Fe3+@polyDOPA-b-polysarcosine, a T1-Weighted MRI Contrast

May 29, 2018 - Department of Medical Imagine, Hangzhou Medical College, Hangzhou 310053 , China. ∥ Innovation Center for Minimally Invasive Techniqu...
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Letter Cite This: ACS Macro Lett. 2018, 7, 693−698

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Fe3+@polyDOPA‑b‑polysarcosine, a T1‑Weighted MRI Contrast Agent via Controlled NTA Polymerization Yuedong Miao,† Fengnan Xie,‡,§ Jiayu Cen,† Fei Zhou,‡ Xinfeng Tao,† Jingfeng Luo,‡ Guocan Han,‡ Xianglei Kong,‡ Xiaoming Yang,‡ Jihong Sun,*,‡,∥ and Jun Ling*,† †

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China ‡ Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China § Department of Medical Imagine, Hangzhou Medical College, Hangzhou 310053, China ∥ Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou 310016, China S Supporting Information *

ABSTRACT: α-Amino acid N-thiocarboxyanhydrides (NTAs) are promising cyclic monomers to synthesize polypeptides and polypeptoids via controlled ring-opening polymerizations. Superior to N-carboxyanhydrides requiring protection on hydroxyl groups, NTAs are able to tolerate such nucleophiles. In this work, we report the synthesis of NTA monomers containing unprotected phenolic hydroxyl groups of 3,4-dihydroxy-Lphenylalanine (DOPA) and L-tyrosine (Tyr). Their controlled ROPs and sequential copolymerizations with polysarcosine (PSar) yield PDOPA, PTyr, and PDOPA-b-polysarcosine (PDOPA-b-PSar) products quantitatively with designable degrees of polymerization. Micellar nanoparticles of Fe3+@PDOPA-b-PSar have been prepared thanks to the strong chelation of iron(III) cation by catechol ligands that act as T1-weighted magnetic resonance imaging (MRI) contrast agents. For instance, Fe3+@PDOPA10-bPSar50 exhibits higher longitudinal relaxivity (r1 = 5.6 mM−1 s−1) than commercial Gd3+-based compounds. Effective MRI contrast enhancement in vivo of nude mice with a moderate duration (150 min) and 3D magnetic resonance angiography in rabbit illustrated by using volume rendering and maximal intensity projection techniques ignite the clinical application of Fe3+based polypept(o)ides in diagnostic radiology as Gd-free MRI contrast agents.

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Fe3+. Early studies mainly focused on the systems of sepia melanin and synthetic melanin-like materials including polydopamine.21−23 Recently, Li et al. designed undegradable FeIII-catecholate amphiphilic block copolymers via ring-opening metathesis polymerization (ROMP) and investigated the T1weighted MRI with HeLa cells in vitro.24 However, the synthetic method is complicated which requires multistep reactions to introduce the catechol groups. Poly(α-amino acid)s (PAAs) including polypeptides and polypeptoids are widely applied in biomedical fields, such as controlled drug release, gene delivery, stimuli-responsive biomaterials, and nanoscaled self-assembly systems due to their excellent biocompatibility and biodegradability.25−39 NCarboxyanhydrides (NCAs) are prepared by phosgenation of α-amino acids after protection of functional side groups. Their ring-opening polymerization (ROP) is the most used method to synthesize PAAs over the past decades.25,40−44 Hydroxyl groups can initiate NCA polymerization resulting in uncon-

agnetic resonance imaging (MRI) is a prominent technique to provide images with excellent anatomical details based on soft-tissue contrast and functional information in a noninvasive and real-time monitoring manner.1−3 On the basis of the different models of longitudinal (T1) and transverse (T2) relaxations, there are two types of MRI contrast agents, that is, positive (T1-weighted) and negative (T2-weighted) ones.4 In general, superparamagnetic iron oxide nanoparticles, for example, Fe3O4 and Fe2O3, are typical T2-agents,5−7 while paramagnetic gadolinium(III) complexes are most prevailing among T1-agents applied in diagnostic MRI.8−10 However, Gd deposition in skin and internal organs increases the risk of nephrogenic systemic fibrosis (NSF) for patients with impaired renal function.11−13 As another paramagnetic metal ion, Fe3+ with five unpaired electrons has high longitudinal relaxivity and low biotoxicity as a normal trace element in the body.14,15 Catechol ligands have a high affinity and binding capacity to coordinate Fe3+ cations, which has been widely applied both in biosome and biomimic systems.16−20 Although the standard tris-catecholate-Fe3+ complexation is extremely simple to encapsulate Fe3+ cations, few examples have been reported as T1-weighted MRI contrast agents despite superb relaxivity of © XXXX American Chemical Society

Received: April 19, 2018 Accepted: May 25, 2018

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DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698

Letter

ACS Macro Letters

Scheme 1. Synthesis of DOPA-NTA (A), Its Homopolymerization (B), and Block Copolymerization with Sar-NTA (C)

Table 1. ROPs of DOPA-NTA and Tyr-NTA, as Well as Block Copolymerizations of DOPA-NTA with Sar-NTA sample c

PD1 PD2c PD3c PTc,d PDS1e PDS2e PDS3e PDS4e

[DOPA-NTA]/[Sar-NTA]/[initiator]

yield (%)

producta

Mna (kg·mol−1)

Đb

10:0: 1 20:0: 1 50:0: 1 20:0: 1 10:50:1 10:20:1 5:50:1 20:50:1

94.4 89.8 81.1 98.6 95.1 97.0 98.4 98.9

PDOPA10 PDOPA19 PDOPA43 PTyr21 PDOPA10-b-PSar50 PDOPA9-b-PSar22 PDOPA5-b-PSar47 PDOPA17-b-PSar55

1.9 3.5 7.8 3.5 5.5 3.3 4.3 7.1

1.12 1.19 1.34 1.18 1.17 1.15 1.18 1.43

Determined by 1H NMR. bDetermined by MALDI-ToF. cInitiator is n-butylamine. [DOPA-NTA]0 = 0.5 mol × L−1, 24 h in THF at 60 °C. dTyrNTA as the monomer. eBenzylamine as the initiator, [DOPA-NTA]0 + [Sar-NTA]0 = 0.5 mol × L−1, 24 h in acetonitrile at 60 °C. a

trolled polymerization and poorly defined products.45,46 Thus, the protection of hydroxyl groups is necessary in the preparation of polypeptide with hydroxyl side groups.47−49 Deming et al. reported 3,4-dihydroxy-L-phenylalanine (DOPA)containing copolypeptides with the protection of phenolic hydroxyl groups before NCA polymerization.50 On the contrary, our group developed α-amino acid N-thiocarboxyanhydride (NTA) monomers and their controlled ROPs exhibited excellent tolerance to hydroxyl groups in primary amine-mediated polymerization.51,52 In this communication, we report two novel NTA monomers derived from DOPA and L-tyrosine (Tyr), that is, DOPA-NTA and Tyr-NTA, respectively, without protection on the phenolic hydroxyl groups. The synthesis can be carried out in open air directly by the treatment of DOPA or Tyr with Sethoxythiocarbonylmercaptoacetic acid (XAA) and ring closing reaction, which is similar to the protocol of sarcosine-NTA (Sar-NTA) with slight modifications (see Experimental Section, Scheme S1A and Figure S1 in Supporting Information). Purified white powders are obtained by recrystallization in a mixture of ethyl acetate and hexane. DOPA-NTA and TyrNTA are well characterized by nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR), and electrospray ionization mass spectrometry (ESI-MS; Figures S2−S5). In the case of DOPA-NTA, the methylene and methylidyne protons of the five-membered ring are shown at 2.85 ppm (p, Hg) and 4.78 ppm (t, Hf) while the signals at 9.26 ppm (s, Ha), 8.81 ppm (s, Hb) and 6.61−6.38 ppm (d, Hc,d,e) are assigned to amide, phenolic hydroxyl and aromatic protons, respectively.

Two characteristic stretching vibrations are observed in FT-IR at 1743 and 1662 cm−1 assigned to carboxyl (a-CO) and aminoformyl carbonyl (b-CO), respectively (Figures S4). A strong signal of 237.95 m/z in MS confirms molecular anion of DOPA-NTA. It is noteworthy that the NTA monomers can be stored at ambient temperature for several months without any decomposition or oligomerization differing from the NCAs requiring extreme anhydrous conditions. After being heated at 60 °C for 24 h, DOPA-NTA does not decompose or oligomerize as confirmed by 1H NMR with 1,3,5-trioxane as an internal standard (Figure S6). Thus, the NTA rings are stable in the presence of phenolic hydroxyl side groups, exhibiting excellent tolerance of the nucleophiles.51,52 Controlled ROPs of DOPA-NTA and Tyr-NTA are initiated by n-butylamine in dry THF at 60 °C (Scheme 1) with the results in Table 1. The obtained PDOPAs have been characterized by 1H NMR (Figure S7) where the molecular weights from 1.9 to 7.8 kg·mol−1 are calculated by the intensities of Hc,d,e and Hh consistent well with the theoretical values from the feed molar ratios of monomer to initiator ([DOPA-NTA]0/[n-butylamine]0). MALDI-ToF mass analysis (Figure S8) reveals a monomodal and symmetrical distribution with moderate polydispersity indices (Đ < 1.34) and illustrates that PDOPA chains contain butyl and amino end groups exclusively. Diblock copolymers of polypeptide-b-polypeptoid, that is, polypept(o)ides,34 were synthesized via the sequential ROPs of Sar-NTA and DOPA-NTA initiated by benzylamine since the secondary amine of the PSar chain-end is an initiator as efficient 694

DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698

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ACS Macro Letters

Figure 1. (A) 1H NMR spectra of PSar and PDOPA-b-PSar in DMSO-d6 (*water, **DMSO, ***diethyl ether). (B) SEC traces of PSar50 (I) and PDOPA10-b-PSar50 (II) in DMF. (C) DLS of Fe3+@PDOPA10-b-PSar50 in aqueous media at 25 °C. (D) TEM image of Fe3+@PDOPA10-b-PSar50 with the scale bar of 50 nm.

as primary amine (Scheme 1C, Table 1).53,54 We select PSar as the hydrophilic block for its great potential in biomedical application.55 Figure 1A illustrates a typical 1H NMR spectrum of polyDOPA-b-polysarcosine (PDOPA-b-PSar) copolymers with full assignment of the proton signals of both units. Methyl protons of sarcosine units (Hk′) arise in a broad range from 2.62 to 3.05 ppm. The PDOPA segment shows the characteristic signals at 8.97−8.25 ppm (Ha′) and 8.06−7.52 ppm (Hb′) attributed to the phenolic hydroxyl and amide protons, respectively. Methylene protons on the backbone of both Sar and DOPA units (Hh′ and Hi′) overlap in the range from 3.64 to 4.61 ppm. The DPs of PSar and PDOPA segments, as well as the molecular weights of the copolymers are calculated according to the intensities of end-group protons (Hc′) and the characteristic proton signals of Hk′ and Hd′,e′,f′. In SEC (Figure 1B), the retention time of PDOPA-b-PSar decreases obviously from that of the first block of PSar indicating the successful growth of PDOPA from the terminal amine groups of PSar. A slight tailing of diblock copolymer may be caused by adsorption phenomena onto the polystyrene column. The amphiphilic diblock products of PDOPA-b-PSar can form micelles by self-assembling in aqueous solution. The chelation of iron cations in the polypept(o)ide micelles was performed by the solvent exchange method. Iron(III) nitrate nonahydrate in DMF was added dropwise into a DMF solution of PDOPA-b-PSar under continuous stirring and followed by a freshly prepared aqueous solution of sodium ethoxide. The mixtures were dialyzed against deionized water to form Fe3+@PDOPA-b-PSar nanoparticles. After investigating polypept(o)ides with various ratios of hydrophobicity and hydrophilicity, i.e. the ratios of PDOPA and PSar segments (Table S1), we find PDOPA10-b-PSar50 is an ideal block composition to form the most stable Fe3+@PDOPA10-b-PSar50 nanoparticles labeled as NPDS1. When NPDS1 is 1.0 mg·mL−1, the concentration of Fe3+ is found to be 95.2 μg·mL−1

according to inductively coupled plasma mass spectrometry (ICP-MS) which is close to the theoretical maximum load. The hydrodynamic volumes and morphologies of the nanoparticles are analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), as shown in Figure 1C,D. NPDS1 micelles have the diameters of 28.6 nm, with uniform sizes and homogeneous distributions. The oxidation state of iron in NPDS1 is confirmed by XPS analysis. The two peaks at 712 and 724 eV are attributed to FeIII 2p3/2 and FeIII 2p1/2, respectively (Figure S9). The as-prepared Fe3+@PDOPA10-b-PSar50 nanoparticles can be directly used as a T1-weighted contrast agent for MRI. The longitudinal relaxivity (r1) of NPDS1 is measured to be 5.6 mM−1·s−1 in a 3.0 T magnetic field at 20 °C, as shown in Figure S10. It is noteworthy that such an r1 value reaches obvious higher enhancement than the commercial agents DOTA-Gd3+ (3.8 mM−1·s−1) and DTPA-Gd3+ (3.3 mM−1·s−1).56−58 The inset of Figure S10 demonstrates brighter solution of NPDS1 in phosphate buffered saline (PBS) with higher concentrations. Fe3+@PDOPA-b-PSar nanoparticles provide sufficient contrast in MRI for theranostic applications, not only the diagnostic angiography, but also the potential ability to screen patients in the tumor based on enhanced magnetic resonance signals. We investigated in vivo time-course positive MRI contrast by injecting 300 μL of NPDS1 solution (3.0 mg·mL−1) in saline via the lateral tail vein of nude mice. Images were acquired before and after the injection to monitor the distribution and the clearance of NPDS1 (Figure S11). By calculating the ratio of blood vessel signals (red circle in Figure S11) and liver signals (yellow circle) to the background noise, respectively, we observed that the blood vessels on T1-weighted MRI rapidly enhanced within 30 min, and then the enhancement gradually decreased until NPDS1 being washed out after 150 min. The duration of NPDS1 is longer than that of the commercial Gd3+-based agents (within 30 min).58 With gradual 695

DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698

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accumulation of nanoparticles into organ tissue like liver, the signal-to-noise ratio (SNR) of liver rapidly increases and then maintains at a high level. The in vivo magnetic resonance angiography of rabbits was performed by the injection via ear vein of 10 mL NPDS1 solution (6.0 mg·mL−1). Coronal 3D magnetic resonance (MR) images of arteries and veins have been recorded by using volume rendering (VR) and maximal intensity projection (MIP) techniques as shown in Figure 2. A video of 3D-

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00287. Experimental procedures and characterization data of 1H NMR, 13C NMR, FT-IR, ESI-MS, XPS, MALDI-ToF MS, MRI images, and cytotoxicity analysis (PDF). 3D-reconstructed MRI video (AVI).

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AUTHOR INFORMATION

Corresponding Authors

*Tel.: +86-571-86006762. E-mail: [email protected]. *Tel.: +86-571-87953739. E-mail: [email protected]. ORCID

Jun Ling: 0000-0002-0365-1381 Notes

The authors declare no competing financial interest.

■ Figure 2. (A) VR MR image of abdominal aorta and inferior vena cava. (B) MIP MR image of abdominal aorta and inferior vena cava. (C) MIP image of the separated abdominal aorta and its branch. (D) Axial time-course MRI images of rabbit abdomen.

ACKNOWLEDGMENTS This study was supported by the National Key Research and Development Program of China (2016YFA0100900), the National Natural Science Foundation of China (21674091, 81571738, 81430040), and the Fundamental Research Funds for the Central Universities (2018QNA4057).

reconstructed MR images can be found in Supporting Information. After the injection of NPDS1, axial MR images show significant and persistent enhancement at kidney and vessels for more than 120 min. The biocompatibility of NPDS1 was evaluated in NIH 3T3 cells (mouse embryonic fibroblast cell line) by the measurement of the inhibition of cell growth using standard 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The relative cell viability was determined by the comparison of the absorbance at 490 nm with that of the controls. Figure S12 illustrates NIH 3T3 cells cultivated for 48 h with various concentrations of NPDS1 from 0 to 500 μg· mL−1 with the data as an average of five repeating tests. The high cell viability over 85% indicates very low toxicity with NIH 3T3 cells. In summary, we provide novel DOPA-NTA and Tyr-NTA monomers with unprotected phenolic hydroxyl groups ready for controlled ROPs initiated by amines. The chain lengths of polypeptides are predictable by the feed ratios of monomer to initiator. The feasible and convenient synthesis of PDOPA without protection encourages its applications. We demonstrate a biocompatible MRI contrast agent of Fe3+@PDOPA-b-PSar nanoparticles which bears higher T1 contrast efficiency and longer circulation time up to 2.5 h than the commercial DOTAGd3+ and DTPA-Gd3+ agents. The MRI contrast enhancement is obtained in vivo of both nude mice and rabbits. As a novel Gd-free T1-weighted MRI contrast agent, such nontoxic Fe3+polypept(o)ides nanoparticles are clinically promising to replace traditional Gd3+ compounds in diagnostic angiography and further tumor imaging.

(1) Fox, M. D.; Raichle, M. E. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat. Rev. Neurosci. 2007, 8 (9), 700−711. (2) Sun, C.; Lee, J. S. H.; Zhang, M. Q. Magnetic nanoparticles in MR imaging and drug delivery. Adv. Drug Delivery Rev. 2008, 60 (11), 1252−1265. (3) Terreno, E.; Delli Castelli, D.; Viale, A.; Aime, S. Challenges for molecular magnetic resonance imaging. Chem. Rev. 2010, 110 (5), 3019−3042. (4) Lauffer, R. B. Paramagnetic metal complexes as water proton relaxation agents for NMR imaging - theory and design. Chem. Rev. 1987, 87 (5), 901−927. (5) Duguet, E.; Vasseur, S.; Mornet, S.; Devoisselle, J. M. Magnetic nanoparticles and their applications in medicine. Nanomedicine 2006, 1 (2), 157−168. (6) Xie, J.; Lee, S.; Chen, X. Y. Nanoparticle-based theranostic agents. Adv. Drug Delivery Rev. 2010, 62 (11), 1064−1079. (7) Corot, C.; Warlin, D. Superparamagnetic iron oxide nanoparticles for MRI: contrast media pharmaceutical company R&D perspective. Wires Nanomed Nanobi 2013, 5 (5), 411−422. (8) Laniado, M.; Weinmann, H. J.; Schorner, W.; Felix, R.; Speck, U. 1st use of Gd-DTPA dimeglumine in man. Physiol Chem. Phys. 1984, 16 (2), 157−165. (9) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Gadolinium(III) chelates as MRI contrast agents: Structure, dynamics, and applications. Chem. Rev. 1999, 99 (9), 2293−2352. (10) Cao, F. Y.; Huang, T. C.; Wang, Y. F.; Liu, F.; Chen, L. M.; Ling, J.; Sun, J. H. Novel lanthanide-polymer complexes for dye-free dual modal probes for MRI and fluorescence imaging. Polym. Chem. 2015, 6 (46), 7949−7957. (11) Grobner, T. Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol., Dial., Transplant. 2006, 21 (6), 1104−1108. (12) High, W. A.; Ayers, R. A.; Chandler, J.; Zito, G.; Cowper, S. E. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J. Am. Acad. Dermatol. 2007, 56 (1), 21−26.

■

696

REFERENCES

DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698

Letter

ACS Macro Letters (13) Aime, S.; Caravan, P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J. Magn Reson Imaging 2009, 30 (6), 1259−1267. (14) Thunus, L.; Lejeune, R. Overview of transition metal and lanthanide complexes as diagnostic tools. Coord. Chem. Rev. 1999, 184, 125−155. (15) Bakewell, S. J.; Carie, A.; Costich, T. L.; Sethuraman, J.; Semple, J. E.; Sullivan, B.; Martinez, G. V.; Dominguez-Viqueira, W.; Sill, K. N. Imaging the delivery of drug-loaded, iron-stabilized micelles. Nanomedicine 2017, 13 (4), 1353−1362. (16) Monahan, J.; Wilker, J. J. Specificity of metal ion cross-linking in marine mussel adhesives. Chem. Commun. 2003, 14, 1672−1673. (17) Harrington, M. J.; Masic, A.; Holten-Andersen, N.; Waite, J. H.; Fratzl, P. Iron-clad fibers: A metal-based biological strategy for hard flexible coatings. Science 2010, 328 (5975), 216−220. (18) Zeng, H. B.; Hwang, D. S.; Israelachvili, J. N.; Waite, J. H. Strong reversible Fe3+-mediated bridging between dopa-containing protein films in water. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (29), 12850−12853. (19) Anderson, T. H.; Yu, J.; Estrada, A.; Hammer, M. U.; Waite, J. H.; Israelachvili, J. N. The contribution of DOPA to substrate-peptide adhesion and internal cohesion of mussel-inspired synthetic peptide films. Adv. Funct. Mater. 2010, 20 (23), 4196−4205. (20) Lee, B. P.; Messersmith, P. B.; Israelachvili, J. N.; Waite, J. H. Mussel-inspired adhesives and coatings. Annu. Rev. Mater. Res. 2011, 41, 99−132. (21) Enochs, W. S.; Petherick, P.; Bogdanova, A.; Mohr, U.; Weissleder, R. Paramagnetic metal scavenging by melanin: MR imaging. Radiology 1997, 204 (2), 417−423. (22) Ju, K. Y.; Lee, J. W.; Im, G. H.; Lee, S.; Pyo, J.; Park, S. B.; Lee, J. H.; Lee, J. K. Bio-inspired, melanin-like nanoparticles as a highly efficient contrast agent for T1-weighted magnetic resonance imaging. Biomacromolecules 2013, 14 (10), 3491−3497. (23) Fan, Q. L.; Cheng, K.; Hu, X.; Ma, X. W.; Zhang, R. P.; Yang, M.; Lu, X. M.; Xing, L.; Huang, W.; Gambhir, S. S.; Cheng, Z. Transferring Biomarker into Molecular Probe: Melanin Nanoparticle as a Naturally Active Platform for Multimodality Imaging. J. Am. Chem. Soc. 2014, 136 (43), 15185−15194. (24) Li, Y. W.; Huang, Y. R.; Wang, Z.; Carniato, F.; Xie, Y. J.; Patterson, J. P.; Thompson, M. P.; Andolina, C. M.; Ditri, T. B.; Millstone, J. E.; Figueroa, J. S.; Rinehart, J. D.; Scadeng, M.; Botta, M.; Gianneschi, N. C. Polycatechol nanoparticle MRI contrast agents. Small 2016, 12 (5), 668−677. (25) Kricheldorf, H. R. Polypeptides and 100 years of chemistry of alpha-amino acid N-carboxyanhydrides. Angew. Chem., Int. Ed. 2006, 45 (35), 5752−5784. (26) Habraken, G. J. M.; Heise, A.; Thornton, P. D. Block copolypeptides prepared by N-carboxyanhydride ring-opening polymerization. Macromol. Rapid Commun. 2012, 33 (4), 272−286. (27) He, C. L.; Zhuang, X. L.; Tang, Z. H.; Tian, H. Y.; Chen, X. S. Stimuli-sensitive synthetic polypeptide-based materials for drug and gene delivery. Adv. Healthcare Mater. 2012, 1 (1), 48−78. (28) Huang, J.; Heise, A. Stimuli responsive synthetic polypeptides derived from N-carboxyanhydride (NCA) polymerisation. Chem. Soc. Rev. 2013, 42 (17), 7373−7390. (29) Deng, C.; Wu, J. T.; Cheng, R.; Meng, F. H.; Klok, H. A.; Zhong, Z. Y. Functional polypeptide and hybrid materials: Precision synthesis via alpha-amino acid N-carboxyanhydride polymerization and emerging biomedical applications. Prog. Polym. Sci. 2014, 39 (2), 330−364. (30) Lu, H.; Wang, J.; Song, Z. Y.; Yin, L. C.; Zhang, Y. F.; Tang, H. Y.; Tu, C. L.; Lin, Y.; Cheng, J. J. Recent advances in amino acid Ncarboxyanhydrides and synthetic polypeptides: chemistry, selfassembly and biological applications. Chem. Commun. 2014, 50 (2), 139−155. (31) Zhao, L. X.; Li, N. N.; Wang, K. M.; Shi, C. H.; Zhang, L. L.; Luan, Y. X. A review of polypeptide-based polymersomes. Biomaterials 2014, 35 (4), 1284−1301.

(32) Knight, A. S.; Zhou, E. Y.; Francis, M. B.; Zuckermann, R. N. Sequence programmable peptoid polymers for diverse materials applications. Adv. Mater. 2015, 27 (38), 5665−5691. (33) Shen, Y.; Fu, X. H.; Fu, W. X.; Li, Z. B. Biodegradable stimuliresponsive polypeptide materials prepared by ring opening polymerization. Chem. Soc. Rev. 2015, 44 (3), 612−622. (34) Klinker, K.; Barz, M. Polypept(o) ides: Hybrid systems based on polypeptides and polypeptoids. Macromol. Rapid Commun. 2015, 36 (22), 1943−1957. (35) Deming, T. J. Synthesis of side-chain modified polypeptides. Chem. Rev. 2016, 116 (3), 786−808. (36) Gangloff, N.; Ulbricht, J.; Lorson, T.; Schlaad, H.; Luxenhofer, R. Peptoids and polypeptoids at the frontier of supra- and macromolecular engineering. Chem. Rev. 2016, 116 (4), 1753−1802. (37) Liu, X.; Xiang, J. J.; Zhu, D. C.; Jiang, L. M.; Zhou, Z. X.; Tang, J. B.; Liu, X. R.; Huang, Y. Z.; Shen, Y. Q. Fusogenic Reactive Oxygen Species Triggered Charge-Reversal Vector for Effective Gene Delivery. Adv. Mater. 2016, 28 (9), 1743−1752. (38) Hoogenboom, R.; Schlaad, H. Thermoresponsive poly(2oxazoline)s, polypeptoids, and polypeptides. Polym. Chem. 2017, 8 (1), 24−40. (39) Birke, A.; Ling, J.; Barz, M. Polysarcosine-containing copolymers: Synthesis, characterization, self-assembly, and applications. Prog. Polym. Sci. 2018, 81, 163−208. (40) Farthing, A. C.; Reynolds, R. J. W. Anhydro-N-Carboxy-DLBeta-Phenylalanine. Nature 1950, 165 (4199), 647. (41) Deming, T. J. Facile synthesis of block copolypeptides of defined architecture. Nature 1997, 390 (6658), 386−389. (42) Deming, T. J. Living polymerization of alpha-amino acid-Ncarboxyanhydrides. J. Polym. Sci., Part A: Polym. Chem. 2000, 38 (17), 3011−3018. (43) Deming, T. J. Polypeptide and polypeptide hybrid copolymer synthesis via NCA polymerization. Adv. Polym. Sci. 2006, 202, 1−18. (44) Yang, S. Q.; Zhou, L. Z.; Su, Y.; Zhang, L. L.; Dong, C. M. Onepot photoreduction to prepare NIR-absorbing plasmonic gold nanoparticles tethered by amphiphilic polypeptide copolymer for synergistic photothermal-chemotherapy. Chin. Chem. Lett. 2018, DOI: 10.1016/j.cclet.2018.02.015. (45) Szwarc, M., The kinetics and mechanism of N-carboxy-α-aminoacid anhydride (NCA) polymerisation to poly-amino acids. Fortschritte der Hochpolymeren-Forschung; Springer, 1965. (46) Kricheldorf, H. R. α-Amino Acid N-Carboxyanhydrides and Related Heterocycles; Springer Pub.: Berlin, Heildelberg, NY, 1987. (47) Deng, C.; Rong, G. Z.; Tian, H. Y.; Tang, Z. H.; Chen, X. S.; Jing, X. B. Synthesis and characterization of poly(ethylene glycol)-bpoly(L-lactide)-b-poly(L-glutamic acid) triblock copolymer. Polymer 2005, 46 (3), 653−659. (48) Luo, K.; Yin, J. B.; Song, Z. J.; Cui, L.; Cao, B.; Chen, X. S. Biodegradable interpolyelectrolyte complexes based on methoxy poly(ethylene glycol)-b-poly(alpha,L-glutamic acid) and chitosan. Biomacromolecules 2008, 9 (10), 2653−2661. (49) Yang, Z. N.; Mao, Z. W.; Ling, J. Phosgene-free synthesis of non-ionic hydrophilic polyserine. Polym. Chem. 2016, 7 (3), 519−522. (50) Yu, M. E.; Deming, T. J. Synthetic polypeptide mimics of marine adhesives. Macromolecules 1998, 31 (15), 4739−4745. (51) Tao, X. F.; Zheng, B. T.; Bai, T. W.; Zhu, B. K.; Ling, J. Hydroxyl group tolerated polymerization of N-substituted glycine Nthiocarboxyanhydride mediated by aminoalcohols: A simple way to alpha-hydroxyl-omega-aminotelechelic polypeptoids. Macromolecules 2017, 50 (8), 3066−3077. (52) Zheng, B. T.; Tao, X. F.; Ling, J. Water Tolerated Polymerization of N-Substituted Glycine N-Thiocarboxyanhydride Initiated by Primary Amines. Acta Polym. Sin. 2018, 1, 72−79. (53) Birke, A.; Huesmann, D.; Kelsch, A.; Weilbacher, M.; Xie, J.; Bros, M.; Bopp, T.; Becker, C.; Landfester, K.; Barz, M. Polypeptoidblock-polypeptide copolymers: Synthesis, characterization, and application of amphiphilic block copolypept(o)ides in drug formulations and miniemulsion techniques. Biomacromolecules 2014, 15 (2), 548−557. 697

DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698

Letter

ACS Macro Letters (54) Liu, J. H.; Ling, J. DFT Study on Amine-Mediated RingOpening Mechanism of alpha-Amino Acid N-Carboxyanhydride and N-Substituted Glycine N-Carboxyanhydride: Secondary Amine versus Primary Amine. J. Phys. Chem. A 2015, 119 (27), 7070−7074. (55) Birke, A.; Ling, J.; Barz, M. Polysarcosine-Containing Copolymers: Synthesis, Characterization, Self-Assembly, and Applications. Prog. Polym. Sci. 2018, 81, 163−208. (56) Zhou, Z. J.; Wang, L. R.; Chi, X. Q.; Bao, J. F.; Yang, L. J.; Zhao, W. X.; Chen, Z.; Wang, X. M.; Chen, X. Y.; Gao, J. H. Engineered iron-oxide-based nanoparticles as enhanced T1 contrast agents for efficient tumor imaging. ACS Nano 2013, 7 (4), 3287−3296. (57) Powell, D. H.; Dhubhghaill, O. M.; Pubanz, D.; Helm, L.; Lebedev, Y. S.; Schlaepfer, W.; Merbach, A. E. Structural and dynamic parameters obtained from O-17 NMR, EPR, and NMRD studies of monomeric and dimeric Gd3+ complexes of interest in magnetic resonance imaging: An integrated and theoretically self consistent approach. J. Am. Chem. Soc. 1996, 118 (39), 9333−9346. (58) Liu, Q. M.; Chen, S.; Chen, J.; Du, J. Z. An asymmetrical polymer vesicle strategy for significantly improving T1MRI sensitivity and cancer-targeted drug delivery. Macromolecules 2015, 48 (3), 739− 749.

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DOI: 10.1021/acsmacrolett.8b00287 ACS Macro Lett. 2018, 7, 693−698