Multicolor Raman Beads for Multiplexed Tumor Cell and Tissue

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Letter

Multi-color Raman Beads for Multiplexed Tumor Cell and Tissue Imaging and in vivo Tumor Spectral Detection Qingqing Jin, Xinli Fan, Changmai Chen, Lei Huang, Jing Wang, and XinJing Tang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b00028 • Publication Date (Web): 13 Feb 2019 Downloaded from http://pubs.acs.org on February 15, 2019

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Analytical Chemistry

Multi-Color Raman Beads for Multiplexed Tumor Cell and Tissue Imaging and in vivo Tumor Spectral Detection QingQing Jin1, Xinli Fan1, Changmai Chen1, Lei Huang2, Jing Wang1, Xinjing Tang1* 1State

Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, NO. 38 Xueyuan Road, Beijing, 100191, China. 2Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 01238, USA

ABSTRACT: Developing new nanomaterials with strong and distinctive Raman vibrations in the biological Raman-silent region (1800–2800 cm -1) were highly desirable for Raman hyperspectral detection and imaging in living cells and animals. Herein, polymeric nanoparticles with monomers containing alkyne, cyanide, azide and carbon-deuterate were prepared as Ramanactive nanomaterials (Raman Beads) for bioimaging applications. Intense Raman signals were obtained due to the high density of alkyne, cyanide, azide and carbon-deuterate in single nanoparticles, in absence of metal (such as Au or Ag) as Raman enhancers. We have developed a library of Raman beads for frequency multiplexing through the end-capping substitutions of monomers, and demonstrated 5-color SRS imaging of mixed nanoparticles with distinct Raman frequencies. In addition, with further surface functionalization of targeting moieties (such as nucleic acid aptamers and targeting peptides), targetable Raman beads were successfully used as probes for tumor targeting and Raman spectroscopic detection, including multi-color SRS imaging in living tumor cells and tissues with high specificity. Further in vivo studies indicated that Raman beads anchored with targeting moieties were successfully employed to target tumors in living mice after tail intravenous injection and Raman spectral detection of tumor in live mice was achieved only through spontaneous Raman signal at biological Raman-silent region without any signal enhancement due to high density of Raman reporters in Raman beads. With further copolymerization of these monomers, Raman beads with super-multiplex barcoding could be readily achieved. Raman spectroscopy has become a powerful nondestructive imaging technique, which contains information on molecular vibrations and provides a highly specific fingerprint of the target molecules1-6. Raman spectroscopy has been widely utilized in cell imaging and in vivo imaging7-11 due to the advantages of narrow spectra (usually less than 2 nm), photo stability and near-infrared excitation scheme12,13. Currently, direct applications of Raman spectroscopy are severely restricted by its low signal intensities. Recent research efforts have been focused on the enhancement of weak Raman signals. Surface enhanced Raman spectroscopy (SERS) as a strategy has been widely utilized14-16. The enhanced substrates, which are made of coinage metals (such as Au and Ag), are generally required to boost the signals17,18. Moreover, the poor reproducibility and quantitative analysis of SERS have also limited their applicability19-23. Different from metal-based materials, metal-free polymer nanoparticles have demonstrated great potentials in bioimaging due to their convenient chemical functionalities24,25 Unfortunately, most polymeric nanoparticles rely on fluorescence reporters, such as fluorescent beads, which are limited by self-quenching, broad

emission, and photobleaching of fluorophores26. Thus, it is imperative to explore a new class of polymeric beads that can be readily synthesized and used for bioimaging and barcoding beyond conventional techniques. Currently, many Raman probes with signals in biological Ramansilent region have been developed as powerful tools in biological applications. In 2012, Sodeoka and coworkers27 synthesized and imaged a series of alkyne-tagged coenzyme Q (CoQ) analogues in live cells, which demonstrated alkyne tags are good candidates as Raman-responsive probes in living biological system. Huang and Chen lab28 later applied the alkyne as Raman reporter to image different biomolecules including nucleic acids, proteins, glycans, and lipids in live cells. In 2017, Min and coworkers29 created a palette of triple bond-conjugated near-infrared dyes that each displays a single peak in the cell-silent Raman spectral window, and demonstrated super-multiplex optical imaging. Moreover, Min and coworkers30 engineered a class of polyyne-based materials for optical supermultiplexing and achieved 20 distinct Raman frequencies, dubbed as ‘carbon rainbow’. Later, Wang et al31 successfully incorporated Raman tag with a single unnatural amino acid to image genetically targeted proteins in cells. Polymer-based material provides an alternative probe modality, offering condensed monomer concentration, convenient formulation, simple bioconjugation, and low toxicity. Min and Campos lab32 demonstrated a Raman-active polymer nanoparticle for live cell imaging using trisaminocyclopropenium. However, its synthesis required multiple steps. During the past several years, we are devoted to developing novel targetable polymeric beads (Figure 1) with different sizes as new Raman active nanomaterials and demonstrating their advantages for multi-color Raman bioimaging in cells as well as Raman spectral detection in living mice. We readily synthesized a series of poly (methacrylate) with high densities

Figure 1. The structure and spontaneous Raman representative Raman beads. a) Schematic structure active monomers. b) Synthetic route of Raman Spontaneous Raman spectra of Raman beads with

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spectra of of Raman beads. c). orthogonal

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vibrational modes of alkyne, nitrile, azido and carbon–deuterium bonds in the cell Raman-silent region. of alkyne, nitrile, azido or carbon–deuterium moieties (Figure 1a), which were defined as a new member of polymeric beads—Raman beads (Figure 1b). All the Raman beads show various vibrational bands in the cellular Raman-silent region (approx. 1800 to 2500 cm-1) with no need of the metal to boost up Raman signals (Figure 1c). End-capping substitutions of Raman-active monomers with alkyne, nitrile, azido and carbon–deuterium bonds expand the number of vibrational frequencies for different colors. To further multiplex the possibility of Raman signal, nine different types of acetylene based Raman monomers were designed simply by changing the substituents on both sides of the alkynes (Figure S1 and Figure S2). These monomers were than used for preparation of Raman beads through miniemulsion polymerization or dispersion polymerization (Table S1-4) and the beads were then characterized (Figure S3 and S4). The different Raman shifts were produced when different groups (such as alkyl, aryl, or silicon) were attached to the termini of alkynes. (Table S5 and Figure S5a) In addition to Raman shifts, the Raman intensities of these beads could be adjusted by using different monomers or controlling the sizes of the beads under different polymerization conditions (Table S1-4 and Figure S2). The results indicated that the bigger particle size, the higher intensity of Raman signal (Figure S5b). Hence, the intensity of Raman signal and the Raman shift could be regulated by simply adjusting the reactants and the reaction conditions.

different kinds of Raman beads in Figure 2b and corresponding Raman spectroscopy of each Raman beads was shown in Figure 2c. Since all the Raman beads exhibited strong Raman activities in the Raman-silent region in biological systems, they were employed as vibrational probes for targeting live-cell imaging under Raman microscopy after surface functionalization. These Raman beads were easily functionalized through the copolymerization with acrylic acid to achieve surface modification of carboxylic acid and further coupling with oligonucleotide aptamers or peptides for targeting specific cancer cells through the amide bond formation, as schematically illustrated in Figure 3a. Scanning electron microscope (SEM) images indicated the uniform spherical shape of Raman beads (Figure 3b). Their narrow size distributions with the average size of ~100 nm were confirmed using dynamic light scattering (DLS) (Figure 3c). In addition, Raman beads showed relative high cell viability with no obvious toxicity, as shown in Figure 3d. The good biocompatibility of Raman beads ensured further biological applications for cell Raman imaging and in vivo tumor Raman detection. Representative live-cell Raman images of Raman beads were displayed in Figure 3e.

Figure 3. a) Schematic illustration for preparation of functional Raman beads. b) representative SEM image of carboxyl modified Raman beads (m-CN-1-COOH, NCCH2CH2-). Scale bar: 5 μm. c) DLS profiles of carboxyl modified Raman beads (m-9-COOH, PhCC-CC-PhCH2-). d) Cell viability assay of Raman beads by incubation with MCF-7 cells for 48 h. e) Live-cell Raman images of MCF-7 cells treated with 10 μg/mL Raman beads AS1411-m-1 (HCC-CH2CH2-) for 6 h. Scale bars: 20 μm.

Figure 2. SRS imaging and spectral characterization of Raman beads. a) Representative SRS imaging of m-CN-2; b) SRS imaging of five mixed Raman beads; c) Raman spectra of five mixed Raman beads. Scale bars: 10 μm. Stimulated Raman imaging (SRS) is a coherent Raman spectroscopy technology29,30,33-35, which provided the enhancement in excitation efficiency and over 1000-fold improvement in imaging speed36-39. SRS images of each kind of Raman beads were also performed using stimulated Raman microscopy, as shown in Figure 2a. We selected five Raman beads with different Raman frequencies and mixed them uniformly to investigate the resolvable frequencies in the biological Raman-silent window. We readily presented a representative combined five-color image for five

Three Raman beads m-1 (2121 cm-1), m-3 (2186 cm-1) and m-4 (2236 cm-1) with carboxylic acid groups on surface were coupled with amine moiety from different targeting moieties throough amide bond formation. The as-prepared Raman beads were then used to to investigate the cellular behavior of Raman beads as contrast agents in live-cell imaging (Figure 4a). Two oligonucleotide aptamers (AS1411, 5′-GGT GGT GGTGGT TGT GGT GGT GGT GG-3′ and MUC1, 5′-GCA GTTGAT CCT TTG GAT ACC CTG G-3′) and one targeting peptide cRGDfk were respectively attached on Raman beads as targeting moieties for specific binding to nucleolin, mucin-1 protein and αvβ3 integrin that were overexpressed in many types of cancer cells, such as MCF-7 breast cancer cells. These three-color targeted Raman beads were used for the multiplex cell imaging experiments. The AS1411-labeled Raman beads (m-1, 2121 cm-1) were first evaluated in MCF-7 and 3T3-L1 cells. After the removal of free nanoparticles by gently washing the cells with media, the cells were then imaged using stimulated Raman microscope at the characteristic frequency of alkyne (2121 cm-1). As shown in Figure 4a, AS1411-Raman beads m-1 could specifically target MCF-7 cells. As expected, the internalization of AS1411 labeled Raman


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Analytical Chemistry beads was almost not observed for 3T3 cells due to the very low expression level of nucleolin protein on the cell surface. These observations clearly indicated that Raman beads with AS1411targeting moiety could be selectively uptaken into MCF-7 cells due to the specific interaction of AS1411 and nucleolin protein on MCF-7 cell surface. To show the generality, MUC1 aptamer and cRGDfk were also charged on the surface of Raman beads (m-3 and m-4, respectively) for Raman imaging of MCF-7 cell through target recognition. Similarly, MUC1-labeled Raman beads (m-3, 2186 cm-1) or cRGDfk-labeled Raman beads (m-4, 2236 cm-1)

cm-1 were observed in tumor tissues of living mice that were injected with Raman beads anchored with specific aptamers or

Figure 5. SRS images of sectioned slices of tumor tissues from mice intraveneously injected with targetable Raman beads (AS1411-, MUC1- and cRGDfk- anchored Raman beads m-9) and untargetable Raman beads (polyT- anchored Raman beads m-9, and nude Raman beads m-9) through tail vein. SRS images of cell morphology (C-H, 2845 cm-1, top row) and different Raman beads (2219 cm-1, down row) for AS1411- (a, b), MUC1- (c, d), cRGDfk(e, f), PolyT-(g, h) and nude beads (i, j) in tumor tissue slices. Scale bars: 20 μm.

Figure 4. a). Three-color targeted Raman beads, m-1 (2121 cm-1), m-3 (2186 cm-1), and m-4 (2236 cm-1), were incubated separately with MCF-7 cells. The images at 2845 cm-1 are lipid CH2 channels showing cell morphology. b). AS1411-m-1 (2121 cm-1), MUC1-m3 (2186 cm-1), and cRGD-m-4 (2236 cm-1) were incubated simultaneously with MCF-7 cells and 3T3-L1 cells. Scale bars: 20 μm. were enriched in MCF-7 cells instead of normal 3T3-L1 cells due to the high expression level of mucin-1 protein or αvβ3 integrin in MCF-7 cells (Figure 4a). In addition, we further employed them for multiplex Raman imaging by SRS microscope. As shown in Figure 4b, after co-culture of above three Raman beads with three different Raman shifts in MCF-7 and 3T3-L1 cells, all the three Raman beads were enriched in MCF-7 tumor cells while scarcely observed in 3T3-L1 cells. Thus, the multi-color Raman beads could target the same tumor cells simultaneously with spectral orthogonality in living cells, which greatly enhanced the accuracy of tumor diagnosis. We further applied these three targetable Raman beads (AS1411-, MUC1- and cRGDfk- anchored Raman beads m-9 around ~100 nm in diameter) for tumor tissue imaging and spectral detection in living mice. For comparison, ployT- (5′ -TTT TTT TTT TTT TTT TTT TTT TTT T-3′) labeled Raman beads m-9 and nude Raman beads m-9 were used as the negative controls. After injection of these Raman beads through tail vein of live mice, fresh tumor tissues were dissected and the sectioned slices of each tissue were then imaged with a SRS microscope at the characteristic frequency of alkyne on m-9 (2219 cm-1). As shown in Figure 5, no Raman signals from Raman beads were observed in tumor tissues that were treated with control beads (both ployT-Raman beads m-9 and nude Raman beads m-9). However, very obvious Raman signals at 2219

cRGDfk. The results further confirmed that these targeting moieties labeled Raman beads showed potential applications in target tumor tissue imaging in the Raman-silent region of biological systems. For in vivo Raman spectral detection of tumors (breast cancer animal model using MCF-7 cells), we then applied two targeting Raman beads (AS1411- and cRGDfk- anchored Raman beads m-9, 2219 cm-1) and one non-targeted control Raman beads (unlabeled nude Raman beads m-9). After injection of these Raman beads through tail vein of living mice, the spontaneous Raman signals from tumors were recorded on a slit-scanning Raman microscope with 785 nm laser. As shown in Figure 6a, we clearly observed the highly resolved Raman signals at 2219 cm−1 in biological Ramansilent region in the tumor of mice that were injected AS1411- and cRGDfk-Raman beads m-9, but not for unlabeled nude control Raman beads m-9. In order to determine the possible biodistribution of Raman beads in living mice, we further applied five different Raman beads, including three targeted Raman beads (AS1411-, MUC1- and cRGDfk- anchored Raman beads m-9, 2219 cm-1) and two non-targeted Raman beads (ployT- anchored Raman beads m-9, and unlabeled nude Raman beads m-9). Tissue slices of tumors and other organs (including heart, liver, spleen and kidney) were also imaged using Raman confocal microscope. As shown in Figure 6b-f, in addition to mice liver, three targetable Raman beads were only accumulated in the tumors of mice after tail intravenous injection of AS1411-, MUC1- and cRGDfk-anchored Raman beads m-9, respectively. While for the mice injected with two nontargeted Raman beads m-9, almost no nanoparticles were accumulated in tumors. For both cases, almost no accumulation of Raman beads was found in heart, kidney and spleen. This observation clearly indicated that the targeting moieties promoted the accumulation of Raman beads in tumors more efficiently, and these targetable Raman beads may be useful for early cancer diagnosis.



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Corresponding Author *E-mail: [email protected]

Competing financial interests Peking University is in the process of filing a patent protection of the reported design, the method and applications of Raman beads (CN 201610312523.9, May 13, 2016).

ACKNOWLEDGMENT This work was supported by National Major Scientific and Technological Special Project for “Significant New Drugs Development” (Grant No. 2017ZX09303013), the National Natural Science Foundation of China (grant No. 21877001, 81821004, 21672015).

REFERENCES

Figure 6. In vivo tumor targeting and Raman spectra detection (2219 cm−1) using AS1411- Raman beads m-9. a) Spontaneous Raman spectral detection of mice tumors in vivo after intravenous injection of three different Raman beads. Raman imaging and spectra of different mice organs after intravenous injection of b) AS1411-Raman beads, c) MUC1-Raman beads, d) cRGDfkRaman beads, and untargeted Raman beads: e) ployT-Raman beads, and f) nude Raman beads. At least three mice for each condition were analyzed. In summary, we have developed a series of novel Raman beads with Raman signals in biological Raman-silent region, which was a new strategy to image organic polymeric nanoparticles free from the use of fluorescent dyes or metals. Targeting moieties (such as oligonucleotide aptamers, peptides or antibody) would be readily conjugated on Raman beads with the carboxylic acid group on the surface through the amide bond formation. Three targeting moieties (AS1411-, MUC1, and cRGDfk-), respectively targeting nucleolin, mucin-1 protein and αvβ3 integrin that are overexpressed on the surfaces of MCF-7 cells were readily displayed on Raman beads and successfully used for Raman imaging of living cells and tumor tissues. multi-color SRS images of the same tumor cells were easily achieved with different targeting moieties with further enhancement of accuracy in tumor detection. In addition, both in vivo spontaneous Raman spectral detection of tumor and other organs in mice indicated that Raman intensity of our Raman beads was strong enough for direct Raman detection with no need of further Raman signal enhancement and Raman beads anchored with targeting moieties were successfully enriched in tumors through blood circulation. We expected that these Raman beads with Raman signals in biological Raman-silent region would be a promising and powerful tool in cancer diagnosis by selectively targeting the receptor proteins on tumor cell surfaces. With further copolymerization of these monomers, Raman beads with supermultiplex barcoding could be readily achieved and is ongoing.

ASSOCIATED CONTENT Supporting Information Supplementary Information accompanies this paper with experimental details and supporting figures. These materials are available free of charge via the Internet at http://pubs.acs.org.

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Multicolor Raman Beads for Multiplexed Tumor Cell and Tissue

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