A Water-Soluble Photothermal Host–Guest Complex with pH-Sensitive Superlarge Redshift Absorption

Open AccessCCS ChemistryCOMMUNICATION1 Oct 2021A Water-Soluble Photothermal Host–Guest Complex with pH-Sensitive Superlarge Redshift Absorption Xiao-Qi Xu, Hongguang Liao, Haocheng Liu, Yanji Chu, Yonglin He and Yapei Wang Xu Department of Chemistry, Renmin University China, Beijing 100872 Google Scholar More articles by this author , Liao Liu Chu *Corresponding author: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.020.202000505 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Near infrared (NIR) absorbers for photothermal therapy are arousing great attention in tumor diagnosis ablation. However, the inevitably wide distribution NIR generally causes equal injuries tissues healthy tissues. An initiative targeting strategy based on pH-sensitive redshift absorption has been proposed NIR-induced hyperthermia only tissue. In work, we develop a absorber superlarge from middle visible light region once pH value drops. We also determined supramolecular route improve water solubility as well thermal stability aqueous solutions. Animal experiments reveal that microenvironment can trigger selective absorbing, which is thus responsible tumor-selective Based easy preparation, low cytotoxicity, excellent selectivity, complex reliable agent intelligent tumor-specific treatment. Download figure PowerPoint Introduction showing potential clinical treatment deeper relative other wavelengths due less hemoglobin.1–5 Among methods utilize light, conversion via nonradiative emission highest quantum efficiency regarded an attractive choice treatment.6–10 It generate diseased tissues, particularly laying groundwork (PTT) against cancer diseases.11–19 Nevertheless, inevitable may cause undesired injury, or side effects, conversion. To surmount obstacle, two strategies including passive have pursued ensure specifically tissues.20–22 The former aims accumulate cells cellular internalization, allowing mainly latter involves chemical change different environment between normal expected those entering ability window. Unlike intense investigations targeting, study such still its infancy because limited number capable distinct tumors. contrast homeostatic condition 7.4, certain possess lower values, range 6.8–4.5, extracellular environment, endosomes, then lysosomes.23 Such distinctly acidic tumors renders possibility program some chromophores. Although pH-responsive chromophores exploited investigated, few them fulfill requirement large-span absorption.24,25 This crucial practically selectivity PTT while being innocuous principle, wavelength (?) decided energy gap (?E) chromophores, following formula ? E ? 1 / ? ; therefore, requires dramatic decrease when chromophore acidified environment. successful examples relied ?-conjugated absorbers, were modified moieties.26–29 longer light-absorption was explained increase conjugation length protonated at pH. Besides difficulty extending within molecular size, another challenge enabling marked degree presence insignificant difference physiological conditions. work describes amine-capped aniline trimer (ACAT), exhibited Its main peak shifted 590 776 nm shoulder 1000 after acid-induced protonation (Figure 1a). ACAT promise PTT. hydrophobic nature suppresses sensitivity medium.30–32 addition discovery ACAT, devoted effort solve poor solutions host–guest complexation. Specifically, incorporated into water-soluble host molecule ?-cyclodextrin (?-CD), significantly improved retaining ACAT. served conditions, ensuring highly efficient success ablation during animal demonstrated feasibility targeted pH-dependent strategy. Figure | (a) Schematic illustration complexation ?-CD intended (b) 2D NOESY NMR spectra ACAT-CD D2O solution. (c) absorbance 550 function feed ratio Inset UV–vis solution [?-CD]?[ACAT] ratios. Studies All handled accordance protocols approved Institutional Care Use Committee (IACUC) compliance Chinese law experimental animals. performed institutional guidelines established Laboratory Research Center Institute Processing Engineering, Academy Science, our procedures. Results Discussion prepare absorber, randomly methylated dissolved ethanol water. Under warming 70 °C, encapsulated cavity form evaporation ethanol. No Tyndall effect observed solution, indicating absence insoluble residues medium ( Supporting Information S1). A powder-like product prepared lyophilizing could be redissolved water, confirmed strong association ?-CD. Detailed synthetic procedures characterizations available Figures S2–S4. Per 1H S2 S3, shift assigned amino group shifts downfield upon Further investigation two-dimensional (2D) nuclear Overhauser enhancement spectroscopy (NOESY) identified specific protons involved interaction. suggests capped end benzyl ring 1b), fully agreeing knowledge CD-based chemistry interaction facilitated size matching.33–36 identify stoichiometric complex, varied concentrations summarized 1c. Accordingly, 530 dramatically increased continuous ?-CD, accounting Two slopes correspond two-step binding process: 1?1 1?2 With beyond 2?1, approximates equilibrium complete dissolution Additional Fourier transform IR (FT-IR) thermogravimetric analysis (TGA) provide substantial evidence explain formation S5 S6). acid-triggered monitoring UV–vis–NIR dimethylsulfoxide (DMSO) glacial acetic acid 2a). Notably, triggered drastic abatement band along significant new nm. intriguing bathochromic wonderfully passed regulation As expected, consisting changed blue cyan dropped 7.4 5.0 2b). shown 2c, obtained keeping concentration constant. alkaline neutral initial dominant, ascribed ?b–?q transition benzene unit (donor) quinone (acceptor) window, above 780 negligible. 715 high 160 aforesaid process should accompanied reconfiguration structure redistribution orbitals. weakened spontaneous appearance 400 nm, both transition, caused bipolaron (dication–diradical) structure. arising attributed polaron doped Despite buffer exhibiting slight blueshift compared DMSO, major locates region, ensures use NIR-triggered concentration-dependent obey Lambert–Beer law, corresponding extinction coefficients 0.70 L/(g·cm) 2d) 1.11 2e), respectively. Additionally, temperatures investigated check 2f). slightly decreased warmed 20 60 °C. reverse acidification temperature-dependent pKa change. Immediately system cooled 30 °C again, intensity recovered. confirms successfully protected aggregation precipitation even temperature. 2 DMSO stepwise acid. Color comparison 5.0. phosphate-buffered saline (PBS) under values. (d) Concentration-dependent PBS 7.4. fitting curve concentration. (e) (f) Temperature-dependent Cyclic voltammetry (CV) used According CV 3a), electrochemical estimated 1.40 eV condition. After protonated, narrowed 1.22 eV, consistent optical calculated onset benefits performance addition, electron spin resonance (ESR) understand structural changes protonation. 3b, ESR signal implies radical cations. analogy polyaniline S8), transformation quinoid benzenoid proton doping generates cations conjugated backbone stayed relatively level M HCl compromised triplet state model. possible mechanism led hypothesized 3c. specific, composed donors one acceptor. resulted structure, generation backbone. model consists singlet switch ambient density functional theory (DFT) calculations 3d), 2.22 accounts By contrast, according 1.63 1.74 state, corresponds absorbing wavelength, explains Noting computed 13 kJ/mol higher than it suggested favored Yet states very likely happen room temperature, paramagnetic spectrum. 3 curves buffer. Proposed Highest occupied orbital (HOMO)/lowest unoccupied (LUMO) DFT [B3LYP/6-311g (d,p)]. faintest fluorescence yield demonstrates dominant relaxation excited S7), promotes absorbs light. investigate ACAT-CD, temperature recorded thermocouple irradiation. 4a, spiked exposed irradiation min, immediately removed laser, underwent rapid cooling dissipation. During three cycles on/off irradiation, fixed exposure time remained almost unchanged, confirming photostability reveals positive correlation amplification power density. reached 48.6 W/cm2, enough effective increment closely related ACAT-CD. 4b, rose (25 °C) 35, 42, 50 300 500 700 ?g/mL, Very importantly, control experiment revealed weaker 4c). Keeping 0.6 W/m2 7.9 9 achieved extraordinary arise unique advantage environments 2c), important give direct process, surface pure conditions thermally imaged camera. 4d, better observation detection. (?PT) eq 1: ? PT = Q I (1)In refers heat rate power. Taking W/cm2 example, ?PT 92.2%, possesses pronounced (see detailed calculation procedure S9). 4 versus 5.0: densities; concentrations. properties images (1 mg/mL) 1.0 W/cm2. laser 750 chosen match maximum evaluated where Before live animals, cytotoxicity first types cells, MCF-7 (human breast adenocarcinoma cell line) HeLa cells. 5a 5b, satisfactory biocompatibility lines. Fifteen nude mice injected establish tumor-bearing models. volume had grown approximately 100 mm3 (ca. week incubation), divided groups subjected Saline-Laser treatment, ACAT-No ACAT-Laser intratumorally followed For groups, received without local skins camera various points 5c). experienced ? 25.1 body 9.4 vivo. Motivated tissue provided data support (ACAT-Skin). camera, ACAT-Tumor ACAT-Skin maintained 5.3 (Figures 5d 5e). resulting line vitro observations stated above. Though central notable, much per larger diffusion area group. noted several factors influence tissue, injection depth, intrinsic matrix, dissipation blood stream, inadequate 5 Cell viability incubated 24 h. Time-dependent site anticancer further assessed volumes every day weeks 6a). bodies formula: (length × width2)/2. height not specified, considerable errors separated bodies. assistance suppressed growth reduced volumes. average eightfold 10-fold only. there no weight loss each toxicity solely 6b). vivo weeks, their weights measured. 6c, groups. photographed 6d demonstrate ACAT-tailored histological hematoxylin eosin (H&E) staining verified damage severely necrotic areas appeared, unaffected 6e–6g S10). Other organs, heart, kidney, lung, stomach, spleen, collected negligible inflammatory responses these organs H&E effects S11).*** Conclusion large 166 interesting phenomenon rare cases small systems owing length. window EPR calculations. property lays foundation Preliminary studies validated microenvironment, offered causing surrounding Future efforts will combination approaches more accumulated intravenous injection. Also, hope extend obtain NIR-II (1000–1400 nm) facilitate 6 Tumor spanning weeks. exact p Values independent sample t test. *p < 0.05, ***p 0.001 (n 5). Optical Scale bar: cm. (e–g) Histological Saline-Laser, (g) ACAT-Laser. 200 ?m. available. Conflict Interest There conflict interest report. Funding financially supported National Natural Science Foundation China (nos. 21825503 21674127). Acknowledgments authors thank Prof. Jian Pei Ziyuan Peking helpful discussion. References 1. Y.; Cao Y.Progress Conversion Second Window On Conjugated Polymers.Asian J. Org. 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