Noninvasive photothermal cancer therapy nanoplatforms via integrating nanomaterials and functional polymers

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1 Biomaterials Science REVIEW Cite this: DOI: /c6bm00600k Received 30th August 2016, Accepted 3rd December 2016 DOI: /c6bm00600k 1. Introduction Noninvasive photothermal cancer therapy nanoplatforms via integrating nanomaterials and functional polymers Qingfu Ban, Ting Bai, Xiao Duan and Jie Kong* Nowadays, cancer is always a great threat to patients of almost all age groups. 1 The main therapy methods are surgery, radiotherapy and chemotherapy. However, surgery and radiotherapy often cause severe body injuries and side effects that weaken the immune system. Chemotherapy resistance occurs in half MOE Key Laboratory of Space Applied Physics and Chemistry, Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Sciences, Northwestern Polytechnical University, Xi an, , P. R. China. kongjie@nwpu.edu.cn; Fax: ; Tel: View Article Online View Journal In the cutting-edge field of cancer therapy, noninvasive photothermal therapy (PTT) has received great attention because it is considered to overcome the drawbacks of conventional surgery, radiotherapy and chemotherapy of severe body injuries and side effects on the immune system. The construction of PTT therapeutic and theranostic nanoplatforms is the key issue in achieving tumor targeting, imaging and therapy in a synergetic manner. In this review, we focus on the recent advances in constructing PTT therapeutic and theranostic nanoplatforms by integrating nanomaterials and functional polymers. The noninvasive photothermal cancer therapy mechanism and achievement strategies of PTT therapeutic and theranostic nanoplatforms are presented as well as the innovative construction strategies and perspectives for the future. Owing to their high tumor ablation efficiency, biological availability and low- or nontoxicity, PTT therapeutic and theranostic nanoplatforms are promising and emerging in medicine and clinical applications. of all the patients and may lead to treatment failure. 2 In particular, non-targeted chemotherapy can indiscriminately deliver anticancer drugs to tumors or healthy organs and tissues. 3 Thus, the new tumor therapy methods with high efficiency are critical to maximize the desired therapy effect and to minimize the injuries and side effects. Since the apoptosis of tumor cells occurs when their surrounding temperature is higher than 43 C, 4 photothermal therapy (PTT) has received more attention in recent years. 5 8 PTT is based on the conversion of near-infrared (NIR, nm) light absorbed by photothermal conversion nanomaterials in tumor cells to heat, resulting in the thermal Qingfu Ban Qingfu Ban received his bachelor s and master s degrees in polymer materials and engineering from Yantai University, China, in He is currently a Ph.D. student at the Northwestern Polytechnical University. His research interests focus on hyperbranched polymers and constructing novel nanoplatforms for tumor photothermal therapy. Ting Bai Ting Bai received her bachelor s degree in polymer materials and engineering from Northwestern Polytechnical University, China, in She is currently pursuing her Ph.D. degree in Polymer Chemistry. Her research interest is in functional nanomaterials for tumor chemo-photothermal therapy.

2 ablation of tumors. Compared with most current cancer therapy, such as surgery, radiotherapy and chemotherapy as mentioned above, the advantages of PTT are that it is noninvasive, targeted and has high efficiency. In particular, its noninvasive characteristic is one of the most important requirements for tumor therapy. Different from ultraviolet (UV) or visible light, the NIR light can penetrate deeply into tissues with a relatively low level of the total extinction coefficient of the tissue component. Hence, the absorption of NIR light is minimal in biological tissues without causing abnormal tissue damage. The penetration depth of NIR light can be optimized for various cancers, achieving efficient and indiscriminate tumor therapy effects Besides, PTT can be combined with current cancer therapy, e.g., chemotherapy, 12,13 photodynamic therapy (PDT), 14 immunotherapy 15,16 or radiotherapy, 17 to achieve tumor ablation via synergic effects of PTT and anti-cancer drugs. For example, PTT with immuneadjuvant nanoparticles together with a checkpoint blockade has achieved effective cancer immunotherapy. 18 Interestingly, the heat from a photothermal conversion can promote drug release and simultaneously combat cancer drug resistance to improve the efficiency of cancer therapy. 19 Since PTT shows potential in precise and effective tumor therapy, the design and construction of PTT nanoplatforms possessing high photothermal conversion and anti-cancer drug loading are of great importance. 12 As presented in Fig. 1, the therapeutic, targeting, imaging and bio-availability multifunctionalities should be fully considered for the construction and application of PTT therapeutic and theranostic nanoplatforms, which are all necessary for achieving tumor diagnosis and therapy. It is a real integrating system with great potential in biomaterials, nanomedicine and translational medicine. For example, Wang et al. reviewed magnetic and fluorescent carbon-based nanohybrids for multi-modal imaging and Xiao Duan Xiao Duan received his bachelor s degree in pharmacy from Changzhi Medical College, China, in He obtained his master s degree with a major in medicinal chemistry from The Fourth Military Medical University in Now he is pursuing his Ph.D. degree at the Northwestern Polytechnical University with a major in chemistry. His interest is in the synthesis of biomaterials and controlled drug release. Fig. 1 Schematic illustration of integrating therapeutic, targeting, imaging and bio-availability functionalities into PTT therapeutic and theranostic nanoplatforms for tumor diagnosis and therapy. magnetic field/nir light responsive drug carriers, which possess both targeting and imaging functionalities. 20 In this review, we present the recent advances in the construction of therapeutic and theranostic nanoplatforms for noninvasive PTT by integrating nanomaterials and functional polymers. The general principle, innovative construction strategies, mechanism and efficiency of tumor therapy and perspectives for the future are presented. 2. General principle for PTT therapeutic and theranostic nanoplatforms For the application in constructing PTT therapeutic and theranostic nanoplatforms, some principles and prerequisites must be considered. First, the imaging functionality should be introduced into the theranostic nanoplatforms to visualize the therapeutic nanoplatforms in vivo, i.e., therapeutic nanoplatforms combined with diagnosis Second, to enhance Prof. Dr Jie Kong is a full professor and leader of the Topological Polymer Centre at the Northwestern Polytechnical University (NPU) of China. He received his Ph.D. from NPU in Dec., Prior to joining NPU, he worked at The Hong Kong Polytechnic University as a postdoctoral fellow and at the University of Bayreuth in Germany as a Humboldt Fellow. Jie Kong His research interests include hyperbranched polymers and their application in ceramics and biomaterials. He has published 120 peer-reviewed papers in archival journals. Prof. Kong is the secretary of Humboldt-Club Xi an, International Advisory Board, the 6 th International Congress on Ceramics and an Editorial Board Member of Scientific Reports.

3 the accumulation of therapeutic and theranostic nanoplatforms at tumor sites, the targeting functionality can be introduced by appropriate design and construction. 24 Otherwise, the accumulation is uncontrollable and mainly determined by the blood circulation time. Moreover, the bioavailability, such as biocompatibility, water solubility and toxicity, is also very important to the in vivo application of nanoplatforms. In detail, functional substances, construction strategies and biologically relevant factors were the basic considerations to construct PTT therapeutic and theranostic nanoplatforms with therapy, targeting, imaging and bioavailability functionalities. Commonly, functional substances, including photothermal conversion nanomaterials, drugs, targeting ligands, imaging contrast agents and functional polymers, are fundamental to the achievement of tumor therapy, targeting, imaging and bioavailability. Construction strategies provide a guideline for the integration of functional substances. Biologically relevant factors, such as the biodistribution and immune responses of nanoplatforms, are also important prerequisites for in vivo applications. Based on the general principles, PTT therapeutic and theranostic nanoplatforms might be constructed with high tumor therapy efficiency. 2.1 Functional substances and construction strategies As shown in Fig. 2, functional construction substances can be divided into therapeutic substances ( photothermal conversion nanomaterials or chemotherapeutic drugs), encapsulating substances (mesoporous silica, hydrogels, micelles or polymer brushes), targeting substances (targeting ligands or external stimuli-responsive components) and imaging substances (Au, iron oxide, or NIR organic dyes). Although the construction substances are fundamental and necessary, they are imperfect both for in vitro and in vivo applications. For the PTT therapeutic substances, the toxicity and poor biocompatibility are inevitable drawbacks. 25 The typical shielding method is to encapsulate the therapeutic substances with functional polymers or inorganic porous materials, Fig. 2 The types of functional construction substances for PTT therapeutic and theranostic nanoplatforms. leading to a better bioavailability. Of course, the encapsulating materials are not always perfect. For example, mesoporous silica can encapsulate photothermal components or load drugs, but it cannot be directly used for in vivo applications. Similarly, some targeting and imaging substances may cause an immune response or poor biocompatibility. Although these inevitable drawbacks are determined by the materials themselves, they can be overcome via proper construction strategies. Coating and loading are the most common construction strategies to integrate functional substances, which are widely used to achieve stealth characteristics of PTT therapeutic and theranostic nanoplatforms. The typical strategy is to coat and load therapeutic, targeting and imaging materials by integrating functional polymers. A detailed construction strategy should be selected based on the inherent characteristics of the functional substances and their available physicochemical properties. For example, therapeutic components, such as inorganic Au nanomaterials 26 and organic NIR dyes, 25 can be modified by chemical reaction, physical encapsulation 27 or chemical interaction, 28 to achieve stealth characteristics and to avoid immune response or poor biocompatibility for in vivo applications. 2.2 Biological availability of nanoplatforms For in vivo applications, the bio-availability of the PTT nanoplatforms must be inevitably considered. The biologically relevant factors, such as bio-distribution and immune response, are important to ensure in vivo bioavailability. Furthermore, the injection method, i.e., intravenous injection and intratumoral injection, plays a key role for the in vivo delivery of PTT nanoplatforms, which determines the accumulation paths Injection methods. To achieve effective tumor therapy, the PTT nanoplatforms must be well accumulated at tumor sites. Hence, the injection method should provide the best opportunity for accumulation. In general, there are two injection methods, i.e., intravenous injection and intratumoral injection. The former is a promising method with a higher clinical relevance, and the bioavailable PTT nanoplatforms can be accumulated at tumor sites via blood circulation. The latter, i.e., in situ injection at tumor sites, allows the PTT nanoplatforms to directly accumulate at tumor sites without going through blood circulation. Nanoplatforms with a large particle size, poor biocompatibility and abnormal immune response, such as self-assembled vesicles based on amphiphilic gold nanorods, 29 carbon-layer-coated manganese dioxide nanoparticles 30 and p-type copper-based multicomponent chalcogenide nanoparticles, 31 can only be injected via intratumoral injection. However, PTT nanoplatforms without the characteristics mentioned above can be injected via either intravenous injection or intratumoral injection. Therefore, the available injection method should be considered during the construction of PTT nanoplatforms Biodistribution and immune response. Intravenous injection provides a good opportunity for the highly effective accumulation of nanoplatforms via blood circulation. During the delivery process of injected PTT nanoplatforms to tumor

4 sites, biodistribution and immune response are two important factors to ensure bioavailability. As illustrated in Fig. 3, during blood circulation, the PTT nanoplatforms are commonly bio-distributed at three locations, i.e., the blood circulation system, tumor sites, and normal organs and tissues To ensure the favorable flow of PTT nanoplatforms in blood circulation with little accumulation in normal organs and tissues, the size is surely important. 35 First, the diameter of the nanoplatforms should be below 4 μm, which is the smallest dimension of human blood capillaries, to ensure favorable circulation and to avoid a blockage in blood vessels. 36 Second, the gaps in the leaky vasculature mostly fall below 400 nm, requiring a much smaller size for efficient extravasations of the nanoplatforms. 35,37 On the other hand, to evade filtration by the kidneys, the nanoplatforms should be larger than 10 nm. To avoid being captured by the liver, the size should be less than 100 nm. 35,38 Based on these considerations, the ideal dimension of the PTT nanoplatforms is between 10 and 100 nm. 39 In practice, the slightly larger sized particles ( nm) can also achieve effective accumulation at the tumor sites. 40 Besides, the surface charges of the PTT nanoplatforms should be neutral or negative to avoid a significant immune response. 35,41 This is because the surface charge on the cells is slightly negative. Therefore, a particle with a neutral or negative charge is more suitable for drug delivery without inducing an immune response to clear the delivery particle. In contrast, the particle with a positive charge on the surface will not like to go through the circulation system. As another important consideration, the immune response to the PTT nanoplatforms should also be studied. The reticuloendothelial system (RES), i.e., the mononuclear phagocyte systems (MPS), is mainly responsible for clearing foreign particles or polymers in circulation via opsonization and phagocytosis. 35,42 45 To avoid the MPS, the surface of the PTT nanoplatforms should be modified to adjust the interface interaction and stealth characteristics. As a result, the accumulation of nanoplatforms at the tumor sites can be Fig. 3 The illustration of in vivo PTT nanoplatform bio-distribution locations, including the blood circulation system, tumor sites, and normal organs and tissues. Reproduced from ref with permission from Wiley and Elsevier. improved. One accepted method is to adjust the interface composition and reduce protein interactions and prevent binding to opsonins. 46,47 For example, the biocompatible hydrogels and polymer brushes have been employed to prepare stealth PTT nanoplatforms from endocytosis It is worth noting that the tumor agonist is also a critical factor to the immune response and success of anti-cancer drug delivery. For example, agonistic CD40 monoclonal antibodies (mab) are a member of the tumor necrosis factor receptor (TNFR) superfamily expressed broadly on a range of tumors and have been developed for immunotherapy. The agonistic antibody is essential for immune activation, which can activate antigenpresenting cells (APC) and promote antitumor T-cell responses in the absence of T-cell immunity. 51,52 Besides, antibody-targeted drugs have also been used to achieve anti-cancer drug delivery, such as CD19 and CD20 targeted delivery Construction strategies for PTT therapeutic nanoplatforms To construct PTT therapeutic nanoplatforms, the therapeutic and encapsulating substances must be carefully chosen and optimized. In general, to enhance the accumulation of nanoplatforms at tumor sites, targeting ligands or other targeting molecules are necessary. Now, passive targeting, active targeting and external stimuli-responsive targeting are the three main types of targeting mechanisms available for therapeutic nanoplatforms. The advances in PTT therapeutic nanoplatforms delivered by intravenous injection are presented in the following sections, mainly based on passive targeting, active targeting and external stimulus-responsive targeting mechanisms, as well as on the latent construction strategies and models. 3.1 PTT therapeutic nanoplatforms with passive targeting Main mechanism of passive targeting. To increase the accumulation of therapeutic nanoplatforms at tumor sites, the optimal size and surface should be designed to increase the circulation time in the bloodstream. Actually, the unique pathophysiology of tumors and abnormal tumor vasculatures can be employed to achieve passive targeting mainly from the enhanced permeability and retention (EPR) effect. 54 The newly formed leaky vasculatures around tumors allow extravasations of PTT nanoplatforms. The impaired lymphatic vessels enable a longer retention of PTT nanoplatforms at the tumor sites. 35,54 However, the nanoplatforms should circulate for enough time in the bloodstream to repeatedly pass through tumor vasculatures for uptake by tumor cells Functional substances. To achieve tumor PTT therapy or PTT/chemotherapy combination therapy, the appropriate NIR photothermal conversion materials and chemotherapeutic anti-cancer drugs are essential. Photothermal conversion materials with favorable photothermal conversion effects and tumor ablation can be divided into inorganic and organic species. The inorganic gold (Au) nano-objects, carbon

5 nano-objects, 40,60 62 palladium (Pd) nanosheets, copper sulfide (CuS), 9,66,67 molybdenum disulfide/bismuth trisulfide (MoS 2 /Bi 2 S 3 ), 68 and albumin-biomineralized nanocomposites 69 have been used as PTT photothermal conversion substances. The organic species mainly contain NIR-absorbing dyes and conjugated polymers. 76,77 Although the two types of substances possess high photothermal conversion efficiency, nonbiodegradable chromophores or heavy metals can be detected and destroyed by the immune system. They will remain in the body for a long time with potential toxicity. On this topic, Nel et al. summarized the cytotoxicity of nanomaterials and potentially safe design features. 25 On the other hand, most of the chemotherapeutic anticancer drugs are hydrophobic, such as doxorubicin and paclitaxel. They are not suitable for direct in vivo application because of their low solubility and stability, and high toxicity and side effects to normal organs and tissues. Thus, the encapsulating substances of polymer brushes, hydrogels and micelles, and inorganic substances of mesoporous silica are frequently employed to overcome these drawbacks The advantages and disadvantages of functional substances for constructing therapeutic nanoplatforms are presented in Table 1. The selection of therapeutic and encapsulating Table 1 substances should be optimized to construct nanoplatforms with the desired tumor therapy effect Construction methods based on passive targeting (1) Polyethylene glycol-mediated PTT nanoplatforms. Bioavailable polyethylene glycols (PEGs) are common substances for preparing PTT therapeutic nanoplatforms to improve water solubility, avoid aggregation and prevent opsonization during blood circulation. 121 The fundamental regimes for the PEGylation of therapeutic nanoplatforms are presented in Fig. 4, including hydrophilic PEG (Type I), PEG-based amphiphilic block copolymers (Type II) and mixtures of hydrophilic PEG and hydrophobic polymers (Type III). 28,103,122,123 They can be conjugated to both organic and inorganic PTT therapeutic components. 94, In the Type I regime, the hydrophilic and bioavailable PEGs are usually employed. This type of polymer brush can be directly conjugated to therapeutic substances to achieve PTT or PTT/chemotherapy combination therapy. The optimized PEGylation conditions are important. At a low PEG grafting density on surfaces, the PEGs are organized in a so-called mushroom topology, which can be transformed into the brush configuration at a high grafting density. 127 The PEG grafting density determines the micelle stability in aqueous solution. 128 Advantages and disadvantages of therapeutic and encapsulating substances for PTT therapeutic nanoplatforms Functional substances Advantages Disadvantages Ref. Photothermal substances Chemotherapeutic drugs Encapsulating substances Gold nanoobjects (particle, rod, shell, cage, star, etc.) Carbon nanomaterials (nanotubes, graphene, graphene oxide, etc.) Metal nanomaterials (Pd, CuS, etc.) NIR-absorbing dyes (indocyanine green, etc.) NIR-absorbing conjugated polymers (polyaniline, polypyrrole, etc.) Organic nanomaterials (porphysomes, Dpa-melanin, etc.) (1) Tunable NIR light absorbance. (2) Easy preparation and multi-functionality. (3) Easy detection for tumor imaging (1) High NIR photothermal efficiency. (2) Easy detection for tumor imaging (1) High NIR photothermal efficiency and stability. (2) Easy detection for tumor imaging (1) Fluorescent imaging or NIR photothermal heating. (2) Indocyanine green is an approved clinical agent (1) Good photostability and biocompatibility. (2) High photothermal conversion efficiency. Good biocompatibility and biodegradability (1) Surface chemistry and dimension dependence of NIR behavior and toxicology. (2) Disruption of protein conformation. (3) Loss of NIR absorbance under high-power photothermal heating Chronic tissue inflammation and DNA oxidative injury caused by frustrated phagocytosis Non-biodegradable and unknown long-term toxicology (1) Insoluble in aqueous media. (2) Instability and concentrationdependent aggregation. (3) Rapid elimination from body Poor biodegradability and unknown long-term toxicology 1, 3, 29, 58, , 8, 33, 57, 60, 61, , 64, 66, 67, , , 76, Increasing in stability 3, Hydrophilic drugs Soluble in blood and good Limited variety. therapeutic effects Hydrophobic drugs Good therapeutic effects Insoluble in blood. Polymer systems (1) Stealthy surface. (2) In vivo Premature drug release 78, stability. (3) Easy design and preparation. (4) Some are medically approved Mesoporous silica (1) High surface area. (2) Uniform and tunable pore size. (3) Easy functionality (1) Reactive oxygen species production by surface defects and impurities. (2) Protein unfolding. (3) Membrane disruption 25,

6 Fig. 4 Schematic of the PEGylation regimes for PTT therapeutic nanoplatforms via conjugation to organic and inorganic therapeutic components. An increase in the grafting density leads to the formation of micelles without aggregation during lyophilization and influences cellular uptake. Cruje et al. studied the cancer cell uptake behaviors of nanoparticles with different PEG lengths and grafting densities (σ p ). 129 A low grafting density and short chain length lead to a high cellular uptake at the cost of greater nonspecific protein adsorption. Thus, the high grafting density and short chain length are the most favorable parameters. The cell endocytosis of PEGylated nanoparticles was accompanied by the structural and free energy change of the grafted PEG with different σ p and chain lengths. 121 To achieve good PTT tumor therapy efficacy, some photothermal conversion substances can be directly conjugated according to the Type I regime. Niidome et al. synthesized PEG-modified Au nanorods with stealth behavior for in vivo applications. 26 Through intravenous injection, the biodistribution was clearly enhanced after PEGylation. Maltzahn et al. studied the computation-guided photothermal tumor therapy based on PEG-modified Au nanorods. 130 Via computationally driven pilot therapeutic studies, they showed that a single intravenous injection of PEG-Au nanorods enabled the destruction of all the irradiated human tumor xenografts in mice. In addition to Au nano-objects, other inorganic photothermal conversion materials can also be modified according to the Type I regime. As shown in Fig. 5, PEGylated Pd@Au nanoplates (Fig. 5a) and CuS nanoparticles (Fig. 5b) can achieve good photothermal tumor therapy efficacy. 32,131 Similar to inorganic photothermal substances, the organic NIR fluorescent dye photothermal micelles from self-assembly (IR-780, Fig. 5c) can also be fabricated for tumor therapy. 27 To achieve PEGylation, some encapsulated components can be integrated as transitional agents. A layer-by-layer (LBL) polymer coating approach based on electrostatic interaction was also adopted. Prussian blue nanocubes (Fig. 5d), 132 magnetic iron sulfide (Fig. 5e) 133 and poly(3,4-ethylenedioxythiophene)/poly (styrenesulfonate) (PEDOT:PSS) nanoparticles (Fig. 5f) 103 were coated successively with oppositely charged poly(allylaminehydrochloride) (PAH) and negative charged poly(acrylic acid) (PAA), where PEGylation can be achieved from the transitional agents. To achieve PTT/chemotherapy combination therapy, the functional encapsulating substances are needed to encapsulate drugs because Type I polymer brushes have no ability to load drugs. By combining photothermal conversion materials with encapsulating substances, nanoplatforms with the PTT/chemotherapy functionality can be constructed. One of the most typical methods is the use of mesoporous silica. Lu et al. prepared PEGylated CuS@mSiO 2 nanoplatforms (Fig. 6a) for PTT/ chemotherapy combination therapy. 134 The PTT/chemotherapy nanoplatform with PEGylated gold nanoshells on silica nanorattles was also presented for intravenous injection therapy. 135 Similarly, the PEGylated Cu 9 S 2 nanoplatforms have also been employed for combination therapy (Fig. 6b), and are promising therapeutic agents for tumor therapy. 136 In the Type II regime, amphiphilic PEG block copolymers are employed, which can simultaneously coat photothermal conversion materials and load hydrophobic drugs via self- Fig. 5 Schematic models of PTT nanoplatforms, (a) PEGylated Pd@Au nanoplate. Reproduced from ref. 32 with permission from Wiley. (b) PEGylated [ 64 Cu]CuS nanoparticle. Reproduced from ref. 131 with permission from Elsevier. (c) PEGylated IR-780 nanoplatform. Reproduced from ref. 27 with permission from Elsevier. (d) PEGylated PB nanocube. Reproduced from ref. 132 with permission from Elsevier. (e) PEGylated FeS nanoplatform. Reproduced from ref. 133 with permission from Elsevier. (f) PEGylated PEDOT:PSS nanoplatform. Reproduced from ref. 103 with permission from ACS.

7 Fig. 6 Schematic nanoplatforms for tumor combination therapy, (a) PEGylated CuS@mSiO 2 nanoplatforms. Reproduced from ref. 134 with permission from RSC. (b) PEGylated msio nanohybrids. Reproduced from ref. 136 with permission from Wiley. assembled micelles or vesicles. 48,123,137 Liu et al. synthesized PEG-grafted poly(maleic anhydride-alt-1-octadecene) (PMHC 18 ). 123 The PEG-PMHC 18 -coated carbon nanotubes have an optimal blood half-life of h to balance the tumor-to-normal organ (T/N) uptake ratio of nanotubes in major organs. As shown in Fig. 7a, the high accumulation at tumor sites leads to a promising tumor treatment efficacy. The micelles assembled from amphiphilic PEG-PMHC 18 can load nearinfrared organic dyes being verified as safe and highly effective photothermal conversion agents for in vivo tumor therapy (Fig. 7d). 28 Some other amphiphilic block copolymers can also be used to load photothermal agents via self-assembled micelles. Yang et al. 138 synthesized copolymers of monomethoxy poly(ethylene glycol) and alkylamine-grafted poly(l-aspartic acid) (mpeg-b-pasp), which can be co-assembled with carbocyanine dyes into theranostic micelles (Fig. 7b). They possess a high loading capacity, good stability, sustained-release behaviors and enhanced cellular uptake. As a result, the preferable biodistribution and long-term retention in tumors can be achieved for PTT therapy. The block copolymers of poly(ethylene glycol)-block-poly(2-diisopropylmethacrylate) (PEG-b-PDPA) were used to load lipophilic fluorescent carbocyanine dyes via self-assembled micelles (Fig. 7c). 139 Through intravenous injection, the micelles induced high accumulation in tumors and penetrated into the deep interior of tumor tissues. The in vivo PTT measurements indicated that the growth and metastasis of breast cancer cells were entirely inhibited by NIR irradiation. To achieve PTT/chemotherapy combination therapy in the Type II regime, the hydrophobic block components or other encapsulating substances can be used to load drugs. For example, the Au nanorods (AuNRs) coated with the lipoylated poly(ethyleneglycol)-b-poly(ε-caprolactone) block copolymer (PEG-b-PCL) achieved drug loading via PCL block-induced hydrophobic interaction (Fig. 8a). 48 In theory, the AuNRs are typical photothermal conversion agents with high conversion efficiency. Thus, the nanoplatforms have potential in PTT/ chemotherapy combination therapy. Zheng et al. constructed DOX/ICG-loaded lipid polymer nanoparticles via single-step self-assembly (Fig. 8b). 49 The integration of poly(lactic-coglycolic acid) (PLGA) can form a core to co-encapsulate DOX and indocyanine green (ICG). Lecithin and two stearic acyl phosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG) can self-assemble around the PLGA core to form a lipid monolayer covered by a PEG shell to stabilize the nanoparticles in aqueous solution. During in vivo experiments using the nanoplatforms, no tumor recurrence was observed under laser irradiation. Mesoporous silica can also be integrated to load drugs according to the Type II regime. Liu et al. 40 developed mesoporous silica-encapsulated single-walled carbon nanotubes conjugated with poly(maleic anhydride-alt-1-octadecene)- PEG (C 18 PMH-PEG) as multifunctional light-responsive nanoplatforms for PTT/chemotherapy combination therapy Fig. 7 Schematic nanoplatforms for PTT/chemotherapy combination therapy, (a) PEG-PMHC 18 -coated carbon nanotubes. Reproduced from ref. 123 with permission from Elsevier. (b) mpeg-b-pasp loaded carbocyanine dyes. Reproduced from ref. 138 with permission from Elsevier. (c) PEG-b- PDPA loaded lipophilic fluorescent carbocyanine dyes. Reproduced from ref. 139 with permission from Wiley. (d) PEG-PMHC 18 loaded IR825 dyes. Reproduced from ref. 28 with permission from Wiley.

8 View Article Online Fig. 8 Schematic nanoplatforms for PTT/chemotherapy combination therapy, (a) PEG-PCL coated Au nanorods. Reproduced from ref. 48 with permission from ACS. (b) DSPE-PEG coated PLGA with DOX/ICG loading. Reproduced from ref. 49 with permission from ACS. (c) C18PMH-PEG coated SWNT@MS nanoplatforms. Reproduced from ref. 40 with permission from Wiley. (Fig. 8c). After intravenous injection into mice, the nanoplatforms could be accumulated in a tumor efficiently and synergistic anti-tumor efficacy was achieved. In the Type III regime, a mixture of hydrophilic PEGs and other hydrophobic polymers is employed. Similarly, the polymer brushes can coat photothermal conversion materials and load drugs. For instance, the Fe3O4@SiO2 particles conjugated with PEGs and PCL brushes (Type III) are able to deliver highly hydrophobic drugs. The hydrophobic/hydrophilic balance of brushes can be adjusted according to the PEG/PCL ratio (Fig. 9 Part A).140 The polymer brush-functionalized substances tend to self-assemble into vesicles. Duan et al.29,122,141 developed a new class of plasmonic vesicular nanostructures based on Type III polymer brush-coated Au nanocrystals and nanorods (Fig. 9 Part B), which illustrate the self-assembly and external-stimuli-triggered destruction based on plasmonic vesicles that are self-assembled from Type III polymer-brush-coated Au nanocrystals. Other plasmonic vesicles also achieved tumor photothermal ablation and drug loading.29 However, these selfassembled vesicle nanostructures are commonly size-limited by biological barriers, restricting the biological application.29 (2) Liposome and inorganic material-mediated PTT nanoplatforms. Similar to the PEG-mediated PTT construction strategy, other functional materials, such as liposomes, mesoporous silica and carbon dots, have also been used to construct nanoplatforms for PTT/chemotherapy combination therapy. Liposomes are important biomaterials with excellent biocompatibility and biodegradation, which are widely used in the delivery of hydrophilic and hydrophobic anti-cancer drugs. When integrated with photothermal conversion materials and chemotherapeutic drugs, the therapeutic nanoplatforms for PTT/chemotherapy combination therapy can be prepared (Fig. 10), such as liposome Au nanoparticles,142 and liposome/sio2/au core shell nanoplatforms.143 For the latter, the nanoliposome template was used to synthesize silica shells, and the Au nanoshells were grown on the outer surface. Then, DOX drugs can be incorporated into the core shell nanoplatforms with good passive accumulation at the tumor sites via intravenous injection. Fig. 9 Schematic illustrations of polymer brush segregation after exposing the mixed brushes to water (Part A). Reproduced from ref. 140 with permission from Wiley. Nanoplatform based on Type III polymer brushes (Part B), brush-coated Au nanocrystals (a). Reproduced from ref. 141 with permission from ACS and brush-coated Au nanorods (b). Reproduced from ref. 29 with permission from ACS. In theory, mesoporous silica (msio2) is not bioavailable as mentioned in Table 1. So PEGylation was commonly used to enhance its bioavailability. However, latent new results

9 Fig. 10 Biomaterial-mediated PTT construction models, (a) integrated Au nanoparticles. Reproduced from ref. 142 with permission from ACS. (b) Liposome/SiO 2 /Au core shell nanocomposites. Reproduced from ref. 143 with permission from Dovepress. (c) PPA pyrolyzed C-dots. Reproduced from ref. 144 with permission from Wiley. (d) msio 2 -coated Au nanorods. Reproduced from ref. 2 with permission from Wiley. show that the silica-induced immune response can play a positive role in the accumulation of nanoplatforms at tumor sites via intravenous injection (Fig. 10d). 2 In fact, the success of intravenously injected Au@mSiO 2 is based on the interaction between nanoparticles and blood proteins. As a result, the protein coating the Au@mSiO 2 -DOX may facilitate its transportation behavior in vivo. Carbon dots are other emerging nanomaterials that have received a lot of attention because of their high water solubility, surface modification flexibility, low toxicity, excellent biocompatibility and high photostability. Recently, their NIR photothermal conversion functionality has been discovered with potential in PTT tumor therapy. For example, polythiophene phenylpropionic acid (PPA) was employed to prepare novel carbon dots. 144 The resultant carbon-dots exhibited a high photothermal conversion efficiency of 38.5% under 671 nm laser irradiation (Fig. 10c). Via in vivo experiment, they can accumulate well at tumor sites to achieve a highly efficient tumor ablation. 3.2 PTT therapeutic nanoplatforms with active targeting Main mechanism of active targeting. Compared with passive targeting, active targeting has a better tumor specificity for the effective accumulation of PTT nanoplatforms at tumor sites via intravenous injection. In general, there are three types of targeting sites in the active targeting model, i.e., angiogenesis-associated targeting, uncontrolled cell proliferation targeting and tumor cell targeting. The receptors provided by them can be recognized by cell-specific ligands. So it gives an opportunity to functionalize PTT therapeutic nanoplatforms based on the active targeting regime. 145 The functionalized nanoplatforms can effectively reach tumor sites via receptormediated endocytosis pathways Functional substances. To construct PTT therapeutic nanoplatforms with active targeting, the therapeutic and encapsulating substances are quite crucial. According to the mechanism of active targeting mentioned above, cell-specific ligands are necessary to achieve tumor targeting through receptor-mediated specific recognition. So these ligands can be integrated to enable PTT therapeutic nanoplatforms with an active targeting functionality. Because the therapeutic and encapsulating substances were introduced in the above section, in this section, more attention is paid to cell-specific ligands, 116 which can increase the accumulation of nanoplatforms through receptor-mediated endocytosis. In detail, based on the specific interactions with receptors that are overexpressed on tumor cells or tumor vasculature and not expressed by normal cells, the targeting ligands can be used to enhance selective cellular binding and further increase the retention and accumulation of nanoplatforms in tumor vasculature as well as internalization by target tumor cells. Commonly, the targeting ligands include proteins, peptides, aptamers, polysaccharides and small biomolecules. For example, antibodies, antibody fragments, growth factors, and transferrin belong to protein targeting ligands. Cyclic RGD, octreotide, AP peptide, and tlyp-1 peptide can be considered as peptide targeting ligands. A10 and AS1411 are aptamer targeting ligands. Hyaluronic acid is a polysaccharide targeting ligands. Folic acid, galactose, bisphosphonates and biotin belong to the small biomolecule targeting ligand group Construction methods based on active targeting. The construction of PTT therapeutic nanoplatforms with active targeting was focused on using targeting ligands to functionalize PTT therapeutic nanoplatforms with passive targeting. Via this functionalization, the nanoplatforms with active targeting can enhance endocytosis. In general, there are two important

10 Fig. 11 Schematic nanoplatforms with targeting ligands, (a) FA targeting nanoplatforms via the Type I regime. Reproduced from ref. 148 with permission from Wiley. (b) RGD targeting a red blood cell with drug and ICG loading via the Type II regime. Reproduced from ref. 150 with permission from Wiley. (c) crgd targeting Au nanorods via the Type II regime. Reproduced from ref. 151 with permission from Elsevier. (d) FA molecules or integrin αvβ3 mab targeting micelles containing indocyanine green. Reproduced from ref. 74 with permission from ACS. aspects that should be considered. One is the basic construction step to construct PTT therapeutic nanoplatforms with the passive targeting mentioned above. The other is how to integrate targeting ligands into these nanoplatforms. The integration of targeting ligands is based on chemical reactions. For instance, folic acids (FA) can be integrated into PTT therapeutic nanoplatforms through the FA-linked Type I regime (Fig. 11a). 148 Lots of PTT nanoplatforms, such as arginine glycine aspartic acid (RGD) functionalized targeting Au nanorods 57 and TAT peptide-functionalized targeting Au nanostars, 149 are constructed via the Type I regime. Similarly, Type II polymer brushes are also linkable agents for targeting ligands. Sun et al. constructed remotely controlled red blood cell carriers that can be loaded with chemotherapeutic drugs and photothermal conversion materials, and can integrate targeting RGD ligands on the surface of red blood cells. 150 The biological experiments indicated that red blood cells were inherently biocompatible with potential for cancer-targeted therapy (Fig. 11b). Zhong et al. prepared crgd-linked PEG-PCL-LA blocks to coat Au nanorods (Fig. 11c). 151 Owing to the self-assembly, the targeting ligand-linked micelles are the available nanoplatforms. A typical example is that the micelles containing indocyanine green were functionalized by FA molecules or the integrin α v β 3 mab (Fig. 11d). 74 Besides, the uptake of human epidermal growth factor receptor 2 (HER2) antibodyconjugated hybrid nanoparticles (HNPs) on cancerous cells is higher than on noncancerous cells based on the selective tumor targeting. 152 Liu et al. constructed induced pluripotent stem (ips) cell loaded Au nanorod nanoplatforms (AuNRs-iPS) (Fig. 12). 153 The ips cells can be used as transporters to target the tumor. Via intravenous injection, the PTT theranostic nanoplatforms can be accumulated at tumor sites. Importantly, the combination of gold nanorods with human ips cells as a theranostic platform paves an alternative road for cancer theranostics and shows great potential for clinical translation in the near future. Fig. 12 Schematic PTT nanoplatforms with ips cells as the surface coating for active targeting. Reproduced from ref. 153 with permission from ACS. 3.3 PTT therapeutic nanoplatforms with external stimulusresponsive targeting Main mechanism of external stimulus-responsive targeting. Similar to passive targeting and active targeting, external stimulus-responsive targeting has also received more attention to enhance the accumulation of PTT nanoplatforms at tumor sites. The responses are mainly caused by external physical stimuli. For example, a magnetic field can pull magnetic nanoplatforms to tumor sites to achieve a high accumulation. 154 The NIR light-induced heat can induce a phase transformation of thermo-responsive components to shrink the size and enlarge the pore size of leaky vessels around the tumor for high accumulation efficiency. 13 The cell internalization can be promoted by means of a ph-triggered surface-charge reversal from negative (or neutral) to positive. 155 Thus, the ph can also be used as an external stimulus to regulate the surface-charge reversal. In addition to these three types of external stimuli, ultrasound can also be employed Functional substances. To construct PTT therapeutic nanoplatforms with external stimulus-responsive targeting, therapeutic and encapsulating substances are fundamental. For magnetic-field-induced targeting, magnetic iron oxide

11 nanomaterials are the most commonly used targeting substances, which have been approved for clinical applications by FDA. For heat-induced targeting, heat-responsive polymers, such as thermosensitive hydrogels with a higher biocompatibility and weaker immune responsiveness in blood, have been used to construct stimulus-responsive nanoplatforms. 13 For ph-induced targeting, ph-responsive amino and carboxyl groups are the most typical targeting substances successfully integrated to achieve reversible protonation. 160 All of these substances can be used to achieve tumor targeting similar to cell-specific ligands in active targeting Advantages of external stimulus-responsive targeting. In view of biological applications, external stimulus-responsive targeting is different from passive and active targeting. First, compared with passive targeting, magnetic-field, heat and phinduced targeting can all be conveniently used to enhance the accumulation of nanoplatforms at tumor sites. Second, compared with active targeting, magnetic-field and heat-induced targeting will not induce an immune response stemming from the introduction of targeting substances. Although phinduced targeting may cause an immune response due to the introduction of ph-responsive functional components, in general, external stimulus-responsive targeting provides an important choice for tumor therapy Construction methods based on external stimulusresponsive targeting. To construct PTT therapeutic nanoplatforms with magnetic-field-induced targeting, the key integrating strategy is the encapsulation or coating of magnetic-fieldresponsive iron oxide (Fe 3 O 4 ) nanoparticles. The strong magnetic property of Fe 3 O 4 makes it easy to achieve magnetic targeting. They are among a few inorganic nanomaterials with high biocompatibility approved in clinical medicine by the FDA. 161 For example, the octahedral Fe 3 O 4 nanoparticles were selected as magnetic cores, and Au and mesoporous silica were subsequently coated on them. The bondable oligonucleotides (referred to as dsdna) were used as pore blockers for mesoporous silica shells, resulting in the formation of NIRresponsive DNA-gated Fe 3 O 2 nanocarriers (Fig. 13a). 162 The nanoplatforms can well reach tumor sites via the blood stream through magnetic-field-induced targeting. In a similar strategy, iron/iron oxide core/shell nanoparticles modified by Type I regime polymer brushes have also been successfully constructed and applied in in vivo experiments via intravenous injection (Fig. 13b). 163 In addition to inorganic photothermal conversion substances, iron oxide can also be combined with organic photothermal substances by an appropriate surface coating. A typical example is iron oxide@- polypyrrole nanoparticles that are assembled via Type II regime polymer brushes (Fig. 13c). 154 In addition, some other magnetic nanostructures, such as Prussian-blue-coated Fe 3 O 4 nanoparticles, have also been used to construct therapeutic nanoplatforms with magnetic targeting. 161 For PTT therapeutic nanoplatforms with heat-induced targeting, the typical strategy is to coat the photothermal conversion substances with thermo-sensitive hydrogels. When exposed to heat, the phase transformation occurs and the accumulation of nanoplatforms at tumor sites can be improved. For instance, mesoporous-silica-coated Au nanorods modified Fig. 13 Schematic PTT nanoplatforms with field-induced targeting, (a) DNA-gated Fe 3 O 2 nanoplatforms. Reproduced from ref. 162 with permission from ACS. (b) Iron/iron oxide core/shell nanoparticles with Type I polymer brush coating. Reproduced from ref. 163 with permission from Elsevier. (c) Iron oxide@polypyrrole nanoparticles with the Type II polymer brush coating. Reproduced from ref. 154 with permission from ACS.

12 Fig. 14 Schematic nanoplatform models with (a) heat-induced targeting, reproduced from ref. 13 with permission from ACS, and (b) ph-induced targeting, reproduced from ref. 160 with permission from Wiley. by a thermosensitive hydrogel (Fig. 14a) were fabricated. The NIR laser-induced cancer thermo-chemotherapy without targeting ligands represented a novel and easily controlled targeting anticancer strategy in practical applications. 13 Under NIR laser irradiation, the photothermal-induced relaxation or dissociation of nanogels (NGs) can also achieve the stimulus-triggered release of loaded DOX and ICG. The in vivo results show a high accumulation of drugs in the tumor tissue and significant tumor growth suppression under NIR irradiation. 164 To construct PTT therapeutic nanoplatforms with phinduced targeting, the ph-responsive components should be integrated onto photothermal conversion substances via surface modification. Functionalizing therapeutic nanoplatforms with mixed-charge surfaces is an effective strategy to avoid nonspecific interactions during circulation. 165,166 Wang et al. delicately decorated gold nanostars (GNSs) with longchain amine-terminated ( positively charged) and carboxylterminated (negatively charged) PEGs to obtain reversible phcontrolled nanoplatforms (Fig. 14b). 160 When the ph is 6.4, the nanoplatforms are positively charged and a high accumulation at the tumor sites can be verified in vivo, resulting in an improved PTT therapeutic efficacy. Also, the ph-responsive nanoplatforms can achieve tumor ablation with high drug delivery efficiency. 167 An acid-sensitive bridged copolymer can also be used to achieve tumor targeting. For example, a ph e responsive PEG-Dlink m -R9-PCL copolymer was synthesized and self-assembled into micelles. Interestingly, the ph e responsive linkage breakage could induce PEG detachment at tumor sites and thereby facilitate cell targeting Construction strategies of PTT theranostic nanoplatforms 4.1 Imaging methods and mechanism The so-called theranostic nanoplatforms possess both therapeutic and diagnostic functionalities for clinical applications. As mentioned above, the therapeutic functionality is based on photothermal conversion substances and chemotherapeutic drugs. The diagnostic aspect is actually called in vivo imaging that enables the visualization of tumor sites. Thus, PTT theranostic nanoplatforms possess a significant advantage and high potential in accurate tumor diagnosis and therapy. 169,170 For the construction of PTT theranostic nanoplatforms, the therapeutic, encapsulating, targeting and imaging substances should be integrated in achieving the therapeutic and diagnostic functionalities. The imaging substances can be therapeutic substances themselves, i.e., imaging contrast agents. Different types of imaging functionalities can be achieved through the integration of contrast agents. In general, there are five types of clinical imaging methods used for tumor imaging, i.e., computed tomography (CT) imaging, 156,171,172 magnetic resonance (MR) imaging, 133,154,170,173,174 NIR fluorescence imaging, 72,73,174 ultrasound (US) imaging, 87,108,109, and positron emission tomography (PET) imaging In addition, photoacoustic (PA) imaging and microwave-induced thermoacoustic (TA) imaging are also developed. 125, These imaging methods are based on contrast agents employed that possess different imaging mechanisms. Table 2 summarizes the imaging methods, mechanisms and applications of imaging contrast agents as a selection guideline. 4.2 Construction strategies and models The construction of PTT theranostic nanoplatforms mainly focuses on using imaging contrast agents to functionalize therapeutic nanoplatforms with a passive targeting functionality. Normally, imaging methods with a high sensitivity possess a relatively poor resolution, while the methods with a high resolution possess a relatively poor sensitivity. 73 In PTT theranostic nanoplatforms, two or more imaging contrast agents are commonly integrated to achieve multi-modal imaging, which effectively enhances both the resolution and sensitivity. The integration of multi-modal imaging into a single nanoplatform can avoid the stress put on the body s blood clearance

13 Table 2 Imaging contrast agents of PTT theranostic nanoplatforms Imaging methods Imaging contrast agents Mechanism Characteristics CT imaging PA imaging MR imaging (T1-weighted MR imaging, T2-weighted MR imaging) Fluorescence imaging US imaging Microwave-induced TA imaging PET imaging Au, NaLuF 4 /NaYbF 4,Bi 2 S 3, FePt, WO x and TaO x, etc. 171,172, Au, carbon, Prussian blue, PPys, quantum dots, etc. 125,170,173,181,182,197,198 Gd-Based nanomaterials, Fe-based nanomaterials 154,170,204,205 Fluorescence dyes, quantum dots 72,73,174,213 Gas-filled microbubbles or microcapsules 108,219 mechanism to accompany the administration of multiple doses of agents. 73 Hence, it is better to introduce multi-modal contrast agents to obtain PTT nanoplatforms with multi-modal imaging. Since the imaging is dependent on the contrast agents, the contrast agent-determined imaging modes should be fully considered. First, the contrast agent should be integrated into theranostic nanoplatforms to achieve the single imaging mode. Mou et al. constructed ultra-small Cu x 2 S nanodots with Type II regime polymer brushes (Fig. 15a). 181 Because of their ultrasmall size and good water dispersity and stability, the PTT nanoplatforms are capable of prolonged circulation in the blood stream and passive accumulation in tumors. More importantly, Cu x 2 S nanodots can be used as imaging contrast agents for PA imaging tumor diagnosis. Another CuS nanomaterial imaging mode was also developed for tumor diagnosis. CuS nanodots with ultra-efficient renal clearance have been synthesized for PET imaging (Fig. 15b). 227 Nanoplatforms based on Au-nanorod-loaded polymeric microcapsules were also constructed, and Au nanorods were used to achieve US imaging and PTT (Fig. 15c). 228 Some other nanoplatforms with US imaging, such as Au-nanorod-loaded polymeric microcapsules and perfluorooctylbromide polypyrrole High X-ray absorption coefficient 169 Transforming heat into ultrasound waves via thermoelastic expansion 170,173,199 High T1 and T2 relaxivity 133,173 High fluorescence quantum yields for fluorescence emission 214,215 High stability and good echogenic properties. 174, ,225,226 Fe 3 O 4 Strong absorption of microwaves Cu Radioisotopes with typical decay characteristics 178 (1) High spatial and density resolution, ease forming 3D visual image for locating tissues. (2) Low sensitivity due to poor soft-tissue contrast. (3) Noninvasive disease diagnosis and real-time monitoring of particle localization. (4) Overcoming the drawbacks of conventional iodine-based contrast agents, i.e. short imaging time, renal toxicity and vascular permeation 29,184,187,190, (1) Soft tissue contrast, high sensitivity and specificity. (2) Spectral selectivity of laser light with high resolution and deep penetration of ultrasound imaging. (3) Noninvasive imaging modality 169,181, (1) High spatial resolution and deep tissue penetration. (2) Relatively safe imaging method without inducing any ionizing radiation. (3) Noninvasive and nonionizing imaging offering high sensitivity and good discrimination for soft tissues 194, (1) High sensitivity, relatively low tissue absorption and minimal auto-fluorescence. (2) Poor spatial resolution. (3) Higher tissue penetration in the NIR window of nm 73, (1) Real-time, low cost, high safety and availability for portable devices. (2) Relatively poor resolution and easily interfered by bone- and gas-filled organs, such as the brain and stomach Deep tissue penetration and high spatial resolution. 225 (1) High sensitivity and superb tissue penetration of signal and quantitative imaging analysis. (2) Noninvasive imaging method 25,178 nano/microcapsules, have also been constructed. 108 Similar to microcapsules, Zha et al. constructed microbubbles for the delivery of CuS nanoparticles. 175 This unique microbubble structure can be used to achieve US imaging and was subsequently destroyed by ultrasound to release the CuS nanoparticles. An organic IR825 NIR dye bound to human serum albumin (HSA) was used to achieve fluorescence imaging and PTT with high potential for future clinical translation into cancer treatment (Fig. 15d). 174 The strategies for achieving NIR-sensible nanocarriers are also a crucial aspect of constructing imageable PTT nanoplatforms. For example, when exposed to NIR light, the Ru(II)-complex can lead to a twophoton excitation, which allows efficient near-infrared light responsive imaging and gold rods show strong two-photon activity in cellular imaging. 229,230 On the other hand, the high two-photon absorption could increase the two-photon-activated photodynamic therapy. 231 As a new generation of optical probes with great potential in biomedical imaging, the lanthanide doped upconversion nanoparticles (UCNPs) are able to emit shorter-wavelength photons under excitation by nearinfrared (NIR) light. 232 Second, to construct theranostic nanoplatforms with dual-modal imaging, it is necessary to integrate two different

14 Fig. 15 Schematic nanoplatform models with the single imaging mode, (a) Cu x 2 S nanodots with a Type II polymer brush coating. Reproduced from ref. 181 with permission from Wiley. (b) PVP stabilized [ 64 Cu]CuS nanodots. Reproduced from ref. 227 with permission from ACS. (c) Gold nanorod-loaded polymeric microcapsules. Reproduced from ref. 228 with permission from the RSC. (d) IR825 NIR dye bound to human serum albumin (HSA). Reproduced from ref. 174 with permission from Elsevier. contrast agents with a single imaging mode or a single contrast agent with dual-modal imaging. For a typical theranostic nanoplatform with two types of contrast agents, the poly(lactic acid) nanocapsules were loaded with perfluorooctylbromide (PFOB) and superparamagnetic iron oxide nanoparticles (SPIOs). At the same time, PEGylated gold nanoshells were integrated on the surface (Fig. 16a). 206 In vivo experiments verified that the nanoplatforms were able to achieve MR/US imaging. Zhang et al. 233 constructed graphene oxide BaGdF 5 nanocomposites to achieve MR/CT imaging-guided tumor therapy (Fig. 16b). The PEGylated polypyrrole nanoparticles conjugated with gadolinium chelates 234 also showed MR/PA Fig. 16 Schematic nanoplatform with the dual-modal imaging functionality, (a) multifunctional poly(lactic acid) (PLA) nanocapsules loaded with perfluorooctylbromide and superparamagnetic iron oxide nanoparticles. Reproduced from ref. 206 with permission from theranostics. (b) Graphene oxide BaGdF 5 nanocomposites with PEG coating. Reproduced from ref. 232 with permission from Elsevier. (c) PEGylated polypyrrole nanoparticles conjugated with gadolinium chelates. Reproduced from ref. 233 with permission from Wiley. (d) PEGylated WS 2 nanosheets. Reproduced from ref. 125 with permission from Wiley. imaging (Fig. 16c). For a single contrast agent with dual-modal imaging, two key points should be noted in the construction of theranostic nanoplatforms. The photothermal conversion substances are the imaging contrast agents, and the imaging contrast agents possess dual-modal imaging. Cheng et al. prepared PEGylated WS 2 nanosheets to achieve dual-modal CT/PA imaging (Fig. 16d). 125 The nanoplatforms can achieve dualmode imaging-guided tumor ablation via intravenous injection. Besides, some other theranostic nanoplatforms with dual-modal imaging have also been constructed to achieve tumor therapy. For example, to achieve MR and PA imaging as mentioned above, iron doped copper sulfide (Cu 5 FeS 4 ) nanoparticles and lipid-micelles incorporated with semiconducting polymer dots and a photosensitizer have also been presented. 235,236 Similarly, for MR/CT and CT/PA dual-modal imaging, the theranostic nanoplatform was also constructed and verified in vivo. 237,238 Third, to construct theranostic nanoplatforms with triplemodal imaging, two types of contrast agents should be at least integrated into nanoplatforms. Wang et al. prepared cypategrafted gadolinium oxide nanocrystals (Cy-GdNCs) coated with bovine serum albumin (BSA). 69 The albumin-based biomineralization exhibits facile and reproducible advantages, biocompatibility and good stability in biological applications. For triple-modal imaging, cypate and gadolinium chelates were often employed to achieve near-infrared fluorescence imaging and MR imaging, respectively. On the other hand, the Cy- GdNCs exhibited excitation-dependent PA signals for PA imaging. Thus, as shown in Fig. 17, the nanoplatforms can achieve triple-modal fluorescence/pa/mr imaging-guided photothermal tumor ablation (Fig. 17a) as well as PA/PET/MR imaging-guided photothermal tumor ablation of iron-oxidedecorated MoS 2 nanosheets with double PEGylation (MoS 2 - IO-PEG) (Fig. 17b). 23 For multimodal imaging, it is also a combination of multiple contrast agents. For example, FeSe 2 -decorated Bi 2 Se 3 nanosheets can achieve tetra-modal image-guided combined photothermal and radiation tumor therapy, including MR imaging, CT imaging, PA imaging and PET imaging. 239

15 Fig. 17 Schematic nanoplatform with the triple-modal imaging functionality, (a) cypate-grafted gadolinium oxide nanocrystals (Cy-GdNCs) coated with bovine serum albumin (BSA). Reproduced from ref. 69 with permission from the RSC, (b) iron-oxide-decorated MoS 2 nanosheets with double PEGylation. Reproduced from ref. 23 with permission from ACS. 5. Summary and perspectives The recent advances in the construction of PTT therapeutic and theranostic nanoplatforms were systematically reviewed. Among the three types of PTT therapeutic nanoplatforms, the nanoplatforms based on passive targeting are basic models. Their construction strategies and materials employed are the foundation for the other two types of PTT therapeutic nanoplatforms based on active targeting and external stimulusresponsive targeting. When the targeting ligands and imaging contrast agents are introduced, the PTT therapeutic nanoplatforms with targeting and imaging functionalities can be constructed. The targeting functionality enhances the accumulation of nanoplatforms at the tumor sites and the imaging functionality can visualize their distribution in vivo. Some aspects are valuable to be noticed for future studies. First, the development of highly effective photothermal conversion substances with high NIR photothermal conversion and low toxicity is an emerging issue. The high photothermal conversion efficiency is helpful to effectively convert NIR light into heat for tumor ablation. The low toxicity is important for biological applications in the long term. Second, the multifunctional nanoplatforms used for imaging, targeting and therapy are a hot topic for the early detection of tumors. The labeling and imaging enable tumor diagnosis at an earlier stage and the targeting enhances the accumulation of nanoplatforms at the tumor site for high efficiency therapy. The third but not the last topic is the full utilization of the tumor microenvironment, such as a less-acidic environment, high levels of protease and leaky blood vessels around the tumor tissues. By using targeting receptors, PTT nanoplatforms can be well constructed for tumor targeting, imaging and therapy. In summary, the PTT therapeutic and theranostic nanoplatforms possessing high tumor ablation efficiency, biological availability and low- or non-toxicity are promising and emerging in biomedical and clinical applications. Abbreviations PTT Photothermal therapy NIR Near-infrared UV Ultraviolet PDT Photodynamic therapy RES Reticulo-endothelial system MPS Mononuclear phagocyte systems EPR Enhanced permeability and retention mab Monoclonal antibodies TNFR Tumor necrosis factor receptor APC Antigen-presenting cells Au Gold Pd Palladium CuS Copper sulfide MoS 2 Molybdenum disulfide Bi 2 S 3 Bismuth trisulfide σ p Grafting density PEG Polyethylene glycols mpeg Monomethoxy poly(ethylene glycol) PB Prussian blue FeS Iron sulfide LBL Layer-by-layer PEDOT: PSS Poly(3,4-ethylenedioxythiophene)/poly (styrenesulfonate) PAH Poly(allylaminehydrochloride) PAA Poly(acrylic acid) msio 2 Mesoporous silica PMHC 18 Poly(maleic anhydride-alt-1-octadecene) T/N Tumor-to-normal PDPA Poly(2-diisopropylmethacrylate) PAsp Alkylamine-grafted poly(l-aspartic acid) AuNRs Au nanorods PCL Poly(ε-caprolactone) DOX Doxorubicin ICG Indocyanine green PLGA Poly(lactic-co-glycolic acid) DSPE Lecithin and two stearic acyl phosphatidyl ethanolamine C 18 PMH Poly(maleic anhydride-alt-1-octadecene) SWNT Single-walled carbon nanotubes Fe 3 O 4 Iron oxide PPA Polythiophene phenylpropionic acid FA Folic acids RGD Arginine glycine aspartic acid ips Induced pluripotent stem FDA Food and drug administration dsdna Oligonucleotides HER2 Human epidermal growth factor receptor 2 HNPs Hybrid nanoparticles