Functionalized theranostic nanocarriers with bio-inspired polydopamine for tumor imaging and chemo-photothermal therapy

Accepted Manuscript Functionalized theranostic nanocarriers with bio-inspired polydopamine for tumor imaging and chemo-photothermal therapy

Mehdi Farokhi, Fatemeh Mottaghitalab, Mohammad Reza Saeb, Sabu Thomas PII: DOI: Reference:

S0168-3659(19)30452-3 https://doi.org/10.1016/j.jconrel.2019.07.036 COREL 9883

To appear in:

Journal of Controlled Release

Received date: Revised date: Accepted date:

3 July 2019 24 July 2019 25 July 2019

Please cite this article as: M. Farokhi, F. Mottaghitalab, M.R. Saeb, et al., Functionalized theranostic nanocarriers with bio-inspired polydopamine for tumor imaging and chemophotothermal therapy, Journal of Controlled Release, https://doi.org/10.1016/ j.jconrel.2019.07.036

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ACCEPTED MANUSCRIPT Functionalized theranostic nanocarriers with bio-inspired polydopamine for tumor imaging and chemo-photothermal therapy Mehdi Farokhi1,* [email protected], Fatemeh Mottaghitalab2,*

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[email protected], Mohammad Reza Saeb3 , Sabu Thomas4 National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran

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Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical

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Sciences, Tehran, Iran 3

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Color and Polymer Research Center (CPRC), Amirkabir University of Technology, P.O. Box

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15875-4413, Tehran, Iran

School of Chemical Sciences, M G University, Kottayam 686560, Kerala, India

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Corresponding authors.

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ACCEPTED MANUSCRIPT Abstract Nanocarriers sensitive to near infrared light (NIR) are useful templates for chemo-photothermal therapy (PTT) and imaging of tumors due to the ability to change the absorbed NIR energy to heat. The conventional photo-absorbing reagents lack the efficient loading and release of drug

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before reaching the target site leading to insufficient therapeutic outcomes. To overcome these limitations, the surface of nanocarriers can be modified with different polymers with wide

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functionalities to provide systems with diagnostic, therapeutic, and theranostic capabilities.

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Among various polymers, polydopamine (PDA) has been more interested due to complex structure with various chemical moieties, and the capacity to be used through different coating

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mechanism. In this review, we describe the complex structure, chemical properties, and coating

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mechanisms of PDA. Moreover, the advantage and surface modification of some relevant nanosystems based on carbon materials, gold, iron oxide, manganese, and upconverting

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nanomaterials by using PDA will be discussed, in detail.

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Keywords: Cancer; Photothermal therapy; Imaging, Polydopamine; Nanocarriers; Surface

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modification.

ACCEPTED MANUSCRIPT 1. Introduction Irrespective of the level of country development, cancer is still the main cause of death in the world due to poor prognosis. In 2018, GLOBOCAN predicted that 18.1 million of people suffer from cancer with 9.6 million morbidity. Different cancers has various incidence and mortality

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rate. Lung cancer is more common than other cancers with 18.4% of the total cancer deaths in both female and male. Other common cancers are female breast cancer, prostate cancer,

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colorectal cancer, stomach cancer, liver cancer with incidence of 11.6%, 7.1%, 6.1%, 9.2%,

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8.2%, and 8.2%, respectively [1]. Furthermore, 1,762,450 new cases with 606,880 death are estimated in the U.S. in 2019 [2]. Despite the improvement in the knowledge about cancer;

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surgery, chemotherapy, and radiotherapy are still the main therapeutic approaches. By using

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these treatments, the life span of patients could be expanded; however, due to significant side effects on normal cells, the quality of life would be decreased. Moreover, multi-drug resistance

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and cancer recurrence are other restrictions of the traditional treatment strategies [3]. Other

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therapeutic possibilities are immunotherapy [4], gene therapy [5], photodynamic therapy [6], and photothermal therapy (PTT) [7], with almost better therapeutic outcomes. PTT is a potential

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treatment strategy of cancer that can induce cancer cell death by increasing the temperature in

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the tumor site by converting light energy to heat using photothermal transduction agents [8, 9]. This strategy is non-invasive and applicable for various cancer types which is attracted more attention due to using external laser beam with the ability to target the tumor by adjusting the dosage that decrease the destruction of the surrounded normal tissues [10]. The progress in nanotechnology opens new avenue for developing various nanocarriers applicable in cancer detection and therapy [3]. Cancer nanotechnology also provides new opportunity for concomitant diagnosing and treating of cancer in a single theranostic nanocarrier

ACCEPTED MANUSCRIPT in four major fields: 1) discovering the specific biomarkers related to cancer, 2) tumor and metastasis imaging, 3) delivering drugs and functional moieties into the targeted tumor, and

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ability for real-time monitoring of the progress in cancer therapy [11]. Many nanoparticles (NPs) can be applied as photothermal agent with appropriate ability to convert energy to heat. They are

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categorized as quantum dots, metallic NPs, graphene based NPs, carbon nanotubes, organic NPs,

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and earth-doped NPs [12]. Nevertheless, there are still some limitations that restrict the effective

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detection and treatment of cancer. To overcome these restriction, multifunctional nanocarriers as the new generation of hybrid nanocarriers with theranostic capabilities have been developed to

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increase the accuracy of imaging and therapy by carrying different drugs, targeting agents, and

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functional moieties [13].

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Since Messersmith et al. suggested mussel-inspired adhesive protein for surface modification in 2007 [14], polydopamine (PDA) has gained great attention for surface modification because of

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its high capacity for self-polymerization and deposition on various materials under alkaline

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conditions [15]. PDA possesses extraordinary physiochemical characteristics with the ability to endow specific functionalities when coated on different materials. PDA is also a photothermal

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reagent with outstanding photothermal conversion capability. Under near-infrared light (NIR)

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laser irradiation (808 nm), PDA converts energy to heat to increase the temperature in the tumor area and kill the cancer cells [16]. PTT effect of PDA under NIR laser irradiation is also applicable for in vivo photoacoustic imaging [17]. So, it is assumed that the extraordinary capabilities of PDA for targeted tumor therapies have provided new opportunities for photothermal therapy, chemotherapy, and theranostics. Many nanocarriers functionalized with PDA have been developed for detection and chemo-photothermal therapy of cancer. There are some studies. Recently, Wang et al. have evaluated different applications of PDA for tumor

ACCEPTED MANUSCRIPT targeting [18]

i et al. have also evaluated application of some nanoplatforms based

on polydopamine for cancer therapy [19]. We think that comprehensive review papers regarding this topic are insufficient. Here, we have focused on the photothermal properties as well as theranostic characteristics of some traditional nanocarriers modified with PDA for cancer

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diagnosis and therapy. The review will start with a summary of the physicochemical properties

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of PDA with focus on its photothermal characteristics. In the next step, the detailed description is

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follo ed on PDA appli ation in nano a ie ’ oating in the a e of an e diagno i and PTT.

therapy will be mentioned at the end of the article.

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2. Hyperthermia in cancer therapy

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Moreover, the prospects for the future application of PDA and some unique insights in cancer

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Hyperthermia or thermotherapy is referred to the increase in the body temperature. Supernormal

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temperatures showed potential in treating various malignant tumor cells. Applying moderate hyperthermia (42°-43°C) on tumor cells selectively destruct the tumors without inducing

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morbidity in normal cells. The major mechanism of hyperthermia in killing cancer cells is based

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on destructing the proteins and other cellular components that stimulate tumor shrinkage [20]. However, the other possible mechanisms that how hyperthermia induce cancer cell death is not

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fully investigated. Increasing the temperature of cells up to 39°C, denatures the proteins and have a destructive effect on cell survival and dynamics [21]. The temperature above 41ºC not only induces protein denaturation but also causes temporary cell inactivation for several hours. Applying the temperatures around 43°-45ºC for several hours induce severe hyperthermia due to production of

high levels of reactive oxygen species (ROS) which cause oxidative damage to

nucleic acids, lipid, and protein [12]. 3. Current approaches of photothermal therapy

ACCEPTED MANUSCRIPT PTT has been introduced as a potential strategy for treating cancer in recent years. The highest efficacy of PTT is in the spectral range of 650-900 nm (Near infrared) which is considered as the first biological window. High light penetration with low scattering occurs in this region [22]. The electrons in PTT agents are excited by light energy and then non-radiative relaxation generates

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heat around the PTT agents in the tumor microenvironment [23, 24]. In this situation,

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evaporation of water molecules generates an acoustic shock wave which is propagated in the

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media and alter the chemical and mechanical conditions in the system. Some molecular absorbents are able to generate heat and radiation less decay to the ground state in a picosecond

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[25]. Furthermore, PTT reduces the oxygen consumption in the tumor microenvironment through

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two mechanisms: 1) production of ROS molecules that can interact with target cells and tissues, irreversibly, and 2) photo-induced damage to blood vessels which consequently decrease the

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oxygen and blood supply [26]. The hypoxia situation stimulates the synthesis of pro-angiogenic

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factors (e.g. vascular endothelial growth factor) in tumor sites [23, 27] which can cause some clinical complications as well. Moreover, the light has low efficiency to reach the deep sections

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of tissues; so, it is only possible to treat the tumors which are located under the skin or in the

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lining of the organs. Therefore, PTT cannot be an appropriate choice for treating large and deep cancers in the skin or other tissues [28, 29]. However, PTT considers as an non-invasive

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approach for thermal therapy of cancers because the produced energy disrupts the cell membrane and denatures the proteins around the tumorigenic cells [30]. 4. Polydopamine structure and properties Marine mussels are strong and adhesive creatives because they contain adhesive proteins comprising dopamine, lysine, and 3,4-hydroxyproline in their structure [31]. PDA is interested more than other catechol-containing coatings which contains covalently crosslinked indoledione,

ACCEPTED MANUSCRIPT dihydroxyindole, and dopamine units [32]. Despite the attractive applications of PDA in different fields, its structure is not fully understood. Figure 1 summarizes the possible structures for PDA

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which are reported in the literature.

Figure 1. Some possible structures for PDA: indole homopolymers (1, 2) or polymers constructed by diverse indoles units in different oxidation states (8). The monomers are connected by benzo moieties and pyrrole segments (e.g., 3−5). It is suggested that indole skeleton is firstly formed by dopamine via oxidative ring closure before the monomer moieties are linked by dehydrogenative C−C bond formation [14, 33]. However, it is also suggested that dopamine forms by formations of primary C−C bonds between the units (6 and 7) [34, 35]. PDA

ACCEPTED MANUSCRIPT can be deduced in the monomer units comprising of two fused indole rings (9). PDA is also formed through H bonding between indoline catechol-like units and indoline-derived quinoid monomers (10). Reprinted with permission from Liebscher et al. [32]. The catechol groups in the structure of dopamine are considered as the key components that

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mediate the adhesion of mussels to other substances [36, 37]. It can be simply produced by exposure of dopamine (3,4-dihydroxyphenylethylamine) to air in basic aqueous buffer solutions

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(Figure 2) [14].

Figure 2. Formation of leucodopaminechrome (DAL) through gentle oxidation of dopamine (DA) to dopamine quinone (DQ) by dopamine semiquinone (DSQ) under Michael-type intramolecular cycloaddition reaction. Heteroaromatic 5,6-dihydroxyindole (DHI) and 5,6-

ACCEPTED MANUSCRIPT indolequinone as its oxidized product are also produced by DAL oxidations and subsequent rearrangement. Reprinted with permission from Lakshminarayanan et al. [38] The major benefit of PDA is easy deposition on many organic and inorganic substrates like super hydrophobic surfaces. Another advantage of PDA is the existence of many functional groups

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e.g., amine, imine, and catechol groups in its chemical structure that facilitate the interaction with various substrates via covalent binding without need for using further functional groups on

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the surface of substrates [39, 40]. Moreover, there are some sites four chemical derivatization of

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dopamine including amine, alkyl, and aromatic groups (Figure 3) [41]. The 3,4-dihydroxy-Lphenylalanine (DOPA) (R1 = CO 2 H) is the most common derivative of dopamine which

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mediates the formation of melanin [41]. Norepinephrine (R2 = OH) is also derived from

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dopamine with the unique characteristic being that conformal poly(norepinephrine) surface coatings are ultrasmooth [42]. Other derivatives of dopamine are commonly produced through

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substitution in the primary amines at position R3 . However, the surface modification using PDA

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commonly occurs through catechol-to-catechol conjugations because conjugations to the R3 primary amine hinders the formation of indole group [43, 44]. The 6-nitrodopamine is related to

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R4 substituted dopamine that is photo-cleavable and applicable for fabricating light-responsive

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smart surfaces [45].

PDA is also useful in biosensors because it contains reactive residual quinone groups that permit derivatization with thiol and nitrogen moieties through Michael-type addition or Schiff base formation [39, 40, 46, 47]. PDA is a cost-effective material with simple structure, and low cytotoxicity which broadened its application in different fields [48].

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Figure 3. Schematic representation of dopamine derivatives chemical structure. Dopamine derivatives are commonly form by substitiations at alkyl (R1 , R2 ), amino (R3 ), and aromatic (R4 )

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groups that define the physiochemical and potential applications of PDA. Reprinted with

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permission from Ryu et al. [41] 5. Advantage of polydopamine for photothermal therapy VS. other photo-absorbing agents

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Developing new nanomaterials with great photothermal conversion properties is a great

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challenge in PTT. Some metal nanomaterials like gold nanoparticles (AuNPs) with good surface plasmon resonance has been considered as a photothermal agent with appropriate photothermal

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conversion [49, 50]. AuNPs can be easily prepared with tailorable aspect ratio and size; however,

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the structural instability and difficulties in tuning the surface plasmon resonance of the branched AuNPs at 808 nm might limit their usage in cancer diagnostic and treatment [51]. Other useful photo-absorbing

materials

for

PTT

are

indocyanine

green

(ICG)

[52],

carbon-based

nanomaterials [53], prussian blue NPs [54], and Pd (palladium) nanosheets [55]. Despite the advantageous properties of these agents for PTT, the low drug loading efficiency and burst release of drugs before reaching the target site, hinder their application for cancer therapy [56, 57]. PDA is another type of material that is used as photothermal agent because of its high

ACCEPTED MANUSCRIPT photothermal conversion efficacy. PDA NPs have low absorption coefficient in NIR which necessitates applying high power density (808 nm@2 W/cm2 ) for PTT of cancer. In this situation, the normal tissues are also affected and some serious side effects may be produced [58, 59]. So, more investigations are required to optimize PDA NPs with low energy density and

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combine the multi-imaging strategies into a single system for cancer theranostics. However, the

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extraordinary photothermal conversion properties (40%) of PDA make it an ideal choice for

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cancer PTT [16]. Based on the recent studies, PDA NPs with more than 50 nm size are able to absorb the light in NIR and convert it into heat which make them potent agents for PTT [16].

Mn2+ which make it applicable as a

magnetic resonance

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metallic ions like Fe3+, Gd3+, and

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Moreover, the amino and catechol groups existed in the structure of PDA chelate with some

imaging (MRI) reagent [60-63]. Thus, iron-chelated PDAs can be considered as T1 contrast

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good choice for PTT based treatments.

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agent. In conclusion, the excellent characteristics of PDA in targeted PTT of cancer make it a

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6. The toxicity of nanostructures functionalization using polydopamine

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In the past decades, one of the major concerns about using nanocarriers in biomedical applications is their cytotoxicity. While in vitro assays have been used as a routine method to

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find the cell cytotoxicity of nanostructures; however, in vivo studies of nanocarriers have not recognized a unified system till now. Some studies have investigated the systemic toxicity of nanoparticles and reported that they might have some degree of toxicity in animal models; however, their toxicological effects on human organs is still unknown [64]. The characteristics of nanoparticles in terms of surface properties, electrical charge, shape, and size affect the biological responses of them [65]. It has been reported that many nanostructures e.g., Au, Ag, CNT, etc. can induce in vitro and in vivo cytotoxicity [64]. Systemic administration of

ACCEPTED MANUSCRIPT nanoparticles interact with organelles, cytoplasm, proteins, small molecules, glycans, and genomic DNA [66]. This phenomenon can serve as essential therapeutic characteristics; however, they may induce toxic effects as well. One of the strategies that reduce the toxicity of nanostructures is surface functionalization with PDA moieties. Despite the progress in using

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PDA for surface modification, the in vivo cytotoxicity is still unknown. Some studies reported

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the cytotoxicity of dopamine [67-69]. However, Ku et al. showed that PDA did not any cytotoxic

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effect on mammalian osteoblasts, fibroblast, neurons, and endothelial cells [70, 71]. It was also reported that PDA coatings highly reduced the blood immunogenicity of quantum dots and poly-

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l-lactic acid substrates [72]. Overall, it can be concluded that PDA coatings possess acceptable

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biocompatibility and can reduce the cytotoxic of nanomaterials.

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6. Factors affected the stability of coated polydopamine

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One of the main concerns in using PDA for surface coating is its stability on the surface of substrates. On the other hand, various conditions that affect the surface stability of PDA coating

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are important. In some studies, the pH value has been reported as one of the factors that affect

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the stability of PDA films coated on different substrates. For instance, the stability of PDA films on silicone oxide substrate have been studied by Bernsmann et al. They reported that exposure to

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0.1M HCL reduced the thickness of PDA to 14%, a quantitative loss was happened when exposed to 0.1M NaOH. However, the solutions with pH 3 and pH 11 did not change the thickness of PDA films, significantly [73]. On the contrary, Muller et al. showed that PDA films were detached from germanium surfaces after rinsing with Tris buffer at pH 8.5. Based on these studies, it seems that pH plays an important role in changing the stability of PDA films [74]. In another

study,

the

stability

of

PDA

and

poly(3,4-dihydroxyphenylalanine)(poly(DOPA))

melanin-like films coated on polypropylene (PP), poly(vinylidenefluoride) (PVDF), and nylon

ACCEPTED MANUSCRIPT substrates was studied [75]. The results showed that rinsing the substrates with HCL and NaOH detached the outer layers of PDA and poly (DOPA) films. It was suggested that the electrostatic repulsion between the polymeric chains existed in the polymer within the film might be responsible for this phenomenon. However, the stability of these two films in strong acidic

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condition was higher; but poly (DOPA) showed higher stability compared with PDA film.

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Moreover, the lowest stability was seen for PP substrates compared with nylon or PVDF surfaces

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probably due to its hydrophobic nature [75]. Yang et al. also confirmed the pH–dependent stability of PDA coating [76]. PDA coatings have the higher stability in the pH values of 4 to 11

ionic

conditions

in

extreme

pH

values.

Dimethyl

sulfoxide

(DMSO)

and

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high

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and the detachments mostly occurred at pH 4 and 11. Besides, PDA coating can be stabilized by

dimethylformamide (DMF) are the solvents that seems to cause the highest detachment of coated

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PDA from the substrates. Ultrasonication has also an insignificant effect on PDA coating [76].

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Thus, it is better to avoid using polar organic solvents and extreme pH values for PDA coating.

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7. Adhesion mechanisms and important factors

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Despite the progress in using PDA for biomedical applications, the definite adhesion behavior and mechanism of deposition are still unclear which can limit its application in fundamental and

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practical research. The adhesion mechanism are mainly attributed to the presence of catechol in PDA structure and the ability to form a cross-linked network through autoxidation by making covalent and non- ovalent inte a tion

u h a π–π ta ing, h d ogen bond, and ha ge t an fe

[14]. Though, Dreyer et al. reported that only non-covalent binding such as hydrogen bonds and π–π ta ing a e e pon ible fo fo ming dopamine agg egate and ovalent inte a tion were not important [77]. Accordingly, deposition of PDA on metal or metal oxide surfaces e.g., Fe2 O3 , TiO2 or Al2 O 3 is accomplished by chelation between phenolic hydroxyl and the metal atom [78,

ACCEPTED MANUSCRIPT 79]; however, PDA also interacts with some no-metallic oxides such as SiO 2 via hydrogen bonds [80]. Moreover, the aromatic groups in PDA structure can form hydrophobic bindings and/or π-π stacking with hydrophobic surfaces [81]. The positively charged amine groups and negatively charged catechol groups of PDA can form electrostatic bonds, Schiff-base reactions or Michael

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addition [82, 83]. It is worthy to note that some parameters can improve the PDA coating

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including longer coating period [14], high concentration of the initial solution [84], higher

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temperature [85], higher alkaline environment [85, 86], and higher dissolved oxygen [87]. Based on thermodynamic analysis and surface force measurements, it is clarified that PDA has different

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deposition mechanisms on the surfaces with different hydrophobicity. The surface wettability

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plays a major role in deposition, adhesion, and morphology of PDA coatings [88].

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8. Functionalized nanocarriers using polydopamine for photothermal therapies: diagnos is and treatment

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8.1. Polydopamine-functionalized gold (Au) nanocarriers for efficient photothermal therapy of tumor

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In recent years, AuNPs have been reputed as potential nanoplatforms due to extraordinary optical properties such as high localized surface plasmon resonance (LSPR) absorption, the ability to

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scatter the light in NIR, and the possibilities for various functionalization. Different Au based

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nanostructures including gold nanoshells [89], gold nanovesicles [90], gold nanorods (GNRs) [91], Au nanostars (AuNSs) [92], and gold nanocages [93] are able to exhibit LSPR in NIR wavelength. AuNPs are also more advantageous as CT contrast agent than conventional reagents like Omnipaque due to enhanced X-ray attenuation [94, 95]. Thus, Au based nanoplatforms not only are applicable for PTT but also can be used in tumor imaging. Accordingly, AuNSs were prepared by simple seed mediated growth technique followed by stabilizing by thiolated polyethyleneimine (PEI-SH); and then PDA was deposited on the functionalized AuNSs [96].

ACCEPTED MANUSCRIPT Au-PEI@PDA NSs were stable in the colloidal state, non-toxic, and water dispersible than uncoated Au NSs. The temperature was remarkably increased in the group treated with AuPEI@PDA NSs compared with AuNSs-PEI indicating the significant role of deposited PDA layer with enhanced PTT effect under NIR irradiation. The mice treated with Au-PEI@PDA NSs

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under laser irradiation was almost 100% survived after 60 days; however, significantly lower

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survival rates were observed in mice treated with control (0%), NSs (0%), and Laser (25%)

b an hed Au−Ag@PDA NP

e e p epa ed b

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confirming the potential of Au- PEI@PDA NSs for PTT of cancer [96]. In another study, eeding silver (Ag) on the basis of Au-Ag NPs

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through galvanic replacement method which was then coated with PDA by polymerization of

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dopamine at oom tempe atu e The high SPR p ope tie of b an hed Au−Ag NP at NIR efle t the potential of this nanomaterial for PTT. Furthermore, coating the Au-Ag NPs with PDA not

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only increased the biocompatibility and structural integrity of the branched NPs but also

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enhanced the efficacy of photothermal transduction up to 70% compared with other Au based nanocomposites [97]. Recently, Au@PDA@BD NPs were prepared to improve the blood

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circulation time of Au@PDA NPs and increased the accumulation of the NPs in the tumor

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microenvironment by enhanced permeability and retention (EPR) effect. The Au@PDA@BD NPs was comprised of Au core coated with a PDA layer which was further functionalized with

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BSA-dextran conjugate (BD) [93]. Au@PDA@BD NPs had 17% photothermal transduction efficacy. Moreover, photothermal tumor toxicity and temperature were raised by PDA convention at 808 nm laser irradiation. Bright and high resolution CT imaging were improved due to the presence of Au in the core of the NPs after injection in H22 tumor-bearing mice. High blood circulation time and more tumor accumulation were also observed probably due to the existence of dextran brush on the surface of NPs. Interestingly, single dose administration of

ACCEPTED MANUSCRIPT Au@PDA@BD NPs into the tumorigenic mice followed by laser irradiation at 808 nm for 10 minutes eradicated the tumors even with sizes ~250 mm 3 [93]. Many tumorigenic cells highly express folate receptors. So, designing folate targeted NPs can actively transport the fabricated NPs into the cancerous cells via receptor mediated endocytosis.

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Weng eta al. fabricated a targeted drug delivery system with AuNPs as the core which was targeted with folate (FA)-conjugated amphiphilic Zein-PDA (Zein-PFA) as a shell and then

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further loaded with needle-shaped hydroxycamptothecin (HCPT) nanocrystals [98]. Modifying

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the surface of AuNPs with PFA enhanced the stability of NPs and induced the receptor mediated endocytosis of the NPs into the tumorigenic cells. In pH 7.4, only 17.1±2.8% of the payload was

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released from the NPs which was remarkably increased to 58.4 ± 3.0% in the acidic condition of

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endosome and lysosome. HCTP-loaded nanocomplexes had high inhibitory effect with IC 50 values of 0.1-1 lg/mL against Hela, KB, and A549 cell lines. HCPT@AuNPszein- PFA also

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exhibited strong fluorescent intensity after 1 h post intravenous administration in the tumor site.

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When fluorescent intensity was declined in normal tissues, the signal was enhanced in the tumor site after 3 h post injection [98]. In a similar study, AuNS@PDA-PEI-FA (APP) was prepared by

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coupling polyetherimidefolate (PEI-FA) on AuNS and then loaded with ICG [99]. ICG has been

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introduced as the only approved NIR imaging agent and PTT by U.S. Food and Drug Administration (FDA) [100]. Based on the results obtained from in vitro and in vivo studies, APP-ICG demonstrated high potential in targeting cancer cells or tumorigenic tissues. Free ICG did not effectively kill the tumor cells at the laser power density of 0.33 W/cm2 . More than 80% of tumor cells were killed by APP-ICG and it was ⁓50% for APP. APP-ICG exhibited high cell ablation potency due to enhanced PTT effect of ICG. Based on the images obtained from fluorescent microscopy, APP showed target and time dependent uptake by MCF-7 cells.

ACCEPTED MANUSCRIPT Injecting APP-ICG into the tumorigenic mice were also practically eradicated the tumor by 0.33 W/cm2 laser power [99]. Zeng et al. prepared a theranostic agent comprising lactobionic acid (LA) that were self-assembled into AuNPs@PDA and further loaded with ICG via electrostatic interactions. The developed nanocomplex was referred to LA-LAPNH applicable for PTT of

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tumor and potency for dual-modal MRI/CT imaging [52]. The LA-LAPNHs had selective

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endocytosis into hepatocellular cell line (HepG2 cells) but they were not able to internalize into

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the Hela cells because LA can specifically recognize asialoglycoprotein receptor that was expressed on HepG2 cells. The potential of aqueous solution of LA-LAPNH for dual modal

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imaging was also confirmed by shorter T1 relaxation time in enhanced MRI imaging and higher

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Hounsfield unit value in CT imaging. The LA-LAPNHs containing ICG AuNPs@PDA showed higher temperature compared with similar amounts of ICG and AuNPs@PDA due to the

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synergistic enhancement in PTT effect. Moreover, irradiation of liver cells with NIR also

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established the remarkable PTT effect of LA-LAPNHs because these nanocomplexes had robust

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absorbance in 700 and 850 nm regions [52]. Epidermal growth factor receptor (EGFRs) or ErbB receptors are the proteins that are frequently

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overexpressed on the surface of different cancer cells like breast cancer [101]. EGFR are used as

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a diagnostic marker and is also applicable as a target for therapeutic purposes; however, in many cases, drug resistant and more invasive tumors will be grown. So, more accurate diagnostic and therapeutic routes are acquired to precisely target EGFR. It was reported that immobilizing antiEGFR on gold nanorod modified PDA substrates killed more cancer cells compared with nonirradiated group and those cells treated with bulk gold nanorod without antibody [102]. Treatment of high overexpressed EGFR cells e.g., oral (OSCC15 cells) or breast cancer cells (MDA-MB-231) with light irradiation could effectively target the tumor cells in comparison to

ACCEPTED MANUSCRIPT control groups. The cytotoxicity in tumor cells was related to the formation of cavitation due to heat production of gold nanorod [102]. In another study, Nam et al. developed spiky gold nanoparticles (SGNPs) with high photothermal stability and good NIR PTT effect (Figure4) [103]. Coating the surface of nano-spike SGNPs with PDA highly improved the photothermal

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stability and PTT effect of bulk nanoparticles both in vitro and in vivo. Interestingly, loading

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sub-therapeutic dose of doxorubicin (DOX) provoked both cellular (CD8+ T and NK cells) and

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humoral responses against tumor cells. Combined chemo-photothermal therapy (chemo-PTT) by PDA coated SGNPs not only treated the local tumors but also helped to remove the residual and

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metastatic tumors that increased the survival rate up to 85% in bilateral murine tumor model of

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CT26 colon carcinoma [103].

Figure 4. Schematic presentation of PDA coated SGNPs with chemo-photothermal effect. Combining chemotherapy with PTT highly removed the tumors in vivo and had robust antitumor efficacy against tumors in the local microenvironment, and distant tumors and possessed

ACCEPTED MANUSCRIPT concurrent immunity against reappearance of tumor for long-term. Reprinted with permission from Nam et al. [103] Zhang et al. also developed PDA coated gold nanorods for angiogenesis-targeted chemo-thermal therapy of tumors [15]. The thin layer of PDA coated on gold nanorods remarkably inhibited the

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cytotoxicity of cetyltrimethylammonium bromide template, increased the loading efficiency of cisplatin, improved the conjugation of arginine-glycine-aspartic acid (RGD) peptide (c(RGDyC))

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I was significantly stable in physiological pH. The

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pH dependent release kinetics while labeled

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and chelator-free iodine-125 labelling (RGD- 125 IPt-PDA@GNRs). Interestingly, cisplatin had

RGD- 125 IPt-PDA@GNRs significantly ta geted αvβ3 integ in and helped ele tive a umulation

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of NPs in the tumors, as confirmed by single photon emission computed tomography/CT

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photoacoustic imaging (Figure 5) [15].

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imaging. The NPs were also accumulated in tumor vessels as evidenced by high-resolution

ACCEPTED MANUSCRIPT Figure 5. Photoacoustic imaging of tumors after intravenous admonition of RGD-IPtPDA@GNRs (RGD) at a dose of 40 mg Au/kg b. w., and RAD-IPt-PDA@GNRs (RAD) as a control groups S ale ba = 10 μm Rep inted

ith pe mi ion f om Zhang et al [15]

In another study, it was reported that PDA-functionalized nano-sized reduced graphene oxide

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(NRGO), gold nanostars (GNS), and DOX (NRGO-GNS@DOX) were able to significantly reduce the proliferation of 4T1 breast cancer cells because of synergistic photothermal effect of

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NRGO-GNS and cytotoxic potential of DOX [104]. NRGO-GNS@DOX exhibited high anti-

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tumor efficacy in orthotopic 4T1 breast tumor-bearing nude mice which also inhibited lung metastasis when combined with NIR laser irradiation. The significant anti-tumor effect of

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NRGO-GNS@DOX nanocomposites might raise from anti-apoptotic effect of DOX and

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destruction of tumor-associated blood vessels by hyperthermia [104]. Overall, these studies confirmed the potential of combining gold modified nanostructures with NIR laser irradiation for

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targeted chemo/photothermal therapy of cancer.

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Taken together, AuNPs possess advantageous properties for PTT of cancer including 1) many

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targeting and passivating agents and drugs can easily conjugate to AuNPs via gold-thiol functionalization, 2) it is possible to tune the optical characteristics of AuNPs through controlling

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their structural dimensions in order to maximum NIR light absorption, and 3) passive internalization of AuNPs into the cancerous cells via EPR effect is useful to detect inherently leaky and unorganized tumor blood vessels [105]. However, the surface catalytic properties of AuNPs may cause some biomedical side effects [106]. Furthermore, AuNPs had different properties than non-nano-scaled ones; so, it is not possible to precisely predict the interactions of AuNPs with biological systems [107]. Rather than size-dependent activity of AuNPs, surface

ACCEPTED MANUSCRIPT charge and chemistry can affect cell cytotoxicity. It is considered that PDA functionalization of AuNPs would be reliable approach to improve the safety and PTT effect of AuNPs. 8.2. Polydopamine-functionalized Fe 3 O4 nanocarriers for efficient photothermal therapy of tumor

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Designing multifunctional NPs with dual T1 and T2 imaging capability would be helpful in tumor

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diagnosis by MRI. The changes in longitudinal relaxivity (r1 ) by T1 -weighted MRI contrast

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agents improve the brightness of the images and the changes in transverse relaxivity (r2 ) by T2 weighted MRI contrast agents resulting in darkening of MRI images [9]. Combining T1 and T2

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contrast agents improve the accuracy of tumor diagnosis in comparison to single modal imaging

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techniques [108, 109]. Superparamagnetic iron oxide nanoparticles (SPIONs) or Fe3 O4 are reputed as T2 contrast agents in MRI for cancer diagnosis [110]. However, the commercially

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available types of SPIONs including carboxydextran-coated Resovist and dextran-coated

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Endorem have ultrasmall diameter (less than 20 nm) that make them susceptible to opsonization in the blood circulation which consequently decrease their stability and induce non-specific

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internalization into reticular endothelial system (RES) before reaching to the targeted site [111,

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112]. Moreover, SPIONs have low photothermal conversion efficiency in NIR region which limit their clinical application for cancer treatment. In some studies, magnetic NPs were surface

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modified with PDA to improve the NIR absorption and the efficiency of photothermal conversion. For instance, it was shown that r1 of gadolinium&Fe3 O4 @PDA nanostructure was 3.4 folds higher compared with gadolinium-diethylenetriamine pentacetate complex (Gd-DTPA) as a commercial MRI T1 contrast agent. Interestingly, the nanostructure showed 27.5% photothermal conversion efficiency which was preserved after 5 on-off cycles of laser irradiation [113]. In another study, it was confirmed that increasing the thickness of the PDA layer enhanced the efficacy of photothermal conversion and NIR absorption of Fe3 O4 @PDA particles.

ACCEPTED MANUSCRIPT This phenomenon was the consequence of high NIR absorption of the particles. Appling NIR irradiation with Fe3 O 4 @PDA particles also efficiently inhibited the tumor cells in vitro and in vivo due to hyperthermia [114]. It was also reported that tuning the core size of Fe3 O4 with layer of PDA shell in Fe3 O4 @PDA superparticles (SPs) improved the performance of MRI and

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photothermal efficacy. Surface coating of Fe3 O4 by PDA enhanced the biocompatibility,

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physiological and colloidal stability, and photothermal properties. The T2 -weighted MRI images

injection of SPs caused

strong T2

signals,

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showed dramatic contrast difference of tumor with or without SPs injection [115]. Intravenous demonstrating significant retention. Surface

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modification of Fe3 O 4 with PDA changed the surface charge into negative which is more

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desirable than neutral or positive charges. The Fe3 O4 with negative charge is more stable and can easily circulate in the blood vessels for a longer period which cause higher accumulation of the

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NPs in the tumor site by EPR effect. The significant photothermal properties of Fe 3 O 4 @PDA

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upon injecting into the tumors almost removed all the tumorigenic cells after 4 days under 808

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nm laser irradiation (Figure 6) [115].

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ACCEPTED MANUSCRIPT

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Figure 6. PTT of tumors created by Hela cells in vivo. Volume of tumor (a), tumor growth and average body weight (b) fo ea h g oup, e pe tivel

AC

indu ed tumo (h−l) taining the tumo

li e

animal at da 16 S ale ba : 50 μm The mi e

( −g) ho

the t pi al mou e model

ith H&E, (m−o) the tumo

ith

ta en f om the

e e divided into 5 g oup in luding ont ol mi e

(c, h, m), the mice received only laser irradiation (d, i, n), the mice received only Fe3 O4 @PDA SPs (e, j, o), the mice under PTT after intratumoral injection (f, k), and the mice received PTT after intravenous injection (g, l). Reprinted with permission from Ge et al. [115].

ACCEPTED MANUSCRIPT Similarly, SPION clusters@PDA nanocomposites increased both r1 and r2 relaxivity in MRI indicating the usefulness structures for r1 and r2 contrast agents. The PDA layer coated on SPION clusters exhibited high efficiency of photothermal conversion after irradiation by NIR laser. Moreover, the nanocomposites were remarkably uptake by HeLa cells and HepG2 cells under an

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external magnetic field which improved the contrast of MRI imaging [116]. In a similar study,

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Chen et al. fabricated a core-shell nanocomposite comprising a magnetic Fe3 O 4 /Fe nanorod in

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the core with 120 nm diameter and a catalase (CAT)-imprinted fibrous SiO 2 / PDA (F-SiO 2 /PDA) in the shell with 70 nm thickness [117]. The Fe3 O4 /Fe@F-SiO2 /PDA NPs had a selective

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function in suppressing the activity of CAT in cancerous cells. It was reported that inhabitation

AN

of CAT induced apoptosis in cancer via burst production of H2 O2 [118]. Simultaneously, Fe ions released from Fe3 O4 /Fe core acted as a catalyzer to convert H2 O2 to ·OH. Ultimately, the

M

increase in the concentration of ·OH induced apoptosis in the cancerous cells. The CAT-

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imprinted PDA layer improved the ability of Fe3 O4 /Fe@F-SiO 2 /PDA NPs in triggering apoptosis in some tumor cells e.g., Hela, MCF-7, and 293T; without any toxicity on normal cells. In the

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presence of NPs, higher T1 -relaxivity was observed confirming the high sensitivity of the

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contrast agent for visualizing the target point [117].

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The remaining challenge of using different NPs as theranostic agents is their low stability in the blood circulation. So, modifying the surface of NPs with polymeric moieties might be a good strategy

to

enhance

their

in

vivo

performance.

Accordingly,

a

core-shell magnetite

nanocluster@poly(dopamine)-PEG@ICG nanobead was fabricated with the SPIONs nanocluster in the core and PDA layer in the shell. The nanocomposite was then conjugated with polyethylene glycol (PEG) and loaded with ICG [119]. Conjugating PEG to the surface of the nanocomposite increased the stability of the NPs in the blood circulation. The prepared

ACCEPTED MANUSCRIPT nanobeads revealed outstanding biocompatibility, remarkable ability to target the magnetic field, and high T2 relaxivity in MRI imaging. Under external magnetic field, the nanobeads were highly accumulated in the target tumor as confirmed by darker T2 -weighted MRI image. Combining SPIONS with a PDA layer increased the PTT conversion efficacy of NPs and thus

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increased the temperature to 36.9◦ C. In addition, loading ICG with high photostability on the

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surface of the nanobeads not only improved the efficacy of photothermal conversion but also

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exhibited an additional photothermal effect in killing HepG2 cells under NIR laser irritation rather than PDA and magnetic nanocluster [119]. In another study, a multifunctional core-shell

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structure based on PEGylated magnetic NPs coated with PDA was prepared that were

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consequently loaded with DOX. The PDA layer increased the NIR absorption of the nanoasytem and the superparamagnetic properties of the NPs enabled the targeted delivery of the drug into

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the tumor site under guided magnetic field [120]. Free DOX was 73.33% uptake by the cells

ED

after 1 h which was increased to 99.32% after 3 h; while, the DOX loaded NPs exhibited 12.25% uptake after 1 h which reached to 43.36% in 3h. Furthermore, the uptake was increased to

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87.71% in 3 h after applying magnetic field. The results confirmed the higher efficacy of

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combination therapy based on PTT and chemotherapy rather than using each of these modalities alone [120]. In a similar study, it was shown that DOX had both thermal and pH responsive

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release from Fe3 O4 @PDA-PEG-EGFR-DOX NPs [121]. After internalization of the NPs into the DLD-1 human colon cancer cells, DOX was released by applying NIR irradiation. So, the cancerous cells were killed by both the released DOX and induced hyperthermia under NIR laser irritation. The Fe3 O4 @PDA-PEG-EGFR NPs were also introduced as MRI-guided therapy of cancer because it showed a dark T2 -weighted MRI after 24 h post-injection (Figure 7) [121].

ACCEPTED MANUSCRIPT Overall, magnetic NPs especially SPIONs, are suitable choice for PTT of cancer as photothermal reagents which can be used alone or in combination with other agents. Combining magnetic NPs with other photothermal reagents helps to specifically direct the NPs into the tumor, increases their accumulation within the tumor area, and facilitates monitoring biodistribution in the tumor

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site. However, low molar absorption coefficient of magnetic NPs in the NIR window is a major

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limitation which can be overcome via controlling the clustering [122]. Moreover, Fe3 O4 NPs

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have shown low therapeutic outcomes due to poor PTT effect as a consequence of low molar extinction coefficient. It seems that modification of magnetic NPs with PDA can improve PTT

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AN

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performance, biocompatibility, and stability, simultaneously [115].

Figure 7. T2 -weighted MRI images in vivo. T2 -weighted MRI images of mice at times 0, 12, and

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24 post intravenous injection of Fe3 O4 @PDA-PEG -EG FR NPs. The position of tumor is indicated by red circle. Reprinted with permission from Mu et al. ]121[

8.3. Polydopamine-functionalized manganese (Mn) nanocarriers for efficient photothermal therapy of tumor Various manganese (Mn) based nanoparticles (e.g. MnSiO 3 , MnO, and Mn3 O4 ) are considered as T1 -weighted contrast agents that have acceptable contrast enhancement efficiency. However, the relaxivity coefficient of Mn based contrast reagents is usually lower than Gd-based reagents

ACCEPTED MANUSCRIPT [123]. In addition, the inherent cytotoxicity of some nanoparticulate Mn derivatives such as Mn3 [Co(CN)6 ]2 (MnCo) restrict their in vivo applications. Blending MnCo with polymeric moieties might be a good choice to enhance its in vivo performance Re entl , metal−o gani frameworks (MOFs) containing clusters or metal ions which are linked together with an organic

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bridge are used to design self-assembled Mn ions loaded with different biomolecules which

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seems to be a good strategy to enhance the MRI performance and NIR absorption. For instance, a

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multifunctional MOF hybrid nanogel was prepared through a single one-pot method in which dopamine monomers were hybridized into MnCo skeleton (named as MnCo–PDA NPs (MCP

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NPs) [124]. The authors suggested that self-polymerization of PDA on MnCo had higher NIR

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intensity than uncoated NPs because the coated NPs had higher electron density with high photothermal conversion efficiency. The hybrid MCP NPs were further modified through two

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steps. Firstly, they were modified with PEG to enhance the bioavailability, stability, and blood

ED

circulation. Secondly, the NPs were functionalized with thiol terminal cyclic RGD (arginine– glycine– aspartic acid) peptide to improve the efficacy of treatment as a photothermal target

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therapy. The r1 value of MCP-PEG NPs was higher (5.175 m m−1 s−1 ) compared with Magnevist

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as a commercial Gd-based contrast agents (4.25 mm−1 s−1 ). Treating Hela tumor bearing mice model with MCP-PEG-RGD + NIR and MCP-PEG + NIR remarkably decreased the tumor size

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compared with those animals only treated with NIR or saline. Moreover, the therapeutic efficacy of MCP-PEG-RGD NPs was much higher than other groups due to the ability of this NPs to target the tumor with RGD peptide [124] In anothe

tud , nano ale metal−o gani pa ti le

(NMOPs) containing NIR dye (IR825) and Mn were prepared. Mn-IR825 NMOPs were then coated with PDA followed by functionalization with PEG [125]. The presence of Mn in the structure of Mn-IR825@PDA−PEG N OP

p ovided high T1 -weighted MRI intensity while

ACCEPTED MANUSCRIPT IR82555 offered enhanced photothermal conversion efficiency due to high photostability and NIR absorption capability. After 24h post intravenous injection of Mn-IR825@PDA−PEG, the temperature raised from 34 to 52°C under 808 nm laser irradiation at 0.6 W/cm2 within 5 minutes; however, the temperature only increased about 4°C in phosphate-buffered saline (PBS) ho ed a eptable photothe mal effi a

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treated group. Interestingly, Mn-IR825@PDA−PEG

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under laser irradiation because the tumor were almost removed after 18 days without recurrence.

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Besides, the mice treated with PBS or NMOP with or without irradiating laser exhibited fast

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M

AN

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growth of tumors (Figure 8) [125].

ACCEPTED MANUSCRIPT Figure 8. Evaluation of in vivo PTT effect: (a) IR thermal images of temperature changes in tumor (b) temperature changes in 4T1 tumor-bearing mice after intravenous injection of MnIR825@PDA−PEG (5 mg/ g) or PBS. After 24h, laser with 808nm beam at 0.6 W/cm2 intensity was used for tumor treatment. (c) Growth curves of 4T1 tumors in mice after treating with

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different samples. (d) Survival curves after treating the mice with various samples. (e) H&E

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staining of the main organs of the mice 60 days after PTT with Mn-IR825@PDA−PEG in

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ompa i on to ont ol (S ale ba : 200 μm) Reprinted with permission from Yang et al. [125]

Mn3 O4 @PDA@PEG

was

prepared.

The

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In another study, a multifunctional target delivery system based on core/shell folic acidultrahigh

relaxivity

(14.47mM-1

s-1 )

of the

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nanotheranostic offered an excellent choice as a contrast agent for diagnosis of tumors both in

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vitro and in vivo [126]. Coating the nanotheranostic with a PDA shell provided many advantages for the complex structure. PDA coating improved the biocompatibility of the nanotheranostic

ED

while preserving its intrinsic properties, enhanced the PPT efficacy, and improved the ability to

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interact with DOX via π–π ta ing and h d ogen bonding. In addition, irradiating laser at 808 nm not only triggered the drug release but also improved the PTT performance by increasing the

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efficacy of anticancer and reducing the side effects of the drug. The combined therapeutic

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strategy based on this nanotheranostic showed a synergistic result of chemo-photothermal therapy [126].

In a similar study, Mn-chelated polydopamine (PMPDA) modified with PEG exhibited strong MRI intensity for in vitro and in vivo imaging [127]. Under laser irradiation, PMPDA NPs showed effective role in killing Hela cells during 10 minutes. The temperature was remarkably increased in PMPDA samples while no significant increase in the temperature was observed in the cells treated with deionized water as a control group. The temperature of PMPDA samples

ACCEPTED MANUSCRIPT ith 100 μg/mL on ent ation was increased from 25.5 to 50.1 °C after laser irradiation which seemed to be sufficient to irreversibly trigger cell death [127]. It was also reported that under laser irradiation with 808 nm wavelength (2 W/cm2 ) for 10 minutes, the temperature of MnCO3 @PDA solution raised to 60 °C; while no significant change was observed in the

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temperature of MnCO 3 NPs solution without PDA coating and water. After three consecutive

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cycles of laser irritation (808 nm), the temperature raised to 60 °C confirming the acceptable

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photostability of MnCO 3 @PDA NPs. The group treated with MnCO 3 @PDA NPs under NIR irradiation showed cell shrinkage with significant tumor disruption, tumor vessels damage, and

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tumor necrosis; while, the groups treated with MnCO 3 @PDA NPs, PBS, and PBS+NIR

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exhibited less tumor damage [128]. In another study, conjugating graphene to Mn3 O4 via PDA improved the water solubility of Mn3 O4 leading to increase cell internalization and accumulation

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within the tumor microenvironment after intravenous administration in a cancerous mice model.

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Moreover, uptake of NPs by cancer cells in dark exhibited low toxicity; however, after light

oxygen species [129].

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exposure, significant phototherapeutic properties was observed by producing toxic reactive

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In general, Mn based nanoparticle are the new generation of materials which are in the early

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stage of research among other nanoparticulate systems, thus more investigations are needed to figure out the possible usage of these materials in medical fields. The Mn based nanoparticles have suitable biodistribution and T1 relaxivity whether alone or in combination with other targeting moieties [130] It i po ible to imp ove

n nano a ie ’ p ope tie in diagno i and

t eatment of tumo b u ing PDA u fa e modifi ation The e a e lot of π-conjugated structures in PDA backbone that an ea il

ea t

ith

n NP via π–π ta ing B u ing thi

t ateg ,

ACCEPTED MANUSCRIPT MnCo–PDA complex nanocarriers might have higher absorption in NIR due to the increase in the electron density which ultimately enhance the PTT effect [124]. 8.4. Polydopamine-functionalized carbon based nanocarriers for efficient photothermal therapy of tumor

and

multifunctional nanocomposites. Among

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outstanding capabilities for preparing hybrid

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In recent years, carbon based nanosystems have been reputed in biomedical fields due to

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carbon based nanomaterials, single walled carbon nanotubes (SWCNTs) seems to be good choices due to high photoacoustic signals, NIR photoluminescence, good T2 relaxivity MRI

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contrast, and intensive Raman scattering [131]. Moreover, suitable NIR absorption of SWCNTs

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make them a good agent for PTT of tumor [132]. In order to use carbon nanotubes (CNTs) in nanomedicine, it is necessary to modify their surface to decrease the cytotoxicity and improve

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the biological behaviors in terms of pharmacokinetics and tumor targeting capabilities. Surface

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modification of SWCNTs/PEG with PDA allowed Mn chelation to increase T1 and T2 relaxivity of MRI imaging and also it was possible to load

131

I radioisotope to treat cancer [133].

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SWNT@PDA- 131 I-PEG had an efficient accumulation in the tumor area after systemic injection

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into a mice model as confirmed by gamma imaging and MRI. The SWNT@PDA-PEG had acceptable heating properties under NIR irradiation (808 nm) than uncoated one due to strong

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NIR absorption capabilities of SWCNT. Concomitant existence of PTT properties of SWCNT and loaded

131

I-based radioisotope induced effective treatment of cancer in an animal model

compared to monotherapies [133]. In another study, hybrid multi-walled carbon nanotube (MWCNT)-Gd@PDA-PEG was used as a nanotheranostic agent for detection of regional lymph nodes

(RLNs) and treating metastatic

regional RLNs [134]. PDA was coated on MWCNT-Gd surface to avoid Gd ions scape from

ACCEPTED MANUSCRIPT MWCNT and reduce biological toxicity. Moreover, MWCNT-Gd@PDA-PEG exhibited a lymphatic mapping capability with good PTT properties for treating primary and metastatic RLNs [134]. Li et al. also prepared CSs@PDA-folic acid@ICG nanocomposite containing carbon sphere (CSs) modified PDA and loaded with ICG via π–π ta ing and h d ophobi

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interactions [135]. The nanocomposite was used for phototherapy and NIR imaging of cancer.

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The PDA layer increased the quenching efficiency of fluorescent signals and provided a good

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surface for anchoring folic acid. Under NIR irradiation, CSs@PDA-folic acid@ICG NCs

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showed more effective photoconversion than ICG alone [135].

It was reported in another study that coating the surface of reduced graphene oxide (rGO) with

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PDA not only helped to absorb higher numbers of ICG molecules but also quenched the ICG’

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fluorescence and improved the optical absorption of PDA-rGO at 780 nm. The PTT efficiency and photoacoustic contrast of ICG-PDA-rGO was strongly higher than PDA-rGO and bulk GO.

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Treating orthotopic and 4T1 breast subcutaneous mice model PTT showed no toxicity and

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completely removed the tumors after photoacoustic imaging-guided PTT treatments [126]. Functionalization of rGO with PDA was also reported as a suitable strategy for carrying

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cytarabine hydrochloride (Ara) [136]. After NIR laser irradiation, Ara showed a burst release

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with cumulative release kinetic up to 50% due to a local raise in the temperature that increased the permeability of PDA films. The results showed that treating Hela tumors with saline and single dose of free Ara had no obvious therapeutic efficacy. Furthermore, treatment of tumorigenic mice with rGO-PDA under NIR irradiation (5 min, every day) significantly inhibited the tumor growth indicating the remarkable PTT effect and antitumor efficacy of rGOPDA. The authors found significant suppression in the tumor growth after combining NIR laser irradiation with rGO-Ara-PDA [136].

ACCEPTED MANUSCRIPT Taken together, carbon nanomaterials possess outstanding physical properties which make them useful for PTT, radiofrequency ablation, and photoacoustic therapy. In comparison to other drug delivery

systems,

carbon

based

nanomaterials

without

any

modification

have

low

biodegradability which limit their usage in biomedical applications. Moreover, the long-term

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cytotoxicity of graphitic nanomaterials is the main challenge for clinic use [137]. Some carbon

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materials like rGO and graphene have low sensitivity for photoacoustic imaging and low PTT

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effect due to broad absorption spectrum and low photothermal conversion, respectively [138]. The capabilities of carbon nanocarriers in terms of bioactivity and photothermal effect can be

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improved by PDA coating. Rather than good effects of PDA on physicochemical properties of

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carbon nanomaterials, provides an opportunity for conjugating various targeting agents for specific internalization of nanocarriers into the cancerous cells due to the existence of various

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functional groups on the surface of PDA.

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8.5. Polydopamine-functionalized upconverting nanoparticles (UCNPs) nanocarriers for efficient photothermal therapy of tumor

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Recently, upconversion nanoparticles (UCNPs) have been extensively used for cancer detection

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and treatment due to the potential for emission of shorter wavelength photons under NIR laser irritation [139]. In comparison with conventional down-conversion fluorescent agents e.g., quantum dots,

AC

organic dyes and

UCNPs have outstanding properties including good

biocompatibility, high photostability, large stroke shifts, narrow emission peaks, and enhanced signal to noise ratio during imaging due to native autofluorescence free characteristics [140]. However, the main lack of ytterbium (Yb3+)-sensitized UCNPs (at ca. 980 nm) is the overlap of their excitation wavelength with maximum absorption of water molecules which remarkably reduce the signals while moving within the biological components [141, 142]. In addition, the overheating induced by contentious irradiation of laser at 980 nm, restricts the application of

ACCEPTED MANUSCRIPT UCNPs in vivo [143]. In recent years, it is attempted to develop new sensitizers and NIR absorbers based on UCNPs that have better excitation wavelengths. Accordingly, a hybrid coresatellite nanotheranostic containing core-shell-shell Nd3+-sensitized UCNPs modified with PDA (PDA@UCNPs) was developed for in vivo imaging and PTT [144]. After 300 s irradiating the

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laser, the temperature was rapidly raised from 25.2 to 57.8 °C (an efficient temperature for

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destructing the tumor cells) which was completely different from low temperature change of

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water. After injection of PDA@UCNPs into the tumor, Upconversion luminescence (UCL) emission was detected without auto-fluorescence emission under laser irradiation (808 nm)

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indicating UCL imaging properties with good sensitivity. However, UCL emission was attuned

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by penetration depth that limit its application in tumor located in depth anatomical positions. PDA in the core of the hybrid nanosystems not only provided high antitumor and PTT effects but

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also exhibited remarkable biocompatibility due to its intrinsic properties [144]. In a similar

nanophosphors

emission,

and

NaLuF4

and

in

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photoluminescence

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study, a three layered NaYF4:Nd3+@NaLuF4 @PDA nanocomposite was prepared for PTT, CT

the

imaging. core

The of

the

presence

of Nd 3+-doped

nanocomposite

stimulated

NaYF4 higher

CE

photoluminescence emission for CT imaging and the hydrophilicity induced by using natureinspired PDA in the shell [145]. The results showed that PDA had a PTT conversion efficiency

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dependent to the thickness. PDA with 20 nm thickness revealed 51.63% PTT conversion effect. Moreover, the CT values (HU valuses) were enhanced by increasing the concentrations of iodixanol (as a commercial X-ray contrast agent) and aqueous solution of NP@PDA nanocomposite. NP@PDA nanocomposites had higher slope (45.23) than iodixanol (20.37) indicating the remarkable capabilities of NP@PDA nanocomposites as contrast agents for in

ACCEPTED MANUSCRIPT vivo CT-imaging. After injecting NP@PDA nanocomposites into the tumor site, the X-ray

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signals were significantly attenuated (Figure 9) [145].

Figure 9. (a) X-ray CT micrographs and (b) CT values (HU values) for aqueous solutions of NP@PDA nanocomposites and iodixanol at various concentrations; X-ray CT imaging of HeLa

ACCEPTED MANUSCRIPT tumor-bea ing nude mi e ( ) befo e and (d) afte inje tion of 100 μL of NP@PDA olution with 3 mg mL−1 into the tumor area. Reprinted with permission from Dai et al. [145]

Additionally,

a

multifunctional

complex

based

on

Mn

nanocomposite

modified

with

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T

NaDyF4 :Yb@NaLuF4 :Yb,Er@PDA (Dy@Lu@PDA-Mn) was prepared. The presence of Yb 3+

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and erbium (Er3+) improved UCL, dysprosium ions (Dy3+) and Mn2+ interfered with T2 and T1 in MRI, and PDA acted as a PTT agent in the NIR window for PTT. The Dy@Lu@PDA-Mn

US

showed bright up-conversion UCL emission at 520–560 nm and 640–680 nm, r1 relaxivity of 314.43 s-1 mM-1 (0.5 T), r2 relaxivity of 277.63 s-1 mM-1 (0.5 T), high PTT conversion effect, and

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great photothermal stability. Moreover, Dy@Lu@PDA-Mn complex exhibited low toxicity in

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the cells and animal studies and was applicable in T1 -T2 -weighted MRI guided PTT of tumor

ED

[146]. In another study, a core-shell nanocomposite based on oleic-acid-capped UCNP coated with PDA (UCNP@PDA) was prepared through water-in-oil emulsion mechanism. The

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nanocomposite was further modified with amino-terminated polyethylene glycol (mPEG-NH2 ) to

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enhance the UCNP@PDA stability in the physiological conditions. The PDA in the shell of the nanocomposite showed great PTT effect and provided a functional substrate for loading agent

li e DOX

ith h d ogen bond

and π–π

ta ing The PEGylated

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hemothe apeuti

UCNP@PDA acted as a tri-modal imaging for colorectal tumors (SW620) in a mice model due to high UCL emission, CT contrast properties, and T1 relaxivity value of UCNP cores. DOX loaded UCNP@PDA-PEG nanocomposite also showed significant synergistic effect in treatment of tumor cells in vitro and in vivo [147]. Lui et al. also developed a PDA coated UCNPs nanoparticles

(UPI)

PTT/photodynamic

loaded therapy

with (PDT)

ICG

molecules

therapy

with

through

self-assembly

improved

anticancer

for

combined

properties

and

ACCEPTED MANUSCRIPT upconversion imaging [148]. The oleic acid-stabilized hexagonal NaYF4 :Yb,Er@NaYF4 :Yb (UCNPs) nanocrystals in the core of UPI provided the capability for UCL imaging. ICG molecules with NIR absorption properties also enabled heat and ROS generation to kill the tumorigenic cells. The PDA shell acted as the interface between UCNPs and ICG molecules and

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enhanced the PTT effect of UPI as an assistant PTT reagent [148]. The UCNPs possess good optical properties as contrast agents for imaging or gene/drug delivery

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because they can emit visible and UV lights under NIR irradiation. Since UCNPs considered as a

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source of UV, emitted UV can easily break the chemical linkage between the nanocarriers with gene/drug that improve the photoisomerization of photosensitive compounds. Despite the

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advantageous properties of using UCNPs for such applications, some major challenges are still

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remained. For effective gene or drug delivery with acceptable therapeutic outcomes, it is necessary to have desirable amounts of the payloads. To increase the functionality of UCNPs,

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PDA can be coated as a shell on the surface of UCNPs for enhancing imaging and therapeutic

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properties [149].

8.6. Polydopamine nanocarriers for efficient photothermal therapy of tumor

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As mentioned earlier, PDA is mostly used for modifying the surface of nanotheranocstics;

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however, new attempts have been performed to fabricate new nanocarriers based on pristine PDA. To prepare multifunctional theranostics based on PDA NPs, various functional moieties including contrast agents, photosentisizers, and drugs can be incorporated within the NPs during fabrication process [150]. PDA NPs with >50nm diameter exhibited great potential for PTT because they can easily absorb NIR light and convert it into heat [16]. Moreover, the negative surface charge of PDA NPs causes the repulsion of many proteins existed in the blood circulation which is advantageous for drug delivery applications [151]. This phenomenon

ACCEPTED MANUSCRIPT increase the half-life of the NPs in the blood circulation and improves their internalization into the tumorigenic cells through EPR effect without requiring any surface modification [152]. Recently, chlorine6 (Ce6) and curcumin (Cur) were loaded on the PEGylated PDA NPs. The Ce6 was used as an oxygen generation agent under NIR irradiation and the Cur was applied as a

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suitable radiosensitizer under X-ray to improve the external radiotherapy [152]. PDA-

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PEG/Cur/Ce6 NPs showed a remarkable toxicity to A549 cell lines under concomitant X-ray and

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NIR irradiation compared with X-ray irradiation alone and PDA-PEG as control groups. However, treating A549 cells with single PDT also induced an acceptable cell toxicity due to

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increased internalization of Ce6 into the cells with the help of PDA-PEG and generation of

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singlet oxygen [152]. PDA-ICG-PEG/DOX(Mn) is another useful nanocarrier for cancer diagnosis and treatment. [153]. Incorporating ICG molecules into PDA-PEG NPs increased the

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photostability of this molecule compared with free ICGs as confirmed by re-shift of absorption

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peak from 780 to 800 nm. Moreover, aromatic DOX can be highly loaded (>150%) into the PDA-ICG-PEG NPs. Existence of residual phenolic hydroxyl groups on the structure of PDA

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NPs facilitated the interaction with Mn2+, introducing an appropriate contrast agent in T1 -

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weighted MRI imaging [153].

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Wang et al. prepared core-satellite 64Cu-labeled DOX-loaded PDA–Gd-metallofullerene NPs (CDPGM NPs) for chemo-photo therapy and multimodal imaging e.g., MRI, PET, and photoacoustic [63]. PDA layer played as a template for assembly of different functional groups. The nanotheranostic had outstanding properties including acceptable biocompatibility, strong relaxivity (r1 = 14.06 mM−1 s−1 ) and NIR absorption, drug release triggered by NIR, and low release of Gd ions. The data also showed that CDPGM NPs were highly accumulated in the tumor site in vivo. In addition, the tumor was completely removed using chemo-photo

ACCEPTED MANUSCRIPT combination therapy under NIR laser irradiation [63]. Ge et al. also prepared multifunctional Cu2+-loaded PDA NPs for combined chemo-photothermal therapy and MRI imaging of cancer [154]. The CuPDA NPs showed strong PTT effect with high chemotherapy performance in response to pH. Moreover, loading Cu2+ on the NPs enabled the use of this nanocomplex for

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MRI imaging. The tumor growth in the group treated with laser only was relatively high. Four

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days after intravenous injection of NPs, the growth rate of tumor was inhibited; however, fast

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growth of tumor was observed in the following days. It was suggested that CuPDA NPs were only able to suppress the growth of tumor but it was not able to completely remove it (Figure 10)

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photothermal therapy are summarised in Table 1.

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[154]. Other selected important studies on the application of PDA nanocarriers for tumor

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Figure 10. Thermo-chemotherapy of KB tumors in vivo. (a) volume of tumor, (b) rising trend and average body weight for each animals in each group, (c-f) typical animal tumor model, (g-j)

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hematoxilin-eosin staining of tumors, and (k-m) tumors of each group in the day 16. Scale bar in g-j i 50 μm

i e e e divided into 4 g oup : ( , g, ) ont ol g oup, (d, h, l) animal t eated

with laser only, (e, i, m) animals treated with intravenous injection of CuPDA NPs, and (f, j) animals treated with intravenous CuPDA NPs. Reprinted with permission from Ge et al. [154]

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Table 1. Most important studies on the application of PDA nanocarriers for tumor photothermal therapy Surface

Additiv

Loade

Nanoparticl

In vitro key

In vivo key

s type

modificatio

e phase

d drug

e size

findings

findings

Ferric

-

≤50 nm

Preparation of

High

[155

PEG‐ Fe‐ PDA

sensitivity for

]

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Nanocarrier

PDA NPs 1

PEG2

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ions

Borate

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PEG

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(Fe3+)

PDA NPs

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n agent

DOX3

200 nm

Ref.

NPs as a MRI

MRI imaging

contrast agent

with

activated by pH

acceptable

with great

photothermal

biocompatibility

effect in

and remarkable

tumor bearing

photothermal

small animal

effect

model

Negligible

Relatively

[156

cytotoxicity

high tumor

]

against MCF-7

suppression

cell without

with low

NIR4 laser

systemic

irradiation and

toxicity,

DOX-loading,

effective

remarkably

targeting

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properties,

MCF-7 cell

and strong

growth over 48

photothermal

h by using DOX

therapy

Ferric

ICG5

146±4.0 nm

Increasing the

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-

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Partial

NIR absorption

inhibition of

of PDA NPs

4T1 tumors

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ions

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PDA NPs

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loaded NPs

upon ICG

growth in the

functionalizatio

groups

n, improving the

treated by

photothermal

PTT using

effect and

PDA

capability of

NPs+laser

photoacoustic

with

contrast agent,

recurrence of

enhanced T1 -

tumor growth

weighted MRI

after 3 days

imaging by

post-

using Fe3+ ions

treatment;

chelated PDA

however,

NPs

complete suppression of 4T1

[62]

ACCEPTED MANUSCRIPT tumors by using PDAFe3+-ICG NPs-laser

PS6 -HA7

-

-

130 nm

High capacity of

Lower rate of

[157

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PDA NPs

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treated group

tumor growth

]

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PDA NPs to

by using

oxygen species

photo

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AN

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generate singlet

for PDT8 ,

activable

acceptable

PDA NP

photothermal

in a mice

conversion

model

effect by using

compare with

fabricated NPs

those animals

HA& TPP 9

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PDA NPs

CE

PT

treated with

BA10 &

β-CD11

PBS injected group PTX12

15 nm

Targeted delivery of PTX into the tumor site by using hybrid HA/TPP conjugated PDA nanocarriers

-

[158 ]

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pH-sensitivity

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confirmed by

emitting intense

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fluorescence wavelengths

RGDC13

DOX

130 nm

PT

ED

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AN

-

CE AC

PDA NPs

High NIR

Synergistic

[159

absorbance of

treatment

]

PDA-

efficiency by

RGDC/DOX

using

NPs, high

PDA-

efficacy for

RGDC/DOX

photoacoustic

under

imaging, high

photoacoustic

photothermal

imaging at

effect, capacity

the precise

to target the

tumor

tumor site and

targeting,

accumulate in

effective

the desired

removal of

region, good

tumors

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nanosphere

n e6

42±2 nm.

Significantly

Significant

higher PDT

therapeutic

effect of PDA-

efficacy of

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PDA

combined

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Chlorin e6

photothermal

compared to

and PDT by

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nanosphere

irradiating

against tumors

dual

indicating

wavelength

higher

(670 nm, and

internalization

808 nm)

into the cells

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and generating

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more reactive oxygen species

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under laser irradiation 670 nm Good stability,

High capacity

[160

nanocapsul

strong NIR

to load DOX

]

e

absorption, and

on the surface

acceptable PTT

of PDA

PDA

-

free Chlorin e6

[57]

-

DOX

200 nm

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nanocapsule and internalize it into the tumor

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cells, High

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efficacy by combining

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photothermal therapy and

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chemotherapy , good ability of

M Polydopamine

5

Indocyanine green, 9

Poly(ethylene

photoacoustic imaging

glycol),

Small-molecule photosensitizers,

Triphenylphosphonium,

10

glycine-aspartic-cysteine acid

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2

PT

6

CE

,

nanoparticles,

ED

1

therapeutic

7

3

Doxorubicin,

Hyaluronic acid,

Boronic acid,11 Diol-lin ed β-cyclodextrin,

4 8

Near

infrared

light,

Photodynamic therapy 12

Paclitaxel,13 Arginine-

ACCEPTED MANUSCRIPT 9. Conclusion and future perspective Photothermal therapy is a common non-invasive method for detecting, monitoring the progression, and treatment of tumors. The main benefit of using PTT is the possibility for concomitant detection and treatment of cancer by using a single material. However, the in vivo

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capability of PTT is only examined in some animal studies and few of them are approved in

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clinical trials. To enhance the clinical application of PTT, it is essential to extend the knowledge

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about the therapeutic effects of PTT nanocarriers. Moreover, it is still challenging to prepare nanocarriers with acceptable biocompatibility, high biodegradability and water swelling, great

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photothermal conversion effect, and high capacity for surface functionalization. At the present

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time, it is hard to find PTT nanocarriers with optimized characteristics, since a large number of parameters are involved. For example, the spectral range of the applied light, type of tumors, and

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tumor location are some important parameters that should be considered for choosing a suitable

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PTT nanocarriers for cancer diagnosis and treatment. PDA coated nanocarriers have been recently considered as good strategies for PTT of cancer and other biological fields. PDA is

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capable to convert the energy to heat and thus it is useful for cancer hyperthermia therapy which

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can be used together with chemotherapy, photothermal, or photodynamic therapies. PDA coating also facilitate the mucosal delivery of hydrophobic drugs at the physiological condition due to

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the inherent zwitterionic property, high hydrophilicity, and isoelectric point at pH 4.5. This phenomena improves their interaction with negatively charged and hydrophobic groups in mucous which consequently restrict their delivery into this environment [161]. Despite the outstanding properties of PDA for PTT, more investigations are needed to figure out the exact mechanism of PDA formation and its chemical structure. In future studies, it is

ACCEPTED MANUSCRIPT essential to discover the effect of post-functionalization on PTT effect and how it could be controlled and optimized. Acknowledgments

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This work was supported by Pasteur Institute of Iran.

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Conflict of interest

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The authors declare no conflict of interest.

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