Semiconducting Perylene Diimide Nanostructure: Multifunctional

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Semiconducting Perylene Diimide Nanostructure: Multifunctional Phototheranostic Nanoplatform Published as part of the Accounts of Chemical Research special issue “Nanomedicine and Beyond”.

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Zhen Yang and Xiaoyuan Chen* Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States CONSPECTUS: Precision medicine requires noninvasive and accurate early diagnosis and individually appropriate treatments. Phototheranostics has been considered a frontier precision medical technology to provide rapid and safe disease localization and efficient cure. Harnessing the power of advanced nanomedicine with photonics, phototheranostics is rapidly developing and progressively becoming irreplaceable in modern medicine. Nanoscale semiconducting materials, such as inorganic semiconductors, organic conjugated polymers, and small molecules with photonic properties, have been extensively explored in medical imaging (fluorescence imaging, optical coherence tomography, and photoacoustic [PA] imaging) and phototherapy (photothermal, photodynamic, and photocontrolled combination therapies). In practical clinical applications, organic semiconducting materials, because of their biocompatibility and natural metabolism, are preferred over inorganic materials for phototheranostics. Supramolecular self-assembly is considered a significant method for preparing organic detachable and multifunctional phototheranostics, as supramolecular interactions, such as π−π interactions, hydrogen bonding, hydrophobic effects, and electrostatic interactions, are non-covalent and dynamic. Developing new and effective organic supramolecular phototheranostics requires exploration of well-designed basic building blocks with optical properties, understanding of the assembly at the nanoscale, and optimization of the phototheranostics with unique and distinctive multifunctional efficacy. In this Account, we summarize our recent work on the development of small molecular semiconducting perylene diimide (SPDI) for advanced phototheranostics. SPDI is modified to have strong near-infrared absorption beyond 700 nm by the push− pull electronic effect and owns the merits of remarkable photostability, large extinction coefficient, and high photothermal conversion efficiency. By hydrophilic modification, the amphiphile can self-assemble into a nanomicellar structure that allows PA imaging and can serve as a photothermal conversion agent. After theranostics delivery is achieved, this SPDI can be further functionalized for multimodality imaging and photothermally triggered multimodal synergistic therapy. Several well-designed asymmetric structures of SPDI can be obtained by stepwise modification of imides. It is noteworthy that the self-assembly of SPDI is controllable, allowing the preparation of different-sized spherical nanoparticles and rodlike nanoparticles and nanodroplets. For biomedical applications of SPDI phototheranostics (SPDIPTs), the size effect of SPDIPTs has been highlighted in lymph node mapping and cancer imaging. The PA properties and targeting peptide modification of SPDIPTs have brought about the ultrasensitive imaging of early thrombus. The supramolecular nanoconstructs of SPDIPTs further permit multimodality-imaging-guided cancer therapy. In brief, the design of SPDIPTs considers synthetic chemistry, supramolecular self-assembly, nanotechnology, and photonics. Furthermore, SPDIPTs have diverse biomedical applications and offer many opportunities for advancing nanomedicine.

1. INTRODUCTION Phototheranostics has been identified as a promising modern medicine integrating medical-photonics-related diagnosis and therapeutics.1−3 The significant progress of phototheranostics is mainly reflected in the rapid development of advanced photonic materials for molecular optical imaging (photoacoustic [PA] and fluorescence imaging), photonic-mediated therapies (photothermal therapy [PTT] and photodynamic therapy [PDT]), and photonics-based multimodal synergistic combination therapies.4,5 Nanosized photonic materials, especially semiconducting nanoparticles, have been developed as phototheranostic This article not subject to U.S. Copyright. Published XXXX by the American Chemical Society

platforms because they can persistently emit light or generate heat in response to laser illumination.6,7 Inorganic semiconductor photonics include quantum dots, carbon-based materials, and metallic oxides or sulfides, which have been extensively exploited and multifunctionalized for phototheranostics.8,9 However, the potential toxicity of most inorganic materials is always a topic of debate, hampering their further clinical translation. Recently, Pu’s group reported that organic semiconducting materials, such as small-molecule Received: February 5, 2019

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DOI: 10.1021/acs.accounts.9b00064 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Accounts of Chemical Research

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Figure 1. (a) General chemical structure of the SPDI molecule and schematic illustration of self-assembled SPDIs for phototheranostics as described in this Account. (b) UV−vis absorption spectra of SPDIs showing the red shift upon addition of electron-donor groups at its bay positions. The NIR absorbance allows SPDIs to be used for photoacoustic (PA) and photothermal (PT) imaging. Reproduced from refs 26 and 36. Copyright 2017 American Chemical Society.

that there are basically two ways to extend their absorption into the NIR region. One option is to prepare long πconjugated planar structures, such as terrylene diimide and quaterrylene diimide, to red-shift the absorption by addition of repeating naphthalene rings.18,19 The other option is to add a strong electron donor in the bay position of SPDIs that can provide strong NIR absorption.20 These two methods to improve SPDIs have recently afforded SPDIs for biomedical applications, especially as phototheranostics.21,22 In this Account, we summarize the recent development of SPDIs for advanced phototheranostics. We first discuss the molecular design of SPDIs to achieve multifunctional amphiphilic photonic building blocks. We then highlight the size effect of self-assembled SPDI phototheranostics (SPDIPTs) for molecular PA imaging (PAI) of lymph nodes (LNs) and cancer. We also explain how SPDIPTs can be used for early detection of thrombus. In addition, we discuss the supramolecular nanostructures of SPDIPTs in multimodalimaging-guided synergistic cancer therapy.

pigments and conjugated oligomers and polymers, also exhibit interesting photonic properties.6,7,10 Such materials are considered as more promising biophotonics because of their better biocompatibility and biodegradability compared with inorganic materials. To prepare multifunctional organic semiconducting nanotheranostics, supramolecular self-assembly is considered to be one controllable and flexible method.2,4,11,12 The dynamic non-covalent intermolecular interactions of supramolecular self-assembly also provide opportunities for the rapid clearance of organic phototheranostics. Perylene diimide (PDI) is a typical organic small semiconducting molecule possessing specific electronic and photophysical properties, and after proper chemical modifications it has been widely used in electronic and optical applications such as organic photovoltaic cells, organic lasers, organic fieldeffect transistors, electronic memory devices, and optical power limiters.13,14 In contrast to the widely reported multifunctional semiconducting conjugated polymers, semiconducting PDI (SPDI) derivatives can have better-defined molecular structures while offering the potential of molecular design to achieve biophotonics with better reproducibility and repeatability. To expand their bioapplications, water-soluble ionic or nonionic substituents are utilized to prepare water-soluble SPDIs for live-cell imaging and imaging-guided therapy, considering their bright emission in the visible or near-infrared (NIR) region.15−17 However, the intrinsic visible-light excitation with limited depth penetration hampers their further in vivo applications. Reviewing the structure of SPDIs shows

2. MOLECULAR DESIGN AND SELF-ASSEMBLY OF SPDI FOR PHOTOTHERANOSTICS The rational design of SPDI molecules is essential for the development of multifunctional supramolecular phototheranostics. Back in the 1910s, the parent compound perylene3,4,9,10-tetracarboxylic dianhydride was first found and subsequently modified into SPDIs as industrial pigments. Although the parent SPDI is barely soluble in organic solvents, proper chemical modification of its imide and bay positiond B



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Figure 2. (a) Schematic illustration of the coassembly of alkyl-chain-based SPDI structures into different-sized nanoparticles with the DOTA chelator incorporated for 64Cu labeling and PET imaging. (b, c) Representative (b) PA and (c) PET images showing size-dependent uptake of SPDIPTs in mouse popliteal and sciatic LNs at different time points after intrapaw injection. (d) Representative 2D and 3D PA images of early venous thrombus region 0 and 48 h postinjection of cRGD-conjugated SPDIPTs (highlighted by yellow and blue dotted circles, respectively). Reproduced from refs 22 and ref 36. Copyright 2017 American Chemical Society.

THF/H2O hybrid solution. The formed SPDIPTs have extinction coefficients as high as 2.00 × 108 M−1 cm−1 at 700 nm and emit strong PA intensity. As a pigment, SPDIs exhibit outstanding structural stability against prolonged laser irradiation compared with many other NIR dyes. Supramolecular self-assembly is considered a significant method27,28 that turns amphiphilic chemical structures into nanostructures in aqueous solution through supramolecular interactions, such as π−π interactions, hydrogen bonding, hydrophobic effects, and electrostatic interactions. Thus, the amphiphilic structural modification of SPDIs is essential for their controllable self-assembly in water and diverse biomedical applications. To obtain biocompatible self-assembled SPDIPTs, asymmetric amphiphilic SPDI structures are preferred. In one such example, by incorporation of poly(ethylene glycol) (Mn ∼ 2000) (PEG2000) as the hydrophilic substituent onto one of the SPDI imides, PEG2000 can form an anti-biofouling coating on the surface of nanoparticles during self-assembly to increase blood circulation time and decrease immunogenicity. Multiple strategies can be applied to modify the other imide position. For example, long alkyl chain modification can make SPDI flexible in THF/H2O mixtures, allowing the realization of controllable self-assembly to produce different-sized nanoparticles, while perfluorocarbon (PFC) modification can form nanoparticles for oxygen delivery22,29 and polyphenol modification allows ferric ion chelation to fabricate “nanoenzymes”.30 One can even couple a

can improve the solubility. Determining its semiconducting properties can contribute to organic energy, electronics, and health fields. A review of the established SPDIs structures shows that the designed functional imide substituents enhance the solubility and adjust the self-assembled morphology.23 The bay position modification not only affects the solubility but also the electronic and optical properties (Figure 1a).24 In SPDIs with centrosymmetric pyrrolidine substituents at the bay positions,25 the effective electronic coupling between the tertiary amino group and PDI core can largely red-shift the absorption from around 500 nm (visible region) to 700 nm (NIR region). The 700 nm absorbance broadened the SPDI with potential biophotonic applications from in vitro cellularlevel investigations to in vivo mouse studies because of the high optical penetration depth of NIR light.20 Because of the inherent rigid planar construct and strong intramolecular and intermolecular electron transfer of SPDI, aggregates of SPDIs in water are almost nonemissive. However, the SPDIs exhibit high photothermal conversion efficiency of up to 40% under NIR laser irritation in water, which turns SPDIs into sensitive PA contrast agents and PTT agents (Figure 1b).26 Fan et al. in 2015 first investigated the PA properties of SPDI. SPDI conjugates with cyclohexylamine at its bay positions displayed strong absorption around 700 nm.20 Then SPDIPTs were prepared by nanoprecipitation using amphiphilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine−N-[methoxy(poly(ethylene glycol))] (DSPE-mPEG) to encapsulate SPDI in C



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Figure 3. (a) Schematic illustration of the preparation of SPDIPTs by supramolecular coassembly of SPDI prodrug, IR790s, and Fe3+ ions and the mechanism of ratiometric PA-imaging-guided synergistic combination therapy. (b) UV−vis spectra and (inset) photograph of different solutions indicating the decrease in absorption of IR970s and consumption of H2O2 in the presence of Fe3+ catalyst with the Amplex Red H2O2 activity kit. (c) Representative PA images of a tumor region at different time points at 680 and 790 nm after i.v. injection of SPDIPTs. (d) Ratiometric PA signal (ΔPA680/ΔPA790) in the tumor region as a function of time postinjection of SPDIPTs. (e) Tumor growth curves in various treatment groups. Reproduced with permission from ref 30. Copyright 2018 Wiley.

For lymph node mapping, the size of the PA imaging agent is an important factor affecting its migration time in the lymphatic system.33,34 To further excavate the application of SPDIPTs in LN imaging, SPDIPTs of different sizes (30, 60, 100, and 200 nm) were synthesized by supramolecular selfassembly of SPDI amphiphiles in a two-phase solution (Figure 2a).22 The variously sized SPDIPTs were applied to the imaging of sciatic and popliteal LNs. PA imaging of the LNs showed that the different-sized SPDIPTs have different migration patterns. Positron emission tomography (PET) is a quantitative imaging technology with high sensitivity and reasonable spatial resolution. Thus, the functional amine group on the surface of SPDI was further modified with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for labeling with the positron-emitting radionuclide 64 Cu. Therefore, dual-modal PA/PET imaging could be applied to monitor the size-dependent accumulation of SPDIPTs in the lymphatic system after local administration (Figure 2b,c). The SPDIPTs migrated from popliteal to sciatic LNs through lymphatic drainage, with 100 nm-sized SPDIPTs

polymerization initiator at the SPDI imide to synthesize a pHsensitive SPDI-based polymer.31 Moreover, amphiphilic SPDI can co-self-assemble with other theranostic agents to achieve multimodal-imaging-guided synergistic cancer phototheranostics.

3. LYMPH NODE IMAGING PA imaging is considered a hybrid imaging paradigm that integrates optical excitation and ultrasonic detection. PA imaging can also provide outstanding spatial resolution and high contrast for noninvasive real-time imaging. This imaging technology has found many uses in oncology, vascular biology, and neurology.32 For PA imaging, a contrast agent is critical, as the PA effect is closely related to the local thermoelastic expansion, which can be amplified by a PA contrast agent with high photothermal conversion efficiency. Semiconductingpolymer-based nanoparticles (SPNs) have demonstrated the capability of lymph node PA imaging. However, precise control of the size of SPNs to investigate their migration and accumulation in the lymph node system can be a challenge. D



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enzyme” property for effective killing of cancer cells with a halfmaximal inhibitory concentration (IC50) of 9.01 μM (Figure 3a). On the one hand, the mechanism is that the released cisplatin can cross-link the nuclear DNA of cancer cells to disrupt DNA replication and transcription and finally trigger apoptosis. On the other hand, nicotinamide adenine dinucleotide phosphate oxidase was activated, and O2 was effectively converted to O2•−, thereby causing an upsurge in cellular H2O2.39 The ferric ion reacted with H2O2 (Fenton reaction) to generate toxic hydroxyl radical (Figure 3b). Therefore, the generated ROS in SPDIPTs could induce apoptosis of the cancer cells. The ratiometric PA imaging could also indicate the ROS level stimulated by the drugs (Figure 3c,d). Such multifunctional SPDIPTs allow not only synergistic multimodality cancer therapy (Figure 3e) but also noninvasive real-time monitoring of the therapeutic effect. The ratiometric PA imaging of the tumor microenvironment (TME) (e.g., acidity, ROS level, and reducibility) can help in understanding tumor pathology and achieving precise tumor diagnosis.32,40,41 Smart TME-responsive cancer therapeutics based upon SPDI were thus developed. By covalent linking of N-methylpiperazine to the bay positions of SPDI, the absorption and PA properties of SPDI become sensitive to pH, presenting decreased signals in a mildly acidic environment.42 Inspired by the pH-responsive properties of SPDI, SPDI-based ratiometric PA theranostics were developed by coassembly of pH-responsive SPDI, pH-inert IR825, and the drug doxorubicin (DOX). These SPDI-based theranostics could light up the tumor by noninvasive real-time ratiometric PA imaging of the tumorous acidic environment and concurrently accelerate the DOX release. Thus, this strategy provides a paradigm for the design of smart PA platforms for cancer theranostics.

displaying the best ability to differentiate popliteal from sciatic LNs with an ideal interval time of 60 min.

4. THROMBOSIS IMAGING With the rapid development of PA technology, PA imaging facilitates a detailed information presentation of its scanning zone by advanced computerized 3D reconstruction, which promotes its application in the investigation of vascular diseases.35 Because of the presence of endogenous PA contrast by hemoglobin in the blood, legible blood vessels can be visualized by PA imaging. Therefore, a thrombus can be seen through PA signal loss in the PA images.36 However, to obtain positive results of selectively lighting up early thrombus, 60 nm SPDIPTs were selected to covalently attach cyclic Arg-GlyAsp-containing peptide (cRGD), a peptide with a high binding affinity for the biomarker GPIIb/IIIa that is overexpressed on activated platelets at the early stage of thrombosis. At 48 h, after tail vein injection of cRGD-SPDIPTs, the representative thrombus in the rat blood vessel became clear with intense PA signals after subtraction of the background signals (Figure 2d). The cRGD-SPDIPTs were also able to monitor the effect of thrombolytic therapy. 5. CANCER PHOTOTHERANOSTICS Tumor imaging is essential for cancer treatment because it allows early and accurate detection of cancerous lesions.37 SPDI phototheranostics, which are fabricated by supramolecular coassembly of various theranostic ingredients, provide additional opportunities for cancer diagnosis and therapy. Hydrophobic SPDI was encapsulated by DSPE-mPEG to fabricate SPDIPTs.20 As a result of the enhanced permeability and retention (EPR) effect (passive targeting process), the SPDIPTs accumulated into orthotopic brain tumor over time. On the basis of the finding of the controllable self-assembly of amphiphilic SPDI, four different-sized SPDIPTs were tested in tumor mice.22 At the 24 h time point, the 60 nm-sized SPDIPTs demonstrated the best tumor PA contrast. SPDI also displayed outstanding photothermal properties in vivo to inhibit the tumor growth. These PAI/ PTT results set the foundation to further develop multifunctional phototheranostics of SPDIPTs to fight against cancer.

5.2. Multimodal-Imaging-Guided Synergistic PTT/Chemo Cancer Therapy

Multimodal cancer imaging is considered to be a more precise diagnosis approach than individual imaging modality because it combines the strengths of multiple imaging techniques. Several strategies have been developed to fabricate SPDI-based multimodal-imaging-guided phototherapy platforms. In 2017, Fan et al. reported a dual-modal PAI and magnetic resonance imaging (MRI) platform consisting of a polymeric framework containing Gd 3+ -chelated poly(isobutylene-alt-maleic anhydride)s and SPDIs.26 The pendent SPDIs in amphiphilic polymers facilitated nanoparticle formation in water. In the cancer theranostics, the SPDIPTs provided detailed information on tumor vessels and tissues through PA imaging, and T1weighted MRI from Gd 3+ obtained physiological and anatomical information on the tumor-bearing mice. After the tumor was located, the dual-modality imaging successfully guided tumor PTT. Smart cancer phototheranostics can diagnose a tumor by “turning on” the imaging signal and treat a tumor with ondemand release of chemotherapeutic drugs by an endogenously or exogenously controlled stimulus, such as tumorous TME, X-ray, ultrasound, laser, etc.43 Therefore, smart phototheranostics generate or amplify image signals with low background after accumulation in the tumor region. Using laser remote control to achieve photothermal conversion and trigger drug release can greatly reduce the side effects of the chemo drug on normal organs.44

5.1. Ratiometric PAI-Guided Theranostics

Ratiometric PAI is a promising imaging method for advanced biomedical applications. Unlike inorganic PA probes, such as SWNTs with a broad and weak PA spectrum and gold nanorods with poor photothermal stability,38 SPDI owns unique properties of photophysical/chemical stability and a narrow PA spectrum, allowing for ratiometric PA imaging of reactive oxygen species (ROS).30 The ROS sensor IR790s has been previously used for real-time imaging of chemotherapyinduced hepatotoxicity.38 Thus, coassembly of SPDIs and IR790s forms a ROS ratiometric PA imaging system based on calculation of the ratiometric signals of two NIR channels at 680 nm (SPDI) and 790 nm (IR790s). The SPDI was designed as an asymmetric multifunctional molecule by its imide position modifications: amine base PEG2000 for cisplatin prodrug conjugation and polyphenols for ferric ion coordination. The supramolecular structure driven by the coordination reaction and hydrophobic interaction of the SPDI and IR790s produced rodlike nanoparticles with sizes of around 120 nm. In the SPDI nanostructure, the cisplatin and polyphenolcoordinated ferric ion combination demonstrated a “nanoE



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Figure 4. (a) Schematic illustration of the preparation and phototheranostic mechanism of SPDIPTs. (b) Release curve of Pt from SPDIPTs at different pH with or without NIR laser irradiation over time. (c) T1-weighted MRI images of U87MG tumor-bearing mice at 0 and 24 h postinjection. (d) Coronal PET images of tumor mice at 1, 4, 24, and 48 h postinjection of 64Cu-labeled SPDIPTs. Tumors are indicated by white arrows. (e) Biodistribution of SPDIPTs in tumor and major organs quantified by region of interest (ROI) analysis of the PET images. (f) Relative tumor volume (V/V0) after various tumor treatments. Reproduced with permission from ref 31. Copyright 2019 Royal Society of Chemistry.

and exhibit a high signal-to-noise ratio of 127 ± 10% at 24 h postinjection (Figure 4c). The accumulation of SPDIPTs was also monitored by PA imaging. 64Cu radiolabeling also enabled whole-body imaging and quantitative analysis of the biodistribution of SPDIPTs (Figure 4d,e). Furthermore, the loosened structure of SPDIPTs could be easily destroyed to release cisplatin drugs in vivo as the local temperature increased under laser irradiation. The controlled release of cisplatin and thermal therapy synergistically delayed tumor growth (Figure 4f). Among the cancer drug delivery systems (DDSs), block copolymers such as PEG−poly(lactic acid-co-glycolic acid) (PLGA) and PEG−poly(ε-caprolactone) (PCL) are the most widely used vehicles because of their safety, biocompatibility, high drug loading efficiency, and biodegradability.45,46 An ideal DDS should securely deliver chemo drugs in the circulation without leakage but burst-release the cargo in the tumor region. In practice, however, drug-loading DDSs through nanoprecipitation often exhibit premature release in the circulation due to the diluted nanoparticle concentration in the bloodstream. The drug leakage often induces a low concentration of drug delivered in the tumor region and causes toxicity to healthy organs. Covalent cross-linking of the core or shell of the DDS is reportedly an effective method to yield a

As a proof-of-concept study, smart MRI-based theranostics were developed by coassembly of SPDI, a polyphenol derivative, and Gd3+ ions (Figure 4a).31 First, a PEG2000SPDI macroinitiator of atom transfer radical polymerization (ATRP) was synthesized. Then ATRP of the pH-sensitive monomer 2-(diisopropylamino)ethyl methacrylate was conducted. Finally, the smart SPDIPTs were prepared by using SPDI polymers to encapsulate Pt prodrug polyphenols and Gd3+ ions. The π−π stacking, electrostatic interactions, and chelation chemistry resulted in a tight self-assembled structure. Therefore, the MRI signal was greatly reduced because of the low exchange rate of H2O molecules to Gd3+ complexes. When the pH was dropped to 6.5, the T1 relaxivity (r1 value) of the SPDIPTs increased to 10.27 mM−1 s−1, which was about a 3fold enhancement of that at pH 7.4 (3.55 mM−1 s−1). It should be noted that the r1 value of commercial Magnevist was only 4.35 mM−1 s−1, independent of pH. Thanks to the photothermal properties of SPDI, under the same laser irradiation conditions the release of cisplatin prodrug was up to 81% in the acidic environment but only 21% at neutral pH (Figure 4b). After intravenous injection and tumor accumulation, the acidic tumor environment induced a loosened nanostructure of SPDIPTs, allowing Gd3+ to contact water. The T1-weighted MRI signal was activated to precisely indicate the tumor region F



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Figure 5. Schematic illustration of the chemical structures of β-CD-NH2, NHS-SS-NHS, cRGDfK-SH, NHS-DOTA, and asymmetric SPDI polymer (a, b) and preparation of supramolecular SPDIPTs (c). A cartoon of the supramolecular self-assembly mechanism of the SPDI polyrotaxane for effective loading of chemo drugs is shown. (d) Representative 3D tumor PA images of tumor-bearing mice at 2 and 24 h time points after i.v. injection of SPDIPTs. (e) Quantitative PA intensity curve of the tumor as a function of time postinjection of SPDIPTs. (f) Tumor volume curves of orthotopic breast cancer mice with various treatments (I, PBS; II, SPDIPTs@PTX [20 mg kg−1]; III, Abraxane [20 mg kg−1]; IV, SPDIPTs@PTX [60 mg kg−1]; V, SPDIPTs plus laser; VI, SPDIPTs@PTX [60 mg kg−1] plus laser). Reproduced with permission from ref 48. Copyright 2018 Nature Publishing Group.

PTX combined with PTT eradicated the subcutaneous HeLa tumor (starting tumor size of ∼220 mm3) without recurrence. This treatment also effectively inhibited the growth of orthotopic breast tumor (Figure 5f). Furthermore, the treated mice showed negligible spontaneous lung metastasis.

stable delivery system that largely prevents drug leakage during blood transportation.47 Therefore, β-cyclodextrin-based polyrotaxane (SPDI-PCL-bPEG-RGD⊃β-CD-NH2)-based interlocked smart SPDIPTs were constructed (Figure 5a).48 After encapsulation of the chemo drugs, the disulfide bond was used for inter-crosslinking of SPDIPTs. To synthesize SPDI-PCL-b-PEG-Mal (Figure 5b), the hydroxy group-based asymmetric SPDI was obtained for ring-opening polymerization with 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD), and then an OH-PEGMal was conjugated to the SPDI-PCL-COOH. Through click chemistry, cRGD was used to seal the polyrotaxane after supramolecular self-assembly of β-CD-NH2 and SPDI-PCL-bPEG-Mal in aqueous solution. In the polyrotaxane, β-CD-NH2 reduced the crystallization of PCL chains in water to be a flexible PCL “sponge” with high drug-loading efficiency (Figure 5c), with paclitaxel (PTX) and camptothecin loading contents of 35.4% and 43.2%, respectively. Also, β-CD-NH2 was used for disulfide bond coupling to cross-link nanoparticles and DOTA conjugation to label the PET isotope 64Cu. With the guidance of dual PA (Figure 5d,e) and PET imaging, a 671 nm laser was utilized for synergetic photothermal and chemo combination therapy. SPDIPTs@PTX under laser irradiation (0.5 W cm−2, 3 min) demonstrated the lowest IC50 of 23.1 ± 5.87 nM toward 4T1 murine tumor cells; this value was lower than those of free PTX (IC50 = 87.9 ± 10.1 nM), SPDIPTs@PTX (IC50 = 211 ± 32.5 nM), and SPDIPTs@PTX with a low-power laser (0.1 W cm−2, 3 min) (IC50 = 141 ± 22.3 nM). For the in vivo study, SPDIPTs@

5.3. Multimodal-Imaging-Guided Synergistic PTT/PDT for Cancer

PDT is an effective tumor therapeutic method that turns oxygen into toxic singlet oxygen.49 However, the TME is intrinsically hypoxic.50 Hence, an artificial oxygen supply can help improve the efficacy of PDT.51 PFC, which has exceptionally high gas-dissolving capacity, has been widely investigated as an oxygen carrier. Gaslike liquid PFC is also advantageous for ultrasound (US) imaging contrast enhancement because of its easy vaporization by a mild increase in temperature (e.g., the boiling points of perfluoropentane and perfluorohexane are only 29 and 57 °C, respectively).52 Laser and US irradiation are two effective and useful external stimuli to vaporize PFC droplets. Laser-triggered PFC vaporization is safer and more controllable than high-intensity focused ultrasound with high acoustic pressures and frequencies. Previously, PFC has been delivered by porphyrin liposome.53 It appears that amphiphilic alkyl-chain-based SPDI is also a good candidate for making PFC droplets.29 This SPDI has hydrophobic parts for PFC encapsulation and photothermal ability for vaporization of PFC (Figure 6a). To exploit the loaded oxygen of SPDIPTs, the photosensitizer ZnF16Pc was added during SPDI droplet fabrication. ZnF16Pc allows SPDI droplets to convert O2 into 1O2 under laser irradiation. G



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Figure 6. (a) Schematic illustration of the supramolecular self-assembly of the SPDIPTs nanodroplet and its phototheranostic mechanism. (b) PA images of U87MG tumor-bearing mice before and after i.v. injection of SPDIPTs and SPDIPTs without PFC. (c) B-mode US images of U87MG tumor before and after laser irradiation. (d) Representative fluorescence images at different time points after SPDIPT injection. (e) Photothermal curves of the tumor with various treatments indicating that laser irradiation at 0.5 W cm−2 can increase the temperature of the tumor to 50 °C. (f) TUNEL assay of tumor slices after the systemic administration of SPDIPTs with subsequent 671 nm laser irradiation (scale bar 20 μm). (g) Tumor growth curves. Complete tumor eradication was achieved by the SPDIPT treatment under 0.5 W cm−2 laser irradiation. Reproduced from ref 29. Copyright 2018 American Chemical Society.

as lymph node mapping, early diagnosis of thrombosis, and cancer theranostics. Compared with conventional theranostics, SPDIs have more merits such as intrinsic PAI/PTT properties, multifunctional modification, tunable push−pull electronic structure, and selfassembly properties. Although several SPDI structures have found proper applications in biomedicine, there is still much to explore. The current SPDIPTs are mostly based on passive targeting for delivery of the vehicles and the cargoes. There are ample opportunities to tag receptor ligands onto SPDIPTs for active targeting of diseases and thus improve delivery over those relying solely on passive targeting and the EPR effect. Most nanoparticles, including SPDIPTs, have prominent and persistent accumulation in the reticuloendothelial system, and one can consider stimuli responsiveness to degrade and reduce the size of supramolecular assemblies to allow excretion from the body more quickly. In addition, even though π conjugation red-shifted the absorbance from the visible region to the NIR I window, recent reports showed that photoacoustic imaging in the far NIR and NIR II window appear to have better spatiotemporal resolution than that in the NIR I window.54−56 Thus, an improved red-shifted SPDI structure is expected to expand the library of SPDIPT candidates.

The hybrid SPDI droplet exhibited synchronous and synergistic PTT/PDT therapy of tumor irrespective of tumor hypoxia. SPDI provided an intense PA signal in the tumor region at 24 h after i.v. injection (Figure 6b). PFC also displayed an enhanced US signal after 671 nm laser irradiation (Figure 6c). The SPDI droplets were also covalently conjugated with IRDye 800CW for fluorescence imaging (Figure 6d). The remarkable PTT effect of SPDI nanodroplets was demonstrated at a laser power of 0.5 W cm−2 (Figure 6f). The PDT effect of SPDI droplets was justified by a TUNEL assay even at a low laser power of 0.1 W cm−2, in which the temperature was below 40 °C. Thus, during the in vivo tumor treatments, the SPDI droplets displayed excellent therapeutic efficacy under laser irritation at 0.5 W cm−2 (Figure 6g).

6. SUMMARY AND OUTLOOK In this Account, we have summarized the recent research progress on the design of SPDIs for multimodal synergistic phototheranostics. SPDI nanostructures have excellent PAI and PTT properties. By modification of the SPDI imide position, a series of PEG-based asymmetric SPDI molecular structures such as a cisplatin prodrug, a pH-sensitive polymer, and multimodality imaging probes were developed. By further integration of other theranostic components, supramolecular self-assembly allows amphiphilic SPDIs to become multifunctional nanomedicines for various biomedical applications such

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Zhen Yang: 0000-0003-4056-0347 Xiaoyuan Chen: 0000-0002-9622-0870 Author Contributions

The manuscript was written through contributions from both authors, and both authors approved the final version of the manuscript. Funding

We thank the intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) for support of this work. Notes

The authors declare no competing financial interest. Biographies Zhen Yang obtained his Ph.D. in Optical Engineering in 2017 at the Nanjing University of Posts and Telecommunications under the direction of Prof. Wei Huang and Prof. Quli Fan. During the Ph.D. study, he joined Prof. Shawn Chen’s Lab at the National Institutes of Health (NIH) as a joint doctoral student from 2015 to 2017, after which he then became a postdoctoral fellow in the same lab. His research interest focuses on the design and synthesis of multifunctional phototheranostics for multimodal-imaging-guided synergistic therapy. Xiaoyuan (Shawn) Chen received his Ph.D. in Chemistry from the University of Idaho in 1999. He joined the University of Southern California as an Assistant Professor in 2002 and then moved to Stanford University in 2004. In 2009, he joined the Intramural Research Program of the NIBIB as a Senior Investigator and Lab Chief. He has published over 700 papers and numerous books and book chapters. He is the founding editor-in-chief of the journal Theranostics. He is interested in developing molecular imaging tools for early diagnosis of disease, monitoring therapy response, and guiding nanodrug discovery/development.

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