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Melanin-Dot–Mediated Delivery of Metallacycle for NIR-II/Photoacoustic Dual-Modal Imaging-Guided Chemo-Photothermal Synergistic Therapy

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Melanin-Dot–Mediated Delivery of Metallacycle for NIR-II/Photoacoustic Dual-Modal Imaging-Guided Chemo-Photothermal Synergistic Therapy Melanin-dot–mediated delivery of metallacycle for NIR-II/photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy Yue Suna,1, Feng Dingb,1, Zhao Chenb,c,1, Ruiping Zhangd,1, Chonglu Lib, Yuling Xub, Yi Zhangb, Ruidong Nie, Xiaopeng Lie, Guangfu Yangb, Yao Sunb,2, and Peter J. Stangc,2 aKey Laboratory of Catalysis and Material Sciences of the State Ethnic Affairs Commission & Ministry of Education, College of Chemistry and Material Sciences, South-Central University for Nationalities, Wuhan 430074, China; bKey Laboratory of Pesticides and Chemical Biology, Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, Chemical Biology Center, College of Chemistry, Central China Normal University, Wuhan 430079, China; cDepartment of Chemistry, University of Utah, Salt Lake City, UT 84112; dThe Affiliated Shanxi Da Yi Hospital, Shanxi Academy of Medical Sciences, Taiyuan 020001, China; and eDepartment of Chemistry, University of South Florida, Tampa, FL 33620 Contributed by Peter J. Stang, July 9, 2019 (sent for review May 22, 2019; reviewed by Phil S. Baran and Jean-Marie P. Lehn) Discrete Pt(II) metallacycles have potential applications in bio- compared with traditional methods such as vesicle carriers, mel- medicine. Herein, we engineered a dual-modal imaging and chemo- anin dots can load more drugs through π–π stacking on the high- photothermal therapeutic nano-agent 1 that incorporates discrete volume surface (16, 18). Recent studies reported that melanin Pt(II) metallacycle 2 and fluorescent dye 3 (emission wavelength in dots can absorb near-infrared (NIR) optical energy and convert it the second near-infrared channel [NIR-II]) into multifunctional into heat for photothermal therapy (PTT). The heat released by melanin dots with photoacoustic signal and photothermal fea- melanin dots can stimulate acoustic waves of the surrounding tures. Nano-agent 1 has a good solubility, biocompatibility, and medium and these are finally converted to photoacoustic signals; stability in vivo. Both photoacoustic imaging and NIR-II imaging this can provide a pretherapy imaging guidance tool. Fluorescence in vivo confirmed that 1 can effectively accumulate at tumor sites imaging in the second near-infrared channel (NIR-II) region is at with good signal-to-background ratio and favorable distribution. the forefront of biomedical research because of its clear-cut ad- CHEMISTRY Guided by precise dual-modal imaging, nano-agent 1 exhibits a vantages, such as relatively lower tissue autofluorescence and superior antitumor performance and less severe side effects higher spatiotemporal resolution (19–24). The NIR-II modality compared with a single treatment because of the high efficiency enables diverse biological procedures to be achieved with high of the chemo-photothermal synergistic therapy. This study shows signal-to-background (S/B) levels and this is beneficial in bio- that nano-agent 1 provides a promising multifunctional theranostic medicine (25–30). Considering the compatibility and flexibility of platform for potential applications in biomedicine. NIR-II fluorescence imaging and photoacoustic (PA) imaging, a supramolecular coordination complexes | metallacycle | chemo- combination of these 2 promising modalities can acquire comple- photothermal synergistic therapy | the second near-infrared channel | mentary information that synergistically improves cancer diagnosis melanin dots and enables precise image-guided therapy with both a superior S/B ratio and high tissue penetration depth (31, 32). ver the last decade, discrete Pt(II) metallacycle-based Oagents have attracted extensive attention in many scien- Significance tific fields such as supramolecular chemistry, molecular imaging, and biomedicine (1–6). Well-defined Pt(II) metallacycles can Clinical applications of Pt(II)-based anticancer agents have been enhance their cellular uptake and binding affinities with bio- hampered because of drug resistance, severe side effects, and molecules. Poor cellular and in vivo stability, low tumor uptake, lack of precise guidance for the therapeutic procedure. To ad- – weak fluorescence properties, and poor selectivity for cancer dress these issues, we use molecular-dye modified melanin cells are major obstacles to the widespread use of macrocyclic dots as a multifunctional drug delivery platform to effectively Pt(II)-based agents in biomedicine (7–9). Various drug-carrier deliver a Pt(II) metallacycle to tumor sites via an enhanced nanosystems, e.g., liposomes, have been actively explored to permeability and retention effect. In vivo studies show that improve the in vivo stability and pharmacokinetics of Pt(II)- nano-agent 1 displays strong NIR-II fluorescence and photo- based agents (10–12). However, some potential issues must be acoustic signals from tumors with a high signal-to-background taken into consideration. Single chemotherapy cannot simulta- ratio and successfully guides chemo-photothermal therapy neously balance the needs for efficiency and safety because se- with a superior antitumor performance and reduced side ef- fects. These promising results will provide an opportunity for rious Pt(II) drug resistance and continuous administration the design of novel multimodal and synergistic therapeutic during the entire therapy period will lead to inefficient therapy agents for biomedical applications. and potentially long-term systemic toxicity (13, 14). In addition, the lack of precise guidance for therapeutic procedures can re- Author contributions: Yue Sun, Yao Sun, and P.J.S. designed research; Yue Sun, F.D., Z.C., duce therapeutic efficiency. Engineered nanosystems with in- R.Z., C.L., Y.X., Y.Z., R.N., and X.L. performed research; Yue Sun, F.D., Z.C., R.Z., G.Y., and trinsic multitherapeutic and imaging properties are therefore Yao Sun analyzed data; and Yue Sun and Yao Sun wrote the paper. needed for precision medicine. Reviewers: P.S.B., Scripps Research Institute; and J.-M.P.L., University of Strasbourg. Inspired by the intrinsic multifunctionality of melanin bio- The authors declare no conflict of interest. polymers in nature, highly biocompatible and water-soluble mel- Published under the PNAS license. anin dots have been used as active nanoplatforms for aromatic 1Yue Sun, F.D., Z.C., and R.Z. contributed equally to this work. – structures for drug delivery (15 18). Compared with inorganic 2To whom correspondence may be addressed. Email: [email protected] or platforms, melanin exists in nature as an endogenous substance [email protected]. and has a better biocompatibility and clearance, which leads to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. reduced immunogenicity. Melanin also can be used as a thera- 1073/pnas.1908761116/-/DCSupplemental. nostic platform without complicated procedures. Additionally, Published online August 7, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1908761116 PNAS | August 20, 2019 | vol. 116 | no. 34 | 16729–16735 Downloaded by guest on September 27, 2021 Herein we describe a multifunctional theranostic nano-agent 1 Results and Discussion which is obtained by incorporating a discrete Pt(II) metallacycle Preparation and Characterization of Nano-Agent 1. The discrete 2 and NIR-II molecular dye 3 into melanin dots (Fig. 1). Nano- Pt(II) metallacycle 2 was readily synthesized via the coordination- agent 1 has the following advantages. Because of its NIR-II driven self-assembly. Multinuclear NMR analysis was used to molecular dye unit, 1 can achieve good photostability and a verify the structure of 2.The1HNMRsignalsfromthepyridine better fluorescence performance in vivo, which results in more Ha and Hb shifted downfield after coordination-driven self- precise diagnosis of cancer and monitoring of tumor develop- assembly to form rhomboid 2 (SI Appendix,Fig.S2). The 31 1 ment (33–35). The melanin dot platform provides 1 good solu- P{ H} NMR of rhomboid 2 showed an upfield shift of ∼6.16 195 bility and stability in vivo and high preferential passive accumulation ppm and a sharp singlet peak at ca. 15.68 ppm with concomitant Pt satellites; this indicates a single phosphorus environment (Fig. at tumor sites via the enhanced permeability and retention (EPR) A effect, which enables more precise cancer detection and efficient 2 ). Electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) confirmed the stoichiometry of rhomboid 2; i.e., treatment. More importantly, the native PA and PTT properties + m/z = 1,184.15 for [M − 3OTf]3 and m/z = 850.58 for [M − of melanin dots can endow 1 with NIR-II/PA dual-modal imaging + 4OTf]4 . These peaks were in good agreement with the calculated and chemo-photothermal synergistic therapeutic functions for 1 theoretical distributions and further support metallacycle forma- theranostic cancer. In vivo results indicate that has a high level of tion (Fig. 2B). The NIR-II molecular dye 3 was synthesized in nonspecific tumor uptake along with a superior S/B ratio, which several steps from commercially available chemicals (Fig. 1A). enables the precise guidance of the therapeutic process and Compound 3 was characterized by multinuclear NMR analysis evaluation of the treatment efficacy. Compared with cisplatin, and MALDI-TOF-MS (SI Appendix,Figs.S20–S22). PEGylated Pt(II) metallacycle 2 in 1 shows more efficient antitumor ac- (poly(ethylene glycol) [PEG]) melanin nanoparticles were syn- tivity and decreased side effects in U87MG tumor-bearing nude thesized
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