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• W3186755366 abstract "Open AccessCCS ChemistryRESEARCH ARTICLE6 Jun 2022Biomimetic Recognition-Based Bioorthogonal Host–Guest Pairs for Cell Targeting and Tissue Imaging in Living Animals Yan-Long Ma†, Chen Sun†, Zeshun Li, Ziyi Wang, Jianwen Wei, Qian Cheng, Li-Shuo Zheng, Xiao-Yong Chang, Kai Li, Ruibing Wang and Wei Jiang Yan-Long Ma† Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055 †Y.-L. Ma and C. Sun contributed equally to this work.Google Scholar More articles by this author , Chen Sun† State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078 †Y.-L. Ma and C. Sun contributed equally to this work.Google Scholar More articles by this author , Zeshun Li Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Ziyi Wang State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078 Google Scholar More articles by this author , Jianwen Wei State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078 Google Scholar More articles by this author , Qian Cheng State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078 Google Scholar More articles by this author , Li-Shuo Zheng Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Xiao-Yong Chang Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Kai Li Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author , Ruibing Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078 Google Scholar More articles by this author and Wei Jiang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101178 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Bioconjugation methods offer very important tools in studying biological systems. Synthetic host–guest pairs provide an alternative and complementary conjugation method to bioorthogonal reactions and biological association pairs. Nevertheless, macrocyclic hosts that can be used for in situ capture are limited and often rely on extremely high binding affinities. Herein, we report an alternative bioorthogonal host–guest pair that relies on highly selective molecular recognition in water. The host, namely amide naphthotube, possesses a biomimetic cavity with inward-directing hydrogen bonding sites and shows selective and strong binding to the guest (2-phenyl pyrimidine) even in biological media. Through anchoring the tetraphenyl ethylene-modified hosts to cell surfaces, the bioorthogonal host–guest pair can be applied in cell surface recognition, cell–cell interactions, and tissue imaging in mice. The bioorthogonality is originated from the high binding selectivity of the biomimetic macrocyclic host, which is different from other known host–guest pairs that have been applied in biological systems. This research provides a new noncovalent bioconjugation tool and a new concept for designing bioorthogonal host–guest pairs for biological applications. Download figure Download PowerPoint Introduction Bioconjugation methods are important tools widely used in chemical biology, molecular biology, and drug discovery. The chemistries underlying bioconjugation should be selective and nonperturbing to biological systems. Therefore, they have been collectively termed bioorthogonal chemistry.1 Over the past two decades, many bioorthogonal reactions2 have been developed for imaging and interrogating biological systems. These reaction-based bioconjugation methods are robust but often suffer from slow reaction kinetics, which limits their applications in animals or humans.3 Noncovalent molecular recognition4 has relatively fast kinetics (diffusion-controlled) and is thus complementary to reaction-based bioconjugation methods. The most widely used noncovalent association pairs are biotin/(strept)avidin pairs which have fast formation kinetics (kon ≈ 107 M−1 s−1) and high association constants (Ka = 1013–1015 M−1).5 Nevertheless, this natural robust binding pair also suffers from several drawbacks: (1) the molecular weight is high (>53 kDa) and it is difficult to modify (strept)avidin; (2) it suffers from background interference and nonspecific binding, limiting its biological applications; (3) the binding pair is irreversible and requires harsh condition to recover the captured proteins. In general, noncovalent association pairs with biological origin are all vulnerable to enzymatic reactions in the biological environment. Synthetic host–guest pairs have been proposed to overcome the problems of biological association pairs in terms of large size and fragility.6 They are usually small in size (∼1 kDa) and robust in biological environment. Noncovalent binding pairs are used in two common ways for biological applications: preassembly for subsequent deployment and in situ capture of target molecules. Many host–guest pairs have been used in the manner of preassembly,7–16 but it is challenging for molecular hosts to capture guests or guest-conjugated targets in complex biological media.17–30 It is even more challenging to achieve in situ capture in living animals, and there are only very limited successful examples via the employment of either monovalent31,32 or multivalent33,34 systems. In situ capture requires the host–guest pairs to be bioorthogonal, that is, the host–guest pairs are not interfered by biomolecules and salt ions. Nevertheless, synthetic hosts with a hydrophobic cavity also bind biological molecules in water.35–37 To be bioorthogonal, high-affinity host–guest pairs (Ka > 1010 M−1) are usually searched for to overcome the competition in complex biological environment.38–41 Recently, the extremely stable binding pair between cucurbit[7]uril and adamantylammonium/ferrocenemethylammonium derivatives (Ka ≈ 1012 ∼ 1015 M−1, in water) has emerged to be a versatile bioorthogonal system for biological applications.38 In contrast, biomolecular recognition systems usually have moderate binding constants (103–109 M−1) but a high binding selectivity.42 Therefore, similar biomimetic host–guest systems, which possess a high binding selectivity, may be bioorthogonal. However, this type of bioorthogonal host–guest pair with a biomimetic nature has not been demonstrated in vivo via monovalent binding mode. By mimicking the binding pockets of bioreceptors,43 we have developed a pair of macrocyclic hosts—amide naphthotubes—with hydrogen bonding donors inside their deep hydrophobic cavities.44–48 These biomimetic hosts are able to selectively recognize a variety of organic molecules in water by combining the hydrophobic effects with shielded hydrogen bonding. The highest association constants of the anti-configured naphthotube reach 106 M−1,49 which is comparable with those of some biomolecular systems. These biomimetic hosts and their complexes show promise to be bioorthogonal but have not been demonstrated in cells or living animals for biological applications. Herein, we report that the host–guest pair between anti-configured amide naphthotube and 2-phenyl pyrimidine is bioorthogonal and their potential for biological applications were demonstrated in cells and living animals. By anchoring the modified hosts to cell surfaces through tetraphenyl ethylene (TPE) sidechains, the bioorthogonal host–guest pair can be successfully applied for cell surface recognition, cell–cell interactions, and tissue imaging in living mice via noncovalent recognition and binding. The bioorthogonality is originated from the moderate binding affinity and high selectivity of the biomimetic macrocyclic host, which is different from other known host–guest pairs that have been applied in biological systems. This research provides a new noncovalent bioconjugation tool through a biomimetic macrocyclic host with an endofunctionalized cavity. Experimental Methods General method The artificial receptors (R1 and R2) and guests (G1, G2, G3, G4, and G5) were synthesized according to Supporting Information Scheme S1, and their intermediates and final products were characterized by standard analytical methods ( Supporting Information Figures S3–S59). 1H and 13C spectra were recorded on a Bruker Avance-400 or 500 NMR (Bruker, Switzerland) spectrometer. All chemical shifts are reported in ppm with residual solvents or sodium methyl sulfonate as the internal standard. Electrospray-ionization time-of-flight high-resolution mass spectrometry (ESI-TOF-HRMS) experiments were conducted on an applied biosystems Elite ESI-quadrupole time of flight (QqTOF) mass spectrometry (Thermo Scientific, United States) spectrometer system. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed on a Bruker Autoflex Speed MALDI-TOF (Bruker Daltonic, United States) equipped with a 337 nm nitrogen laser. α-Cyano-4-hydroxycinnamic acid (HCCA) was used as the matrix. Fluorescence (FL) and UV spectra were obtained on a Shimadzu RF-5301pc (Shimadzu, Japan) spectrometer and a UV–vis spectrophotometer (UV-2600, Shimadzu, Japan), respectively. Absolute emission quantum yields were recorded on Hamamatsu absolute photoluminescence (PL) quantum yield spectrometer C11347 (Hamamatsu, Japan) equipped with an integrating sphere. Isothermal titration calorimetry (ITC) experiments were carried out in 10 mM phosphate-buffered saline (PBS) buffer pH 7.4 (or fetal bovine serum, FBS) at 25 °C on a Malvern VP-ITC instrument (Malvern, United Kingdom). Further details on the titration experiments can be found in the Supporting Information. The size distribution and polydispersity index (PDI) of liposomes were evaluated by dynamic light scattering (DLS) [HORIBA scientific nano particle analyzer SZ-100 instrument (HORIBA, Ltd., Japan)]. The measurements were conducted in triplicate at 25 °C. Further details of the experimental methods for preparation of liposomes can be found in the Supporting Information. In vitro imaging experiments were performed on an inverted confocal laser scanning microscopy (CLSM; Zeiss LSM710, Zeiss, Germany). In vivo imaging experiments were performed on an IVIS Spectrum (Caliper LifeSciences, PerkinElmer, United States) imaging system. Cell culture All cell lines involved in this research were obtained from American Type Culture Collection (ATCC). All cells were incubated in Dulbecco’s modified Eagle’s medium (DMEM) and supplemented with 10% FBS at 37 °C in a humidified atmosphere containing 5% CO2. Cells were subcultured regularly using trypsin/ethylenediaminetetraacetic acid (EDTA). Further details of the experimental methods for biocompatibility analysis of the receptors in vitro, cell membrane anchoring, and molecular recognition in vitro can be found in the Supporting Information. In vivo experiment All animal experiment procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of Southern University of Science and Technology, and approved by the Animal Ethics Committee, Southern University of Science and Technology (Shenzhen, China). Male BALB/c mice at 8–10 weeks and male and female nude BALB/c nude mice at 6–8 weeks were purchased from Vital River Laboratory Animal Technology (Zhejiang, China). Animals were housed in a barrier facility on a 12 h light/dark cycle with food and water provided ab libitum. For building B16 tumor models, male BALB/c nude mice were subcutaneously injected B16 cells on the right flank. For building 4T1 tumor models, female BALB/c nude mice were subcutaneously injected 4T1 cells on the right flank. Further details of the experimental methods for the biocompatibility test of the receptors in vivo and R2 and R1 mediated tumor targeting investigations in vivo can be found in the Supporting Information. Statistical analysis All of the data are expressed as the mean ± standard error of the mean (s.e.m.) or mean ± standard deviation (SD) as indicated. Statistical analysis was conducted by one-way analysis of variance (ANOVA) for comparison of multiple groups using OriginPro 2015 software. 0.01 < *P ≤ 0.05 was considered significant, **P ≤ 0.01 was considered highly significant, ***P ≤ 0.001 was considered extremely significant. Results and Discussion Design and synthesis of the receptors and guests It has been reported that 2-phenyl pyrimidine shows a relatively high binding affinity to the anti-configured naphthotube in water (Ka = 7.0 × 105 M−1).49 This host–guest pair is very robust and thus selected for biological studies. To be used in a biological environment, the host and guest should be modified. Naphthotube H1 with an alkyne sidechain and G1 with a tetraethylene glycol unit were used to test the binding affinity of the host–guest pair in complex environment after modification. The binding constants between H1 and G1 were determined by ITC in PBS buffer and in FBS to be (1.5 ± 0.2) × 106 M−1 and ∼105 M−1, respectively ( Supporting Information Figure S2 and Table S1). The 1H NMR experiments ( Supporting Information Figure S1) indicate that the naphthotube binds to the phenyl pyrimidine unit (Figure 1a) rather than the tetraethylene glycol unit, although both of them can work as guests.50 These results suggest that the host–guest pair between the naphthotube and phenyl pyrimidine may be bioorthogonal and used in a complex biological environment. Figure 1 | The structures of artificial receptors, guests, and liposomes, as well as the mechanism of artificial receptors anchored onto cell membrane. (a) Cartoon representations of the binding models of H1 recognition of G1. (b) Cartoon representation of membrane insertion of the artificial receptors. (c) Chemical structures and cartoons of the artificial receptors (R1 and R2). (d) Chemical structures and cartoons of guest molecules. (e) Cartoon representations of the composing and structure of liposomes. Download figure Download PowerPoint For biological applications, we thought to anchor the host to cell surfaces. There are several reports that artificial receptors can enter into cell membranes and then undergo cellular internalization.21,51–55 Therefore, it is not easy to design an artificial receptor that can be firmly anchored onto cell membranes and retain molecular recognition ability to guest molecules in solution. However, it is known that hydrophobic molecules can be inserted into the cell membrane. Molecules with multiple negatively-charged groups cannot easily cross cell membranes due to the negative intramembranous resting potential of mammalian cells (−10 to −90 mV).56 These two features may be combined to construct artificial receptors that can stably anchor onto cell membranes (Figure 1b). Water-soluble naphthotubes carry multiple negatively-charged carboxylates and may not easily cross cell membranes, which may be the reason why their cytotoxicity is low.49 In addition, a hydrophobic moiety is required for membrane insertion. TPE57–60—a typical AIE luminogen (AIEgen)—was selected as the membrane anchor for three reasons: (1) it is relatively hydrophobic and would perfectly fit for membrane insertion; (2) it would show enhanced FL when inserted into the cell membrane due to the restricted motion (aggregation-induced emission (AIE) effect)61,62; (3) other AIEgens have shown firm membrane anchoring with a retention time (ca. 6 h) longer than that of commercial cell membrane dye DiD (ca. 1 h).63,64 Consequently, artificial receptors R1 and R2 (Figure 1c) were designed and synthesized by attaching a TPE moiety to the anti-configured naphthotube65 through Cu(I)-catalyzed click reaction ( Supporting Information Scheme S1 and Figures S3–S27). The optical properties of R1 and R2 demonstrate that both of them have good AIE features (R1, λem = 480 nm; R2, λem = 590 nm, Supporting Information Figures S61 and S62). These receptors may be anchored onto cell membranes via hydrophobic TPE moiety. The negatively-charged naphthotube with three carboxylate groups would avoid cellular internalization and is left outside cell surface for molecular recognition (Figure 1b). In addition, guest molecules G2–G5 (Figure 1d) were synthesized for cell and animal experiments ( Supporting Information Figures S46–S59). Guests (G2 and G4) exhibited green FL corresponding to 4-nitro-2,1,3-benzoxadiazole (NBD) in water (λex = 470 nm, λem = 540 nm, Supporting Information Figure S65). G5 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)2000 (DSPE-PEG2000) were used to prepare guest-modified liposomes (Figure 1e). Biocompatibility of the receptors in vitro and in vivo The cytotoxicity and acute toxicity of the receptors were first evaluated before cell and animal experiments. The cytotoxicity of R1 and R2 were evaluated with AML-12 (normal mice hepatocytes) and B16 (mouse melanoma cell) cell lines by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.66 Both R1 and R2 displayed minimal cytotoxicity against these two cell lines even at relatively high concentrations, except for R2 against AML-12. The cellular viabilities of AML-12 and B16 treated with R1 (up to 100 μM) were all over 85%, while the survival rates of AML-12 and B16 treated with R2 (100 μM) were over 75% and 95%, respectively ( Supporting Information Figure S66), suggesting that both R1 and R2 have generally good biocompatibility. To verify whether the artificial receptors (R1 and R2) could be administered safely in vivo, the acute toxicity and biocompatibility of R1 and R2 were studied on male BALB/c mice. Mice were randomly divided into three groups with five mice in each group, followed by the intravenous (i.v.) tail vein injection of PBS buffer (10 mM, pH 7.4), R1 (100 mg/kg), and R2 (25 mg/kg), respectively, according to the dose-escalation studies in our preexperiment. Then, these mice were observed for 14 days. During the 14-day follow-up, all the mice showed normal increments in body weight without significant differences between the three groups ( Supporting Information Figure S67a). In addition, the levels of the hepatic and renal function biomarkers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Crea), and urea ( Supporting Information Figures S67b and S67c), were similar across all three groups, suggesting that R1 and R2 did not induce toxicity to the kidneys and livers. Furthermore, the major organs’ histopathological analysis of the mice from all three groups also reveals no tissue injuries ( Supporting Information Figure S68). Based on these results, we conclude that the i.v. administrations of R1 (100 mg/kg) and R2 (25 mg/kg) in mice were at a tolerable dose level. Cell membrane anchoring and molecular recognition in vitro B16 cell line was taken as an example to demonstrate the anchoring abilities of artificial receptors (R1 and R2) onto cell membrane surfaces. B16 cells were incubated with R1 or R2 (40 μM) for 24 h and then were washed with PBS buffer for CLSM analysis. As shown in Figure 2a and Supporting Information Figure S69, the membrane surface of the cells was stained with blue or red FL, suggesting that R1 or R2 can be firmly and specifically anchored onto cell membrane surface. This conclusion was further confirmed by co-localization experiments with a specific cell membrane staining dye Dil. As shown in Figure 2b and Supporting Information Figure S70, the merged image showed co-localization of R1 and Dil on the membrane surface of B16 cells, and the Pearson correlation coefficient (PCC) between them is 0.86. Further experiments show that increasing the incubation time, concentration, and temperature gives rise to stronger fluorescent signals ( Supporting Information Figures S71–S73), suggesting that the number of artificial receptors on cell membrane could be fine-tuned by varying these parameters. R1- or R2-incubated B16 cells were monitored for 21 days to analyze the stability and retention time of the receptors on cell membranes. Surprisingly, the receptors remain on the cell membranes for over 12 days even when cells were dead (Figure 2c and Supporting Information Figures S74 and S75). However, the fluorescent intensity varies during the lengthy incubation because the cells undergo division, proliferation, and death. This astonishing long-term retention of the artificial receptors on cell membrane surface endowed them with a significant potential to anchor onto any selected tissues for targeted delivery in vivo. Figure 2 | Cell membrane anchoring in vitro. (a) CLSM images of B16 cells after treatment with R1 (left, 40 μM) or R2 (right, 40 μM) at 37 °C for 24 h. (b) Fluorescent co-localization of B16 cells stained with R1 (40 μM) and Dil (10 μM). (c) CLSM images of B16 cells stained with R1 (left, 40 μM) and R2 (right, 40 μM) for various durations. Download figure Download PowerPoint Moreover, these receptors are also applicable for membrane anchoring of AML-12, Raw 264.7 (mouse leukemia cells of monocyte macrophage), 4T1 (mouse breast cancer cells), LO2 (Human normal hepatocytes), HUVEC (human umbilical vein endothelial cells), 293T (human renal epithelial cells), A549 (human nonsmall cell lung cancer cells), and HepG2 (human hepatocellular liver carcinoma cells) cell lines ( Supporting Information Figures S76–S83). In addition, control experiments by treating 4T1 and HepG2 cells with R1 or R1-encapsulated liposomes ( Supporting Information Figure S84) clearly show that R1 alone stain on the cell membrane surfaces and does not obviously enter cells within 24 h. However, control compounds (C1 and C2) with one carboxylate group can enter cells by showing fluorescent signals intracellularly ( Supporting Information Figure S85). These results support that these receptors are successful cell membrane anchors for a wide scope of cell lines and these three carboxylate groups on the naphthotubes are important to avoid cell internalization. Molecular recognition on membrane surface was studied by using B16 cells anchored with R1 and guests G2 or G3. B16 cells were treated with R1 (40 μM) for 24 h, and were then incubated with G2 (40 μM) in DMEM medium for another 30 min before CLMS imaging. As shown in Figure 3a and Supporting Information Figure S86, the FL of R1 and G2 (the PCC of 0.83) is co-localized on the membrane surface of B16 cells, indicating that the naphthotube should be left on the cell surface and is still available for guest binding. The recognition properties of the naphthotubes were almost unaffected by the cell culture medium containing sugars, amino acids and other biological entities, suggesting the bioorthogonal nature of the recognition systems. In contrast, free G2 slowly diffused into cells that were not pretreated with R1 ( Supporting Information Figure S87). Additionally, ditopic guest G3 can conjugate two different cells (B16 and AML-12 cells) together (Figure 3b and Supporting Information Figure S88) to enable cell–cell interaction, further supporting that the recognition property of the naphthotubes is retained after the artificial receptors are inserted onto cell membrane. Figure 3 | Molecular recognition on the membrane surface in vitro. (a) Fluorescent co-localization of B16 cells stained with R1 (40 μM) and G2 (40 μM). (b) CLSM images of B16 (DiO) and AML-12 (Dil) cells conjugations via host–guest interaction (host: R2; guest: G3), the detailed experiments show in Supporting Information Figure S88. CLSM images of the recruitment and uptake of liposomes by B16 cells affected via R1: B16 cells pretreatment with PBS buffer or R1 (80 μM) for 12 h were further incubated with liposomes for 5 min, then analyzed at different time points (5 min, 1 and 2 h). (c) Cells without pretreatment with R1, incubated with 50 μL G5-modified liposome (G5, ∼0.56 mM; DSPE-PEG2000, ∼0.56 mM). (d) Cells with pretreatment with R1, incubated with 50 μL PEG-modified liposome (DSPE-PEG2000, ∼1.12 mM). (e) Cells with pretreatment with R1, incubated with 50 μL G5-modified liposome (G5, ∼0.56 mM; DSPE-PEG2000, ∼0.56 mM). The MFI of Cy 7.5 in these three groups after incubation with liposomes for 5 min was measured by Image J software. Download figure Download PowerPoint To further reveal the applicability of these receptors in complex nanosystems, guest-modified liposomes were studied with R1-anchored B16 cells. 4',6-diamidino-2-phenylindole (DAPI) and Cy 7.5 were employed to stain the nucleus of the cells and phospholipid bilayer of liposomes, respectively. Three groups of experiments were performed: (1) B16 cells pretreated with PBS buffer was incubated with G5-modified liposome (the control group); (2) B16 cells pretreated with R1 were incubated with PEG-modified liposome (the PEG group); (3) B16 cells pretreated with R1 were incubated with G5-modified liposome (the G5 group). After incubation with liposomes, cells were washed by PBS buffer three times and incubated with a fresh DMEM medium, before analysis by CLSM at different time points (5 min, 1 and 2 h). As shown in Figures 3c–3e, at 5 min, B16 cells from the G5 group exhibited stronger red FL when compared with the control group according to their mean FL intensity (MFI) of Cy 7.5. The fluorescent response of the control group should be due to nonspecific adsorption of liposomes on cells. The enhanced FL in the G5 group suggests that the artificial receptor can assist the recruitment of liposomes. Surprisingly, the PEG group also displays stronger FL than that of the control group. The low binding affinity between the naphthotube and PEG2000 (ca. 1.6 × 104 M−1, PEG2000:naphthotube = 1:1)50 is usually considered to be insufficient in biological systems. Thus, the observed, improved recognition is likely attributed to the multivalent binding14,15,17 between naphthotubes and PEG2000 ligands of liposome. Thereby, the current experimental results further support the bioorthogonal recognition property of the naphthotubes. In addition, the recruitment efficiency depends on the guest binding affinity: the G5 group shows stronger FL than that of the PEG group because phenylpyrimidine (7.0 × 105 M−1) is a better guest to the naphthotube than PEG2000. Under extended incubation, liposomes were gradually internalized by B16 cells presumably via artificial receptor mediated endocytosis. Therefore, these results further demonstrate that the artificial receptors can also endow cells with the ability to recruit and uptake guest-modified liposome via bioorthogonal molecular recognition. Tissue targeting and imaging in living animals The success achieved on cell experiments encouraged us to further explore the application of these host–guest pairs for tissue targeting and imaging in living animals. For animal experime" @default.
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