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. 2020 Jul 20;11(8):1562–1566. doi: 10.1021/acsmedchemlett.0c00212

An Amphiphilic Micromolecule Self-Assembles into Vesicles for Visualized and Targeted Drug Delivery

Weiwei Ma †,‡, Jingjing Bi †,*, Hao Wu †, Guisheng Zhang †,*
PMCID: PMC7430949  PMID: 32832024

Abstract

graphic file with name ml0c00212_0005.jpg

Described here is the first example of the construction of multifunctional drug delivery systems by employing an amphiphilic micromolecule. The intrinsic aggregation-induced emissive and tumor-targeting amphiphilic conjugate of β-d-galactose with tetraphenylethene (TPE–Gal), in which the hydrophobic TPE moiety spontaneously acts as the imaging chromophore and the hydrophilic Gal moiety spontaneously acts as the targeting ligand and galactosidase trigger, can self-assemble into fluorescent vesicles that can efficiently load both water-soluble and -insoluble anticancer drugs. In vitro and in vivo evaluations revealed that the pH/β-d-galactosidase dual-responsive doxorubicin (DOX)-loaded vesicles TPE–Gal@DOX exhibited good targeting effect and higher antitumor efficacy than free DOX. H&E staining analysis displayed remarkable necroses and weak cell proliferation in the tumor area and no toxicity to major organs, indicating the superior targeting antitumor therapeutic efficacy of TPE–Gal@DOX.

Keywords: β-d-Galactose-modified tetraphenylethenes, aggregation-induced emission, fluorescent vesicles, cell imaging, targeted drug delivery

Chemotherapy is an indispensable cancer treatment method. However, the poor pharmacokinetics and lack of tumor targeting of conventional chemotherapeutic drugs has limited their clinical use.1−3 Drug delivery systems (DDSs) are essential for improving the effectiveness of chemotherapy.4−8 Over the past years, amphiphilic block copolymers self-assembled into liposomes, micelles, or vesicles in selective solvents as DDSs for use in cancer treatment have attracted much attention.9−11 Recent research concerning DDSs has stressed multifunctionalization, which can achieve targeted delivery and triggered release of the drugs inside targeted cells as well as real-time monitoring of drug localization.12−16 The general multifunctionalization method was to physically wrap or chemically integrate a fluorescent dye and a targeting unit into the self-assembled skeletons to construct a visualized and targeted DDS. However, with such functionalizations, the physical and chemical properties of the DDSs may be changed: the behavior of labeled DDSs in endocytosis or phagocytosis may be different from that of unlabeled DDSs, and fluorescent dyes may be hydrolyzed and dissociated from the DDS during phagocytosis17 Especially, the toxicity and aggregation-caused quenching (ACQ) characteristics of traditional fluorescent dyes seriously limit their applications.18 Since the first report of the aggregation-induced emission (AIE) phenomenon by Tang et al.,19 fluorescent nanoparticles based on AIE-active tetraphenylethene (TPE) chromophores20 have emerged in bioimaging and drug delivery.21−26 These TPE-based copolymers or coordination polymer nanoparticles used for targeted drug delivery can efficiently address the ACQ drawbacks of traditional fluorescent-labeled multifunctional DDSs.

It is noteworthy that almost all of the known nanoparticle DDSs of liposomes, micelles, and vesicles were constructed by self-assembly of amphiphilic polymers. However, the polymeric DDSs have some manufacturing-related problems like low drug entrapment and stability problems due to the sensitive degradation of the polymer main chain or the spontaneous escape of the nanoparticles.27,28 Therefore, if multifunctional DDSs were self-assembled by amphiphilic micromolecules with intrinsic AIE and targeting characteristics (instead of wrapping or integrating a fluorescent dye and a targeting unit into the polymeric skeletons), this would produce a new generation of multifunctional DDSs that overcome most of the drawbacks of the traditional multifunctional DDSs. Herein we present an intrinsic AIE and tumor-targeting amphiphilic micromolecule, a conjugate of tetraphenylethene with β-d-galactose (TPE–Gal), which can facilely self-assemble into pH/β-d-galactosidase dual-responsive vesicles for cancer cell imaging, targeted drug delivery, and chemotherapy (Scheme 1). The hydrophobic TPE moiety of the novel amphiphile spontaneously acts as the imaging chromophore, and the Gal moiety spontaneously acts as the targeting ligand and galactosidase trigger.

Scheme 1. Synthesis of TPE–Gal and TPE–Gal Vesicles for Visualized and Targeted Drug Delivery.

Scheme 1

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Galectin-1, a 14 kDa laminin-binding lectin that is widely expressed in and around the membrane of various solid tumors cells,29,30 can bind to β-galactosides through a rigorous carbohydrate recognition domain.31 Meanwhile, β-galactosidase, a lysosomal enzyme that is known to be upregulated in various cancer subtypes, can be utilized to activate galactoside-containing DDSs.32−36 Based on the AIE behavior of hydrophobic TPE and the unique tumor-targeting ability of hydrophilic β-galactose, a rational design for developing novel visualized and targeted anticancer DDSs has emerged: the conjugates of TPE with β-d-galactose self-assemble into uniform and robust vesicles to load anticancer drugs. To the best of our knowledge, employing amphiphilic micromolecules in the construction of DDSs has not been reported previously.

The synthesis of TPE–Gal is illustrated in Scheme 1. The reaction of 4-hydroxybenzophenone with 1,6-dibromohexane in the presence of K2CO3 afforded 2, from which the TPE derivative 3 was obtained through the McMurry reaction.37 Further treatment of 3 with excess NaN3 gave azido compound 4. Finally, TPE–Gal was synthesized using the classic CuAAC reaction between 4 and propargyl-2,3,4,6-tetra-O-acetyl-β-d-galactoside (1) followed by global deacetylation with NaOMe/MeOH.

TPE–Gal exhibited extremely weak fluorescence in DMSO (10 μM), and the maximum peak was generally located at 390 nm. However, with the addition of water, the fluorescence intensity dramatically increased, and the maximum emission was broadened and red-shifted to 473 nm (Figure S1). When the water fraction reached to 90%, the fluorescence intensity of TPE–Gal was nearly 50-fold stronger than in pure DMSO, indicating the AIE characteristics of TPE–Gal. The morphology of TPE–Gal vesicles was observed by transmission electron microscopy (TEM) (Figure 1A) and exhibited a hollow spherical shape with a particle size of about 120 nm. In addition, the dynamic light scattering (DLS) assay (Figure S2) demonstrated that the average hydrodynamic size and the polydispersity index of TPE–Gal vesicles were 157.4 ± 7.69 nm and 0.074, respectively, disclosing that the vesicles had a relatively homogeneous size and good dispersibility in aqueous media without significant aggregation. The difference in particle size between TEM and DLS can be attributed to the measurement technique conditions. The zeta potential of TPE–Gal vesicles was determined to be −25 ± 2.3 mV (Figure S3). It is well-known that 150 nm nanoparticles with a slightly negative charge have good stability under physiological conditions and tend to accumulate in tumors more efficiently.38 The TPE–Gal vesicles were stable in water, PBS, and plasma of mice over multiple weeks without significant aggregation (Figure S4).

Figure 1.

Figure 1

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(A) TEM photograph of TPE–Gal vesicles. (B) Cumulative release profiles of DOX from TPE–Gal@DOX in different media. (C, D) Viabilities of (C) HepG2 cells and (D) normal L02 cells upon treatment with TPE–Gal@DOX and free DOX.

Water-soluble doxorubicin (DOX) and water-insoluble paclitaxel (PTX) were chosen as model drugs to investigate the loading capacity of TPE–Gal vesicles. TPE–Gal vesicles show a decent DOX loading capacity with a drug-loading content (DLC) of 15.4 wt %, which corresponded to an encapsulation efficiency (EE) of 88.5%. Furthermore, TEM images (Figure S5) clearly showed that the DOX-loaded TPE–Gal@DOX vesicles had a spherical morphology and good dispersion with a diameter of 165.2 ± 8.31 nm (Figure S6) and zeta potential of −17.1 ± 4.4 mV (Figure S7). Similarly, TPE–Gal@PTX also showed good PTX loading capacity with a DLC of 7.6 wt % and EE of 82.3%.

UV–vis absorption (Figure S8), IR (Figure S9), and fluorescence spectra (Figure S10) of different samples demonstrated the successful fabrication of TPE–Gal@DOX. Moreover, the distribution state of DOX in TPE–Gal@DOX was detected by differential scanning calorimetry (DSC) (Figure S11). The DSC thermogram of DOX shows one endothermic peak at 218 °C, while this peak cannot be observed for TPE–Gal@DOX, indicating that DOX is dispersed in the vesicles in an amorphous state instead of a crystalline state. This result also strongly proved the successful fabrication of TPE–Gal@DOX.

For an ideal DDS, it is critical to release the drug upon triggering by stimuli associated with specific microenvironmental changes. Under intracellular-mimicking high expression of galactosidase conditions (in the presence of 100 units of β-galactosidase), DOX can be rapidly released from TPE–Gal@DOX (Figure 1B), with cumulative DOX releases of ca. 25% and 50% in 2 and 12 h, respectively. In contrast, less than 10% drug release was observed in 12 h for TPE–Gal@DOX in the absence of galactosidase. Moreover, the fluorescence change could be detected with the naked eye under UV light (365 nm; Figure S12). It is well-known that the microenvironment of tumor tissues is more acidic than that of normal tissues. Then, the controllable DOX release at different pH was carried out. As shown in Figure 1B, the release of DOX from TPE–Gal@DOX was pH- and time-dependent. Consequently, the pH/β-galactosidase dual-responsive release behavior of TPE–Gal@DOX provides a theoretical basis for safe and efficient tumor chemotherapy.

The determination of hemolytic properties is a common biocompatibility test in drug carrier development. After 4 h of incubation, there was no obvious hemolysis at different concentrations of TPE–Gal, even at high dosages (Figures S13 and S14). It caused only 4.78 ± 1.04% hemolysis in fresh human blood at a concentration of 1000 μg/mL, suggesting that TPE–Gal possesses high hemocompatibility and low toxicity. The MTT assay showed that the cytotoxicity of TPE–Gal vesicles toward HepG2 cells was similar to that of controls (Figure S15), and the cells retained 85% viability even at a maximum concentration of 100 μg/mL. TPE–Gal@DOX and free DOX had almost the same antiproliferative effects on cancer cells at the same concentration of DOX (Figure 1C). Moreover, compared with free DOX, TPE–Gal@DOX showed a significantly lower cytotoxicity toward normal L02 cells (Figure 1D). These results indicated that the vesicle formulation had the capability of delivering DOX molecules into tumor cells, causing the intracellular release and leading to cytotoxicity.

The cellular uptake of TPE–Gal@DOX was evaluated by confocal laser scanning microscopy (CLSM). As shown in Figure 2A, in CLSM images using the blue (TPE) and red (DOX) fluorescent channels, the fluorescence intensity steadily increased over time, suggesting efficient uptake of vesicles by HepG2 cells and successful drug release from TPE–Gal@DOX in a time-dependent manner. After treatment with TPE–Gal@DOX for 0.5 h, HepG2 cells exhibited distinct fluorescence, with each cell showing a region of particularly high fluorescence intensity where both TPE and DOX were gathered. We hypothesized that this region might correspond to lysosomes, where the release of DOX from TPE–Gal@DOX led to the fluorescence of both TPE and DOX. After 2 h of incubation, the fluorescence of TPE appeared only in lysosomes and not in the nucleus, indicating that the vesicle just performs its delivery function and does not influence the biological fate of the drug. In the DOX fluorescence channel, the DOX molecules were released from vesicles in the lysosome and translocated into the cell nucleus. However, compared with HepG2 cells, similar TPE fluorescence but weak DOX fluorescence was observed at the same time for L02 cells. These phenomena illustrated that the TPE–Gal vesicles can be taken efficiently by cells for imaging but exhibit a sustained drug-release pattern only in tumor cells. Furthermore, the blue fluorescence of TPE from TPE–Gal vesicles mostly colocalized with the “green” fluorescence of LysoTracker near the nucleus (Figure 2B), indicating the indeed colocalization of TPE–Gal with lysosomes.

Figure 2.

Figure 2

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(A) CLSM images of the cellular uptake and controlled release behaviors of HepG2 cells and L02 cells. (B) CLSM images of HepG2 cells in TPE–Gal vesicles.

Encouraged by the exciting results of in vitro evaluations, the in vivo antitumor efficacy and tumor-targeting effect of TPE–Gal@DOX were evaluated in tumor-bearing mice by giving drugs intravenously. As shown in Figure 3A, the average tumor volume in the mice treated with saline solely and the blank TPE–Gal vesicles increased rapidly. In strong contrast, the tumor volume in the animals treated with free DOX increased slowly. To our delight, TPE–Gal@DOX exhibited a stronger inhibition effect on tumor growth compared with the free DOX group (Figure S16), which might be attributed to the enhanced cellular uptake of TPE–Gal@DOX by targeted delivery and pH/β-galactosidase-sensitive drug release at tumor sites. The biodistribution of DOX clearly expressed the amount of drug in each tissue (Figure S17). According to the results, the distribution of TPE–Gal@DOX was significantly lower in heart, spleen, lung, and kidney compared with that of free DOX, implying that DOX can be gradually eliminated in major organs with extended time. Notably, TPE–Gal@DOX achieved a higher concentration in the tumor in comparison with free DOX. Photographs of tumors on day 21 after the treatment also showed that TPE–Gal@DOX inhibited the tumor growth much better than free DOX (Figure 3C). In addition, as shown in Figure 3B, TPE–Gal@DOX showed no obvious influence on the bodyweight of mice, implying good biocompatibility of this delivery system. The histological examination of the tumors and main organs were evaluated after 21 days of treatment. As shown in Figure 3D, H&E staining of sectioned tumor tissues showed that increased apoptosis of tumor cells was observed in the TPE–Gal@DOX group compared with tissues in other groups, further indicating the superior antitumor therapeutic efficacy of TPE–Gal@DOX. Furthermore, the TPE–Gal@DOX group showed no apparent morphological difference with the saline groups in the heart, liver, spleen, lung, or kidney, proving that TPE–Gal@DOX caused no harm to the mice (Figure S18). All of these results imply that TPE–Gal vesicle is a very promising tumor-targeting drug carrier for cancer chemotherapy.

Figure 3.

Figure 3

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(A) Growth curves of the relative tumor volume. (B) Body weight of tumor-bearing mice. (C) Photographs of tumors excised on day 21 after treatment. (D) H&E staining of tumors.

In summary, a brand-new strategy for constructing multifunctional DDSs through self-assembly of intrinsic AIE and tumor-targeting amphiphilic micromolecules has been developed to overcome the drawbacks of traditional DDSs functionalized by wrapping or integrating a fluorescent dye or a targeting unit into polymeric carrier skeletons. The synthesized amphiphile, TPE–Gal, can facilely self-assemble into uniform and robust vesicles with an average hydrodynamic size of 157.4 ± 7.69 nm and a zeta potential of −25 ± 2.3 mV, disclosing that the vesicles could efficiently tend to accumulate in tumors. In vitro and in vivo investigations demonstrated that such nanovesicles with high biocompatibility can efficiently load both water-soluble and water-insoluble anticancer drugs, and the drug-loaded vesicles showed remarkably selective toxicity toward tumor cells and significantly higher antitumor efficacy than the free drugs. Therefore, the first-generation pH/β-galactosidase dual-responsive TPE–Gal vesicle DDSs are suitable for visualized and targeted anticancer drug delivery and the treatment of solid tumors. This work might provide a new perspective for developing a new generation of multifunctional DDSs.

Acknowledgments

We thank the NNSFC (U1604285 and 21877206), PCSIRT (IRT1061), and the 111 Project (D17007).

Glossary

Abbreviations

TPE

tetraphenylethene

Gal

β-d-galactose

DOX

doxorubicin

PTX

paclitaxel

DDS

drug delivery system

ACQ

aggregation-caused quenching

AIE

aggregation-induced emission

DMSO

dimethyl sulfoxide

DLS

dynamic light scattering

TEM

transmission electron microscopy

DLC

drug-loading content

EE

encapsulation efficiency

DSC

differential scanning calorimetry

UV–vis

ultraviolet–visible spectrophotometry

IR

infrared radiation

CLSM

confocal laser scanning microscopy; H&E, hematoxylin and eosin.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00212.

  • Additional figures as described in the text, synthetic and activity test procedures, and spectral data of the target compounds (PDF)

Author Contributions

All of the authors approved the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml0c00212_si_001.pdf (2.2MB, pdf)

References

  1. Riehemann K.; Schneider S. W.; Luger T. A.; Godin B.; Ferrari M.; Fuchs H. Nanomedicine—challenge and perspectives. Angew. Chem., Int. Ed. 2009, 48, 872–897. 10.1002/anie.200802585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Karthika V.; Kaleeswarran P.; Gopinath K.; Arumugam A.; Govindarajan M.; Alharbi N. S.; Khaled J. M.; Al-Anbr M. N.; Benelli G. Biocompatible properties of nano-drug carriers using TiO2-Au embedded on multiwall carbon nanotubes for targeted drug delivery. Mater. Sci. Eng., C 2018, 90, 589–601. 10.1016/j.msec.2018.04.094. [DOI] [PubMed] [Google Scholar]
  3. Guha P.; Roy B.; Nahak P.; Karmakar G.; Chang C. H.; Bikov A. G.; Akentiev A. B.; Noskov B. A.; Mandal A. K.; Kumar A.; Hassan P. A.; Aswal V. K.; Misono T.; Torigoe K.; Panda A. K. Exploring the dual impact of hydrocarbon chainlength and the role of piroxicam a conventional NSAID on soylecithin/ion pair amphiphiles mediated hybrid vesicles for brain-tumor targeted drug delivery. Colloids Surf., A 2018, 546, 334–345. 10.1016/j.colsurfa.2018.03.025. [DOI] [Google Scholar]
  4. Tibbitt M. W.; Dahlman J. E.; Langer R. Emerging frontiers in drug delivery. J. Am. Chem. Soc. 2016, 138, 704–717. 10.1021/jacs.5b09974. [DOI] [PubMed] [Google Scholar]
  5. Wilhelm S.; Tavares A. J.; Dai Q.; Ohta S.; Audet J.; Dvorak H. F.; Chan W. C. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 2016, 1, 16014. 10.1038/natrevmats.2016.14. [DOI] [Google Scholar]
  6. Yu J.; Chen Y.; Zhang Y. H.; Xu X.; Liu Y. Supramolecular assembly of coronene derivatives for drug delivery. Org. Lett. 2016, 18, 4542–4545. 10.1021/acs.orglett.6b02183. [DOI] [PubMed] [Google Scholar]
  7. Kostka L.; Kotrchová L.; Šubr V.; Libánská A.; Ferreira C. A.; Malátová I.; Lee H. J.; Barnhart T. E.; Engle J. W.; Cai W.; Šírová M.; Etrych T. HPMA-based star polymer biomaterials with tuneable structure and biodegradability tailored for advanced drug delivery to solid tumours. Biomaterials 2020, 235, 119728. 10.1016/j.biomaterials.2019.119728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Xia D.; Li Y.; Jie K.; Shi B.; Yao Y. A Water-soluble cyclotriveratrylene-based supra-amphiphile: synthesis, pH-responsive self-assembly in water, and its application in controlled drug release. Org. Lett. 2016, 18, 2910–2913. 10.1021/acs.orglett.6b01264. [DOI] [PubMed] [Google Scholar]
  9. Wicki A.; Witzigmann D.; Balasubramanian V.; Huwyler J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J. Controlled Release 2015, 200, 138–157. 10.1016/j.jconrel.2014.12.030. [DOI] [PubMed] [Google Scholar]
  10. Discher D. E.; Eisenberg A. Polymer vesicles. Science 2002, 297, 967–973. 10.1126/science.1074972. [DOI] [PubMed] [Google Scholar]
  11. Maeda H.; Nakamura H.; Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Delivery Rev. 2013, 65, 71–79. 10.1016/j.addr.2012.10.002. [DOI] [PubMed] [Google Scholar]
  12. Rahimi M.; Safa K. D.; Alizadeh E.; Salehi R. Dendritic chitosan as a magnetic and biocompatible nanocarrier for the simultaneous delivery of doxorubicin and methotrexate to MCF-7 cell line. New J. Chem. 2017, 41, 3177–3189. 10.1039/C6NJ04107H. [DOI] [Google Scholar]
  13. Prabaharan M.; Grailer J. J.; Pilla S.; Steeber D. A.; Gong S. Gold nanoparticles with a monolayer of doxorubicin-conjugated amphiphilic block copolymer for tumor-targeted drug delivery. Biomaterials 2009, 30, 6065–6075. 10.1016/j.biomaterials.2009.07.048. [DOI] [PubMed] [Google Scholar]
  14. Rejeeth C.; Vivek R.; NipunBabu V.; Sharma A.; Ding X.; Qian K. Cancer nanomedicine: from PDGF targeted drug delivery. MedChemComm 2017, 8, 2055–2059. 10.1039/C7MD00391A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Srinivasarao M.; Galliford C. V.; Low P. S. Principles in the design of ligandtargeted cancer therapeutics and imaging agents. Nat. Rev. Drug Discovery 2015, 14, 203–219. 10.1038/nrd4519. [DOI] [PubMed] [Google Scholar]
  16. Paul A.; Biswas A.; Sinha S.; Shah S. S.; Bera M.; Mandal M.; Singh N. D. P. Push–pull stilbene: visible light activated photoremovable protecting group for alcohols and carboxylic acids with fluorescence reporting employed for drug delivery. Org. Lett. 2019, 21, 2968–2972. 10.1021/acs.orglett.9b00124. [DOI] [PubMed] [Google Scholar]
  17. Xue X.; Zhao Y.; Dai L.; Zhang X.; Hao X.; Zhang C.; Huo S.; Liu J.; Liu C.; Kumar A.; Chen W. Q.; Zou G.; Liang X. J. Spatiotemporal drug release visualized through a drug delivery system with tunable aggregation-induced emission. Adv. Mater. 2014, 26, 712–717. 10.1002/adma.201302365. [DOI] [PubMed] [Google Scholar]
  18. Wang X.; Yang Y.; Yang F.; Shen H.; Wu D. pH-triggered decomposition of polymeric fluorescent vesicles to induce growth of tetraphenylethylene nanoparticles for long-term live cell imaging. Polymer 2017, 118, 75–84. 10.1016/j.polymer.2017.04.064. [DOI] [Google Scholar]
  19. Luo J.; Xie Z.; Lam J. W. Y.; Cheng L.; Tang B. Z.; Chen H.; Qiu C.; Kwok H. S.; Zhan X.; Liu Y.; Zhu D. Aggregation-induced emission of 1-methyl-1,2,3,4,5-pentaphenylsilole. Chem. Commun. 2001, 1740–1741. 10.1039/b105159h. [DOI] [PubMed] [Google Scholar]
  20. Tong H.; Hong Y.; Dong Y.; Haussler M.; Lam J. W.; Li Z.; Guo Z.; Guo Z.; Tang B. Z. Fluorescent ‘‘light-up’’ bioprobes based on tetraphenylethylene derivatives with aggregation-induced emission characteristics. Chem. Commun. 2006, 35, 3705–3707. 10.1039/B608425G. [DOI] [PubMed] [Google Scholar]
  21. Han X.; Liu D. E.; Wang T.; Lu H.; Ma J.; Chen Q.; Gao H. Aggregation-induced-emissive molecule incorporated into polymeric nanoparticulate as FRET donor for observing doxorubicin delivery. ACS Appl. Mater. Interfaces 2015, 7, 23760–23766. 10.1021/acsami.5b08202. [DOI] [PubMed] [Google Scholar]
  22. Song S.; Zheng Y. S. Hollow spheres self-assembled by a tetraphenylethylene macrocycle and their transformation to bird nests under ultrasound. Org. Lett. 2013, 15, 820–823. 10.1021/ol3035005. [DOI] [PubMed] [Google Scholar]
  23. Li M.; Hong Y.; Wang Z.; Chen S.; Gao M.; Kwok R. T.; Qin W.; Lam J. W.; Zheng Q.; Tang B. Z. Fabrication of chitosan nanoparticles with aggregation-induced emission characteristics and their applications in long-term live cell imaging. Macromol. Rapid Commun. 2013, 34, 767–771. 10.1002/marc.201200760. [DOI] [PubMed] [Google Scholar]
  24. Yu G.; Zhang M.; Saha M. L.; Mao Z.; Chen J.; Yao Y.; Zhou Z.; Liu Y.; Gao C.; Huang F.; Chen X.; Stang P. J. Antitumor activity of a unique polymer that incorporates a fluorescent self-assembled metallacycle. J. Am. Chem. Soc. 2017, 139, 15940–15949. 10.1021/jacs.7b09224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wang L.; Wang W.; Xie Z. Tetraphenylethylene-based fluorescent coordination polymers for drug delivery. J. Mater. Chem. B 2016, 4, 4263–4266. 10.1039/C6TB00952B. [DOI] [PubMed] [Google Scholar]
  26. Ye F.; Liu Y.; Chen J.; Liu S. H.; Zhao W.; Yin J. Tetraphenylene-coated near-infrared benzoselenodiazole dye: AIE behavior, mechanochromism, and bioimaging. Org. Lett. 2019, 21, 7213–7217. 10.1021/acs.orglett.9b02292. [DOI] [PubMed] [Google Scholar]
  27. Wan Q.; Liu M. Y.; Xu D. Z.; Huang H. Y.; Mao L. C.; Zeng G. J.; Deng F. J.; Zhang X. Y.; Wei Y. Facile fabrication of amphiphilic AIE active glucan via formation of dynamic bonds: self assembly, stimuli responsiveness and biological imaging. J. Mater. Chem. B 2016, 4, 4033–4039. 10.1039/C6TB00776G. [DOI] [PubMed] [Google Scholar]
  28. Wang X.; Yang Y. Y.; Zuo Y.F.; Yang F.; Shen H.; Wu D. C. Facile creation of FRET systems from a pH-responsive AIE fluorescent vesicle. Chem. Commun. 2016, 52, 5320–5323. 10.1039/C6CC01706A. [DOI] [PubMed] [Google Scholar]
  29. Rabinovich G. A. Galectin-1 as a potential cancer target. Br. J. Cancer 2005, 92, 1188–1192. 10.1038/sj.bjc.6602493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Liu F. T.; Rabinovich G. A. Galectins as modulators of tumour progression. Nat. Rev. Cancer 2005, 5, 29–41. 10.1038/nrc1527. [DOI] [PubMed] [Google Scholar]
  31. Thijssen V. L.; Hulsmans S.; Griffioen A. W. The galectin profile of the endothelium altered expression and localization in activated and tumor endothelial cells. Am. J. Pathol. 2008, 172, 545–553. 10.2353/ajpath.2008.070938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Asanuma D.; Sakabe M.; Kamiya M.; Yamamoto K.; Hiratake J.; Ogawa M.; Kosaka N.; Choyke P. L.; Nagano T.; Kobayashi H.; Urano Y. Sensitive β-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo. Nat. Commun. 2015, 6, 6463. 10.1038/ncomms7463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sharma A.; Kim E. J.; Shi H.; Lee J. Y.; Chung B. G.; Kim J. S. Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation. Biomaterials 2018, 155, 145–151. 10.1016/j.biomaterials.2017.11.019. [DOI] [PubMed] [Google Scholar]
  34. Legigan T.; Clarhaut J.; Tranoy-Opalinski I.; Monvoisin A.; Renoux B.; Thomas M.; Le Pape A.; Lerondel S.; Papot S. The first generation of β-galactosidase-responsive prodrugs designed for the selective treatment of solid tumors in prodrug monotherapy. Angew. Chem., Int. Ed. 2012, 51, 11606–11610. 10.1002/anie.201204935. [DOI] [PubMed] [Google Scholar]
  35. Liu X.; Shao W.; Zheng Y.; Yao C.; Peng L.; Zhang D.; Hu X. Y.; Wang L. GSH-responsive supramolecular nanoparticles constructed by β-d-galactose-modified pillar[5]arene and camptotecin prodrug for targeted anticancer drug delivery. Chem. Commun. 2017, 53, 8596–8599. 10.1039/C7CC04932C. [DOI] [PubMed] [Google Scholar]
  36. Yang K.; Yang K.; Chao S.; Wen J.; Pei Y.; Pei Z. A supramolecular hybrid material constructed from pillar[6]arene-based host-guest complexation and ZIF-8 for targeted drug delivery. Chem. Commun. 2018, 54, 9817–9820. 10.1039/C8CC05665J. [DOI] [PubMed] [Google Scholar]
  37. Dong Y.; Wang W.; Zhong C.; Shi J.; Tong B.; Feng X.; Zhi J.; Dong Y. Investigating the effects of side chain length on the AIE properties of water-soluble TPE derivatives. Tetrahedron Lett. 2014, 55, 1496–1500. 10.1016/j.tetlet.2014.01.062. [DOI] [Google Scholar]
  38. Yu Q.; Wei Z.; Shi J.; Guan S.; Du N.; Shen T.; Tang H.; Jia B.; Wang F.; Gan Z. Polymer-doxorubicin conjugate micelles based on poly(ethylene glycol) and poly(N-(2-hydroxypropyl)methacrylamide): effect of negative charge and molecular weight on biodistribution and blood clearance. Biomacromolecules 2015, 16, 2645–2655. 10.1021/acs.biomac.5b00460. [DOI] [PubMed] [Google Scholar]

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Supplementary Materials

ml0c00212_si_001.pdf (2.2MB, pdf)

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