three independent experiments.
Figure 5.
Figure 5.
Assessment of mitochondrial dysfunction induced by the peptide-containing materials using JC-1 probe. Live-cell confocal microscopy images of HeLa cells incubated with KLA peptide, CCCP, NP5 for desired periods of time. Prior to imaging, cells were stained with 2 μM of JC-probe (green, monomer, λex/em = 488 nm/510–550 nm; red, J-aggregates, λex/em = 488 nm/585–649 nm) and then Hoechst 33342 (blue, λex/em = 405 nm/ 420–480 nm). Scale bars, 20 μm.
See this image and copyright information in PMC

References

    1. Yu B, Hwang D, Jeon H, Kim H, Lee Y, Keum H, Kim J, Lee DY, Kim Y, Chung J, Jon S, Angew. Chem. Int. Ed 2019, 58, 2005–2010. - PubMed
    1. Drucker DJ, Nat. Rev. Drug Discov 2020, 19, 277–289. - PubMed
    1. Navaratna T, Atangcho L, Mahajan M, Subramanian V, Case M, Min A, Tresnak D, Thurber GM, J. Am. Chem. Soc 2020, 142, 1882–1894; - PMC - PubMed
    2. Kasper MA, Glanz M, Oder A, Schmieder P, von Kries JP, Hackenberger CPR, Chem Sci 2019, 10, 6322–6329; - PMC - PubMed
    3. Menacho-Melgar R, Decker JS, Hennigan JN, Lynch MD, J. Control Release 2019, 295, 1–12; - PMC - PubMed
    4. Roberts MJ, Bentley MD, Harris JM, Adv. Drug Deliv. Rev 2012, 64, 116–127; - PubMed
    5. Webber MJ, Appel EA, Vinciguerra B, Cortinas AB, Thapa LS, Jhunjhunwala S, Isaacs L, Langer R, Anderson DG, Proc. Natl. Acad. Sci. USA 2016, 113, 14189–14194; - PMC - PubMed
    6. Gentilucci L, De Marco R, Cerisoli L, Curr. Pharm. Design 2010, 16, 3185–3203; - PubMed
    7. Chatterjee J, Gilon C, Hoffman A, Kessler H, Accounts Chem. Res 2008, 41, 1331–1342; - PubMed
    8. Itoh H, Miura K, Kamiya K, Yamashita T, Inoue M, Angew. Chem. Int. Ed 2020, 59, 4564–4571; - PubMed
    9. Wu YT, Villa F, Maman J, Lau YH, Dobnikar L, Simon AC, Labib K, Spring DR, Pellegrini L, Angew. Chem. Int. Ed 2017, 56, 12866–12872. - PubMed
    1. Guidotti G, Brambilla L, Rossi D, Trends Pharmacol. Sci 2017, 38, 406–424. - PubMed
    1. Pokorski J, Church DC, Angew. Chem. Int. Ed 2020;
    2. Blum AP, Kammeyer JK, Gianneschi NC, Chem. Sci 2016, 7, 989–994; - PMC - PubMed
    3. Blum AP, Kammeyer JK, Yin J, Crystal DT, Rush AM, Gilson MK, Gianneschi NC, J. Am. Chem. Soc 2014, 136, 15422–15437. - PMC - PubMed

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