Amphiphilic Near-Infrared Conjugated Polymer for Photothermal and

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Amphiphilic Near-Infrared Conjugated Polymer for Photo-thermal and Chemo- Combination Therapy Jingke Yao, Shusen Kang, Jian Zhang, Jia Du, Zhe Zhang, and Mao Li ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.7b00344 • Publication Date (Web): 06 Sep 2017 Downloaded from http://pubs.acs.org on September 11, 2017

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ACS Biomaterials Science & Engineering

Amphiphilic Near-Infrared Conjugated Polymer for Photothermal and Chemo- Combination Therapy Jingke Yao,†,‡ Shusen Kang,†,‡ Jian Zhang,†,‡ Jia Du,†,‡ Zhe Zhang,*,† Mao Li*,† †

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, Remin Street 5625, Changchun 130022, P. R. China ‡

University of the Chinese Academy of Science, Yuquan Road 19, Beijing 100049, P. R. China

KEYWORDS

amphiphilic

conjugated

polymer;

near-infrared;

combination

therapy;

photothermal therapy

ABSTRACT Amphiphilic conjugated polymer was designed and utilized as nanocarriers without further general encapsulation using PEGylated materials for photothermal therapy (PTT) and chemotherapy. These nanocarriers have maximum absorption in ideal phototherapeutic window between 800 and 850 nm and excellent photothermal conversion efficiency of 76% at 808 nm. It provides the simultaneous therapy of chemotherapy and PTT with the monitoring of photoacoustic imaging. After combined therapy via tail vein injection, complete remission and no recurrence of tumors can be observed over a course of 20 days, indicating these amphiphilic NPs has great potential for NIR photoacoustic imaging-guided photothermal and chemocombined therapy.

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Near-infrared photothermal agents, which can convert corresponding light into thermal energy for photothermal therapy (PPT), have attracted considerable attentions.1-4 Of the inorganic nanomaterials, such as metal nanomaterials,5-8 semiconductor nanoparticles (NPs),9,

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and

carbon-based materials,11-14 conjugated polymers could be the most promising and extensively used in nanomedicine or clinic because of their high photothermal conversion efficiency and excellent biostability.15-18 Generally, amphiphilic PEGylated polymers are popularly utilized to encapsulate conjugated polymers for further PTT application in order to enhance biocompatibility of nanomaterials.19-21 Unfortunately, such strategy can cause a series of problematic issues, such as: (1) encapsulating efficiency of PEGylated polymer is relatively low and limited; (2) Conjugated polymers loaded PEGylated NPs may not have extra enough space for additional functions (c.a. bioimaging and combination therapy); (3) a large amount of PEGylated polymers can lead to lower absorption efficiency and photothermal efficiency of a unit mass of nanomaterials. Herein we report a novel amphiphilic conjugated polymer with pendent PEG units (Figure S1S9). The molecular weight of amphiphilic conjugated polymer is about 31200 (PDI=3.12). The ratio of poly(diketopyrrolopyrrole-thiophene) main chain in amphiphilic conjugated polymer was 32.6%. As shown in Scheme 1, as a model drug, the doxorubicin (DOX) can be directly encapsulated into self-assembled PEGylated poly(diketopyrrolopyrrole-thiophene) (PDPPT) as nanoparticles without the assistant of other PEGylated polymer, ensuring a high content loading of NIR polymer for facilitating the photothermal efficiency of NPs. These nanoparticles as nanocarriers can be utilized in “PTT+ chemotherapy”, which was difficultly reformed by hydrophobic polymers. Thanks to structure-tailoring ability of organic materials, the maximum


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absorption of this NPs solution covers ideal phototherapeutic window between 800 and 850 nm, which enables light to perfectly reach high penetration depth to target tumors.

Scheme 1. DOX-loaded PEGylated PDPPT NPs for photothermal (a) and chemo- combination therapy (b). As shown in Figure 1A, Diameter (Dh) of NPs measured by dynamic light scattering (DLS) at pH 7.4 is 81±14 nm, but around 50 nm from TEM observation (Figure 1B), probably due to dehydration shrinkage of TEM micelles and larger hydrodynamic diameter in DLS measurement. Hydrodynamic diameters and zeta-potentials of NPs in PBS, serum-free and serum-containing media were studied and listed in Table S1. The results show no obvious change of hydrodynamic diameters and zeta-potentials in both serum-free and serum-containing media. The critical micelle concentration of NPs was 2.8 µg mL-1 determined by pyrene as the probe (Figure S10). The Drug loading content and drug loading efficiency of DOX-loaded NPs (DOX-NPs) are 4.75% and 50.5%, respectively. Up to 50% of DOX can be released from NPs in phosphate buffer solution (PBS) at pH 7.4 for 48 h (Figure 1C). No difference observed is found on both irradiation and in PBS at pH 5.5. PBS solution of NPs at pH 7.4 has a broad NIR absorption region from 700 to 1000 nm with maximum absorption coefficient peak of 860 nm, which is ideally covering best phototherapeutic window between 800 and 850 nm (Figure 1D).


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The temperature of NPs solution rises as increasing power density, indicating these NPs can efficiently convert the light to heat (Figure 2A). Upon laser irradiation of 5 min, NPs solution of 0.4 mg mL-1 shows significant temperature change from 26℃ to 46℃ (Figure 2B), while from 26℃ only to 28℃ for pure water. Visible thermal images of NPs under laser irradiation are additionally presented in Figure 2C. Photothermal conversion efficiency of this NPs solution can significantly reach 76% at 808 nm, which is one of the best values according to previous studies (Figure S11, Table S2), indicating great potentials in thermal images and photoacoustic images. The laser power used is a little higher due to the calculation was performed in a small beaker with 5mL NPs solution. Laser irradiation area is relatively less than area of small beaker. Therefore, higher laser intensity was adopted in PTT to get enough temperature. To confirm this viewpoint, Temperature evolution is calculated with 200 µL NPs solution (100 µg mL-1, 0.3 W cm-2) and listed in Figure S11. Upon laser irradiation of 5 min, NPs solution also shows significant temperature change from 26 ℃ to 44 ℃ . Photothermal stability is an important parameter in photothermal therapy. In order to further investigate the photothermal stability of NPs, the samples were irradiated by the 808 nm laser to the equilibrium and then turned off, to allow the system to cool to room temperature, and the ON/OFF cycle was repeated three times. Au nanorods, widely used for phototherapy, were chosen as control. As shown in Figure S12, after five ON/OFF cycles of irradiation at 3 W cm-2 , NPs still maintain a high photothermal effect, while that of Au nanorods loses obviously under the same conditions. It is noted that the NIR absorbing ability of NPs does not change in this process, while that of Au nanorods decrease after five cycles.


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Figure 1 (A) Hydrodynamic Dh distribution of NPs; (B) TEM image of NPs; (C) In vitro DOX release at different conditions; (D) UV-vis absorption spectrum of NPs in aqueous solution.

Figure 2 (A) Temperature evolution of NPs with 0.4 mg mL-1 under 808-nm laser irradiation at various power densities; (B) Temperature evolution of NPs under 808-nm laser irradiation of 3.0 W cm-2 with various concentrations; (C) Thermal images of 0.4 mg mL-1 NPs solution under 808-nm laser irradiation of 3.0 W cm-2 during time lasting.


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HepG2 cells were double-labeled with fluoresceine isothiocyanate (Annexin V-FITC) and propidium iodide (PI) before analysis by flow cytometry to reveal the cell death mechanism of NPs in PTT. The percentage of total apoptotic cells (including early and late apoptosis) treated with NPs plus irradiation dramatically increases to ~29%, which is much more than those in the control group (~1%), demonstrating that NPs with irradiation are efficient for PTT (Figure 3AB).

Figure 3 (A) Apoptosis of HepG2 cells after photothermal treatment. (B) The percentage of apoptotic cells of (A). The data are represented as a mean ± SD (n = 3; *P

Amphiphilic Near-Infrared Conjugated Polymer for Photothermal and

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