Poly(photosensitizer) Nanoparticles for Enhanced in Vivo

May 3, 2019 - Nan Zheng† , Zhiyi Zhang† , Jia Kuang† , Chunsen Wang‡ , Yubin Zheng† , Qing Lu§ , Yugang Bai§ , Yang Li† , Aiguo Wang*‡...
0 downloads 0 Views 1MB Size
Subscriber access provided by UNIV OF LOUISIANA

Biological and Medical Applications of Materials and Interfaces

Poly (photosensitizers) Nanoparticles for Enhanced In Vivo Photodynamic Therapy by Interrupting the #-# Stacking and Extending Circulation Time Nan Zheng, Zhiyi Zhang, Jia Kuang, Chunsen Wang, Yubin Zheng, Qing Lu, Yugang Bai, Yang Li, Aiguo Wang, and Wangze Song ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b04351 • Publication Date (Web): 03 May 2019 Downloaded from http://pubs.acs.org on May 3, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Poly (photosensitizers) Nanoparticles for Enhanced in Vivo Photodynamic Therapy by Interrupting the π-π Stacking and Extending Circulation Time Nan Zheng a, Zhiyi Zhang a, Jia Kuang a, Chunsen Wang b, Yubin Zheng a, Qing Lu c, Yugang Bai c, Yang Li a, Aiguo Wang b, *, Wangze Song a, *

a

State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian

University of Technology Linggong Rd.2, Dalian, Liaoning, 116023 (China) b

Department of Comparative Medicine Laboratory Animal Center, Dalian Medical

University No.9 Lvshun South Road, Dalian, Liaoning 116000 (China) c

Institute of Chemical Biology and Nanomedicine, State Key Laboratory of

Chem/Bio-sensing and Chemometrics, Department of Chemistry, Hunan University Changsha, Hunan, 410000 (China)

Corresponding authors E-mail address: [email protected] (W. Song). [email protected] (A.Wang)

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT: The natural planar and rigid structures of most of the hydrophobic photosensitizers (PSs) (such as tetraphenyl porphyrin (TPP)) significantly reduce their loading efficiencies in polymeric nanoparticles (NPs) due to the strong π-π interactions induced aggregation. The aggregation caused quenching (ACQ) will further reduce the quantum yield of singlet oxygen (1O2) generation and weaken the efficiency of photodynamic therapy (PDT). In addition, the small-molecular PSs exhibit short tumor retention time and tend to be easily cleared once released. Herein, poly (TPP) NPs, prepared by cross-linking of ROS degradable, thioketal linkers and TPP derivatives, followed by co-precipitation were firstly developed with quantitative loading efficiency (> 99%), uniform NP sizes (without aggregation), increased singlet oxygen quantum yield (ΦΔ = 0.79 in DMSO compared with 0.52 for original TPP), increased in vitro phototoxicity, extended tumor retention time, light-triggered on-demand release and enhanced in vivo antitumor efficacy, which comprehensively address the multiple issues for most of the PSs in PDT area. KEYWORDS: photodynamic therapy; π-π interactions; ROS degradable poly (TPP); quantitative TPP loading; improved singlet oxygen quantum yield

ACS Paragon Plus Environment

Page 2 of 41

Page 3 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

1. INTRODUCTION Photodynamic therapy (PDT) is regarded as a promising cancer-therapy modality for clinical use.1-3 Photosensitizer (PS) plays the crucial role in transferring the energy of light to the surrounding oxygen, followed by the generation of reactive oxygen species (ROS) such as the singlet oxygen (1O2) and hydroxyl radicals, thereby induce the cell apoptosis or necrosis by destroying DNA, RNA, lipids and proteins.4-7 Current clinically used PSs are mostly based on the porphyrins and their derivatives, such as Photofrin and Visudyne, which have been approved by the Food and Drug Administration (FDA) and widely utilized for clinical PDT. The tetraphenyl porphyrin (TPP) is the common structure among the PSs, which is an efficient singlet oxygen generator with excellent therapeutic window (red light region) and relatively low dark-toxicity.8-12 However, most of the PSs are small molecules (MW99

7

Poly (TPP)

8:1

141.6

11.2

>99

8

Poly (TPP)

10:1

142.5 9.0 >99 [a] Sizes were evaluated using DLS. [b] LC, the weight ratio of TPP to NPs. [c] LE, the ratio of the TPP in the NPs to the TPP used in formulation.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1. a. Intensity size distributions of TPP and poly (TPP) NPs at the polymer/PS weight ratio of 1:1. b. SEM images of the poly (TPP) NPs at the polymer/poly (TPP) weight ratio of 1:1. Bar = 250 nm. c. Stability of poly (TPP) NPs following dilution with buffer (PBS/FBS = 9/1, v/v) for different folds. d. Stability of poly (TPP) NPs following 10-fold dilution with buffer (PBS/FBS = 9/1, v/v) and further incubation for another 0.5 day, 1 day and 3 day. e. Intensity size distribution of poly (TPP) NPs before lyophilization. f. Intensity size distribution of poly (TPP) NPs after lyophilization.

ACS Paragon Plus Environment

Page 22 of 41

Page 23 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

3.3. Light triggered, ROS mediated TPP release from the NPs Thioketal linkers could be cleaved by ROS overproduced in the tumor tissues or generated by TPP. As the degradation ability of poly (TPP) has been demonstrated by NMR study upon light irradiation, we next investigated the light induced release profile. Poly (TPP) NPs with thioketal linkers exhibited an accumulative release upon light irradiation and 60% of TPP moieties were released in 30 min, while poly (TPP) NPs without light exhibited negligible release (< 5%). TPP NPs and poly (TPP-NTK) also showed limited release (< 5%) with or without light (Figure 2a and 2b). Since TPP, poly (TPP) and the TPP moieties after degradation showed slightly different UV-Vis spectra (Figure S8), (the highest absorbance for TPP was at 412 nm, poly (TPP) was 416 nm while degraded TPP moiety was 415 nm), the standard curve was performed at 415 nm for poly (TPP) group to evaluating the release profile. The long-term release profile of the TPP and poly (TPP) NPs without light were also evaluated. As shown in Figure 2d, the released TPP at the first 12 h was ~20% while was only ~10% for poly (TPP) at 37 oC (pH = 7.4), which to some extent mitigated the “burst release” effect presumably due that the core cross-linked poly (TPP) NPs exhibited improved stability. Considering the high level of ROS in cancer cells, TPP moieties would be selectively released in the tumor sites from the poly (TPP) NPs instead of a severe “burst release” during circulation. The light irradiation at the tumor site would furthermore accelerate the release. Sizes of poly (TPP) NPs remarkably increased to almost micrometers upon light irradiation, while TPP

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

and poly (TPP-NTK) NPs remained stable, which is in consistent with the release profile (Figure 2c and S10).

Figure 2. a. TPP release profile of TPP NPs and poly (TPP) NPs with or without light (n=3). b. TPP release profile of non-degradable poly (TPP-NTK) NPs with or without light (n=3). c. Size change of poly (TPP) NPs upon light irradiation for different time. d. Long term release profile of TPP and poly (TPP) without light.

3.4. Singlet oxygen quantum yields The singlet oxygen quantum yield (ΦΔ) as a crucial parameter for PDT was further evaluated using 1,3-diphenylisobenzofuran (DPBF) as an singlet oxygen generation trap, which showed decreased absorption at the peak of 414 nm when exposed to 1O2. The

ACS Paragon Plus Environment

Page 24 of 41

Page 25 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

decreased rate of the absorbance at 414 nm revealed the capability of singlet oxygen generation and the exact ΦΔ was calculated to be 0.79 for poly (TPP) (standard ΦΔ for TPP in DMSO was 0.52). The ΦΔ of poly (TPP) is about 1.5-fold of the TPP monomer, indicating that the introduction of thioketal linkers effectively improved the singlet oxygen generation ability by stretching out the TPP moieties and reducing the stacking effect between TPP units (Figure 3). Even though the light irradiation would trigger the degradation of poly (TPP), the cleavage of the thioketal linkers was time-dependent and the TPP moieties were released step by step. That means most of the TPP moieties existed as the oligomers during irradiation and the flexible chains always inhibited the aggregation during the degradation. Even after the total degradation, the residues covalently linked to four arms of TPP could also prevent the aggregation and favor the singlet oxygen generation.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3. Absorbance of DPBF (at the wavelength of 414 nm) in the presence of TPP or poly (TPP) upon light irradiation.

3.5. Cell uptake of TPP and poly (TPP) NPs The cellular internalization of TPP and poly (TPP) NPs in HeLa cells at 24 h incubation was evaluated by confocal laser scanning microscopy (CLSM). It has been reported before that the internalization mechanism of free TPP is mainly based on a trans-membrane diffusion mechanism, which is a passive pathway and the intracellular internalization efficiency is relatively low.

45

The NPs exhibited excellent cell uptake

level and different internalization pathway, which was demonstrated by CLSM. Both TPP and poly (TPP) NPs performed obvious red fluorescence representing the signal of TPP moieties and they were internalized in the cells by an endocytic route, as indicated by the punctated intracellular fluorescence. 46 The fluorescence intensity of poly (TPP) NPs was a bit stronger than that of TPP NPs, which was mainly due that poly (TPP) inhibited the ACQ effect (Figure 4).

ACS Paragon Plus Environment

Page 26 of 41

Page 27 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Figure 4. a. Cell uptake level of TPP, poly (TPP), poly (TPP-NTK) and their NPs in HeLa cells following the incubation for 24 h. b. CLSM images of HeLa cells treated with TPP or poly (TPP) NPs for 24 h. Cell nuclear were stained by DAPI. Bar = 20 μm.

3.6. In vitro dark and phototoxicity The cytotoxicity including the in vitro dark and phototoxicity were next evaluated using MTT assay in HeLa cells and H22 cells. No significant dark cytotoxicity observed for TPP, poly (TPP) and their NPs even with the concentration of TPP moiety at 20 μM, indicating that they were relatively safe without light. However, upon light irradiation, TPP, poly (TPP) and their NPs would generate

1O

2

which exhibited improved

cytotoxicity through PDT. Free TPP or poly (TPP) before the formation of the NPs exhibited relatively low phototoxicity, which was mainly due to the limited intracellular internalization efficiency. After the formation of NPs, both TPP and poly (TPP) NPs

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

showed increased phototoxicity with the increase of the concentrations, indicating that the NPs could effectively enter the cells and generate the ROS upon light irradiation to damage the cells. Poly (TPP) NPs had the higher phototoxicity compared with TPP NPs, which was due to the increased amount of cytotoxic substance generated by poly (TPP) and was in consistent with the results of the singlet oxygen quantum yield (Figure 5a and 5b). Similar trends were also observed in H22 cells (Figure S11).

Figure 5. a. In vitro cell viability of TPP or poly (TPP) NPs with/without light irradiation in HeLa cells (n = 3). b. In vitro cell viability of TPP or poly (TPP) with/without light irradiation in HeLa cells (n = 3).

3.7. In vivo biodistribution via intravenous injection of TPP NPs or poly (TPP) NPs The in vivo biodistribution of NPs was then explored. After intravenous administration, both TPP and poly (TPP) NPs exhibited tumor targeting ability by enhanced permeability and retention (EPR) effect. As shown in Figure 6a, red fluorescence of TPP NPs was observed 4 h post injection and the fluorescence became fairly weak at 8 h, and further disappeared after 12 h. That means most of TPP get cleared from the tumor tissues 12 h

ACS Paragon Plus Environment

Page 28 of 41

Page 29 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

post injection. In contrast, mice receiving poly (TPP) NPs at the equivalent doses of TPP loading moieties showed the enhanced tumor retention time up to 24 h and sustained the highest intensity from 4 h to 8 h. The tissue distribution of TPP and poly (TPP) NPs was also investigated by comparing the fluorescence in major organs 8 h post injection. TPP moieties were mainly accumulated in tumor tissues, livers and lungs. It was obvious that the fluorescence in tumor site was much stronger for poly (TPP) NPs than TPP NPs at 8 h, which was in consistent with the results mentioned above (Figure 6b). The stronger fluorescence for poly (TPP) NPs at 8 h indicated that they tend to stay at the tumor site for a longer time. The elongated tumor tissues retention of poly (TPP) NPs would also lead to a slow renal clearance rate. The results clearly demonstrated the advantage of poly (TPP) in elongating the circulation time.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 6. a. Fluorescence images of mice bearing H22 tumors after the intravenous administration of TPP NPs or poly (TPP) NPs. b. Fluorescence images of tumors and major organs harvested from TPP NPs or poly (TPP) NPs treated mice at 8 h post administration.

3.8. In vivo anti-tumor efficacy via intravenous injection of TPP NPs or poly (TPP) NPs

ACS Paragon Plus Environment

Page 30 of 41

Page 31 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Subsequently, the in vivo antitumor efficacy of NPs was explored. As indicated by the distribution results, poly (TPP) NPs could efficiently accumulate in tumor site at 8 h post injection. Light irradiation was set at 4 h and 8 h after every injection. As indicated in Figure 7a and Figure S12, PBS groups and the NPs without light irradiation exhibited no therapeutic efficacy. TPP NPs with 650 nm light irradiation significantly inhibit the growth of tumors and the size of the tumor was almost 1/10 of that in PBS group after ten days. Comparatively, poly (TPP) NPs showed the best therapeutic efficacy and the notable depression of the tumor progression. The final volume of poly (TPP) NPs group were almost 1/5 of the original volume and 1/50 of the volume in PBS group. The body weight changes slightly for all of the mice after treatment (Figure 7b). Standard H&E staining of tumors and major organs were performed. As expected, TPP and poly (TPP) NPs with light irradiation exhibited damaged tumor cells in the images, indicating the desired antitumor efficacy of PDT (Figure 7c). No significant and obvious abnormalities were observed in heart, liver, spleen, lung, kidney and muscle in the mice post treatment, indicating the safety of the NPs (Figure S13).

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 7. a. Tumor volume of the mice after different treatments: PBS, TPP NPs with or without light irradiation and poly (TPP) NPs with or without light irradiation (n = 4). The arrows indicated the injection time. b. Body weight of the mice after different treatments: PBS, TPP NPs with or without light irradiation and poly (TPP) NPs with or without light irradiation (n = 4). c. H&E-stained tumors post treatment. Bar = 50 μm.

4. CONCLUSIONS

ACS Paragon Plus Environment

Page 32 of 41

Page 33 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

In summary, ROS degradable poly (TPP) was prepared to form the NPs with quantitative loading efficiency, elongated tumor retention time, improved singlet oxygen quantum yield and antitumor efficacy. By introducing a ROS degradable and flexible linker, TPP units were stretched out and the long-range-ordered aggregation was inhibited. Quantitative TPP loading without undesired aggregation was achieved by interrupting the π-π stacking. Polymerized TPP NPs also improved the tumor retention time by increasing the MW to avoid the leakage from the tumor. The design of poly (TPP) also improved the singlet oxygen generation ability by avoiding the ACQ effect existing in most of PSs. Therefore, poly (TPP) NPs showed efficient drug release upon red light irradiation and excellent in vivo antitumor activity, providing a comprehensive “one stone, three birds” strategy for the cancer-therapy by PDT SUPPORTING INFORMATION 1H-NMR

spectrum, UV-VIS spectrum and other supported results and images

ACKNOWLEDGEMENTS This work was supported by grants from the National Natural Science Foundation of China (51703018, 21702025). Natural Science Foundation of Liaoning Province (20180510058, 20180550576), the Fundamental Research Funds for the Central Universities (DUT18LK25, DUT19LK60) REFERENCES [1] Dolmans, D.; Fukumura, D.; Jain, R. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[2] He, H.; Zhu, R.; Sun, W.; Cai, K.; Chen, Y.; Yin, L. Selective cancer treatment via photodynamic sensitization of hypoxia-responsive drug delivery. Nanoscale 2018, 10, 2856–2865. [3] Castano, A.; Mroz, P.; Hamblin, M. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 2006, 6, 535-545. [4] Lovell, J.; Liu, T.; Chen, J.; Zheng, G. Activatable photosensitizers for imaging and therapy. Chem. Rev. 2010, 110, 2839-2857. [5] Wu, W.; Mao, D.; Hu, F.; Xu, S.; Chen, C.; Zhang, C.; Cheng, X.; Yuan, Y.; Ding, D.; Kong, D.; Liu, B. A highly efficient and photostable photosensitizer with near-infrared aggregation-induced emission for image-guided photodynamic anticancer therapy. Adv. Mater. 2017, 29, 1700548. [6] Higgins, S.; Brewer, K. Designing red-light-activated multifunctional agents for the photodynamic therapy. Angew. Chem. Int. Ed. 2012, 51, 11420-11422. [7] Fan, Y.; Zhou, T.; Cui, P.; He, Y.; Chang, X.; Xing, L.; Jiang, H. Modulation of intracellular oxygen pressure by dual-drug nanoparticles to enhance photodynamic therapy. Adv. Funct. Mater. 2019, doi.org/10.1002/adfm.201806708. [8] Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 2011, 40, 340-362. [9] Schmitt, J.; Heitz, V.; Sour, A.; Bolze, F.; Ftouni, H.; Nicoud, J.; Flamigni, L.; Ventura, B. Diketopyrrolopyrrole-porphyrin conjugates with high two-photon absorption

ACS Paragon Plus Environment

Page 34 of 41

Page 35 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

and singlet oxygen generation for two-photon photodynamic therapy. Angew. Chem. Int. Ed. 2015, 54, 169-173. [10] Celli, J.; Spring, B.; Rizvi, I.; Evans, C.; Samkoe, K.; Verma, S.; Pogue, B.; Hasan, T. Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem. Rev. 2010, 110, 2795-2838. [11] Huang, Z. A review of progress in clinical photodynamic therapy. Technol. Cancer Res. Treat. 2005, 4, 283-293. [12] Wang, D.; Niu, L.; Qiao, Z.; Cheng, D.; Wang, J.; Zhong, Y.; Bai, F.; Wang, H.; Fan, H. Synthesis of self-assembled porphyrin nanoparticle photosensitizers. ACS Nano, 2018, 12, 3796-3803. [13] Lucky, S.; Soo, K.; Zhang, Y. Nanoparticles in photodynamic therapy. Chem. Rev. 2015, 115, 1990-2042. [14] Fan, H.; Yan, G.; Zhao, Z.; Hu, X.; Zhang, W.; Liu, H.; Fu, X.; Fu, T.; Zhang, X.; Tan, W. A smart photosensitizer-manganese dioxide nanosystem for enhanced photodynamic therapy by reducing glutathione levels in cancer cells. Angew. Chem. Int. Ed. 2016, 55, 5477-5482. [15] Liu, K.; Xing, R.; Zou, Q.; Ma, G.; Möhwald, H.; Yan, X. Simple peptide-tuned self-assembly of photosensitizers towards anticancer photodynamic therapy. Angew. Chem. Int. Ed. 2016, 55, 3036-3039.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 41

[16] Cui, L.; Lin, Q.; Jin, C.; Jiang, W.; Huang, H.; Ding, L.; Muhanna, N.; Irish, J.; Wang, F.; Chen, J.; Zheng, G. A PEGylation-free biomimetic porphyrin nanoplatform for personalized cancer theranostics. ACS Nano, 2015, 9, 4484-4495. [17] Voskuhl, J.; Kauscher, U.; Gruener, M.; Frisch, H.; Wibbeling, B.; Strassert, C.; Ravoo, B. A soft supramolecular carrier with enhanced singlet oxygen photosensitizing properties. Soft Matter 2013, 9, 2453-2457. [18] Li, F.; Du, Y.; Liu, J.; Sun, H.; Wang, J.; Li, R.; Kim, D.; Hyeon, T.; Ling, D. Responsive

assembly

of

upconversion

nanoparticles

for

pH-activated

and

near-infrared-triggered photodynamic therapy of deep tumors. Adv. Mater. 2018, 30, 1802808. [19] Liu, L.; Qiu, W.; Zhang, Y.; Li, B.; Zhang, C.; Gao, F.; Zhang, Lu.; Zhang, X. A red light activatable multifunctional prodrug for image-guided photodynamic therapy and cascaded chemotherapy. Adv. Funct. Mater. 2017, 27, 1700220. [20] Zhang, Y.; Huang, F.; Ren, C.; Yang, L.; Liu, J.; Cheng, Z.; Chu, L.; Liu, J. Targeted chemo-photodynamic combination platform based on the DOX prodrug nanoparticles for enhanced cancer therapy. ACS Appl. Mater. Interfaces 2017, 9, 13016-13028. [21] Wicki, A.; Witzigmann, D.; Balasubramanian, V.; Huwyler, J. Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J. Control Release 2015, 200, 138-157.

ACS Paragon Plus Environment

Page 37 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

[22] Talelli, M.’ Barz, M.’ Rijcken, C.; Kiessling, F.; Hennink, W. E.; Lammers, T. Core-crosslinked polymeric micelles: Principles, preparation, biomedical applications and clinical translation. Nano today, 2015, 10, 93-117. [23] Dai, Y.; Xu, C.; Sun, X.; Chen, X. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem. Soc. Rev. 2017, 46, 3830-3852. [24] Tao, D.; Feng, L.; Chao, Y.; Liang, C.; Song, X.; Wang, H.; Yang, K.; Liu, Z. Covalent organic polymers based on fluorinated porphyrin as oxygen nanoshuttles for tumor hypoxia relief and enhanced photodynamic therapy. Adv. Funct. Mater. 2018, 28, 1804901. [25] Cai, K.; He, X.; Song, Z.; Yin, Q.; Zhang, Y.; Uckun, F.; Jiang, C.; Cheng, J. Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficienc. J. Am. Chem. Soc. 2015, 137, 3458-3461. [26] Lv, S.; Wu, Y.; Cai, K.; He, H.; Li, Y.; Lan, M.; Chen, X.; Cheng, J.; Yin, L. High drug loading and sub-quantitative loading efficiency of polymeric micelles driven by donor-receptor coordination interactions. J. Am. Chem. Soc. 2018, 140, 1235-1238. [27] Yin, Q.; Yap, F.; Yin, L.; Ma, L.; Zhou, Q.; Dobrucki, L.; Fan, T.; Gaba, R.; Cheng, J. Poly(iohexol) nanoparticles as contrast agents for in vivo X‑ray computed tomography imaging. J. Am. Chem. Soc. 2013, 135, 13620-13621. [28] Bae, K. Intravenous contrast medium administration and scan timing at CT: considerations and approaches. Radiology 2010, 256, 32−61.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[29] Murakami, Y.; Tabata, Y.; Ikada, Y. Tumor accumulation of poly(ethylene glycol) with different molecular weights after intravenous injection. Drug Delivery, 1997, 4, 23-31. [30] Ji, C.; Gao, Q.; Dong, X.; Yin, W.; Gu, Z.; Gan, Z.; Zhao, Y.; Yin, M. A Size-reducible nanodrug with an aggregation-enhanced photodynamic effect for deep chem-photodynamic therapy. Angew. Chem. Int. Ed. 2018, 57, 11384-11388. [31] Liu, K.; Liu, Y.; Yao, Y.; Yuan, H.; Wang, S.; Wang, Z.; Zhang, X. Supramolecular photosensitizers with enhanced antibacterial efficiency. Angew. Chem. Int. Ed. 2013, 125, 8285-8289. [32] Jin, J.; Zhu, Y.; Zhang, Z.; Zhang, W. Enhancing the efficacy of photodynamic therapy through a porphyrin/POSS alternating copolymer. Angew. Chem. Int. Ed. 2018, 57,16354-16358. [33] Ideta, R.; Tasaka, F.; Jang, W. D.; Nishiyama, N.; Zhang, G.; Harada, A.; Yanagi, Y.; Tamaki, Y.; Aida, T.; Kataoka, K. Nanotechnology-based photodynamic therapy for neovascular disease using a supramolecular nanocarrier loaded with a dendritic photosensitizer. Nano Lett. 2005, 5, 2426-2431. [34] Song, H.; Reed, C.; Scheidt, W. Metalloporphyrin. pi-cation radicals: intrinsically ruffled or planar core conformations? Molecular structure mesitylporphinatocopper(II) hexachloroantimonate. J. Am. Chem. Soc. 1989, 111, 6865-6866. [35] Helmich, F.; Lee, C.; Nieuwenhuizen, M.; Gielen, J.; Christianen, P.; Larsen, A.; Fytas, G.; Leclere, P.; Schenning, A.; Meijer, E. Dilution-induced self-assembly of

ACS Paragon Plus Environment

Page 38 of 41

Page 39 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

porphyrin aggregates: a consequence of coupled equilibria. Angew. Chem. Int. Ed. 2010, 49, 3939-3942. [36] Rochford, J.; Chu, D.; Hagfeldt, A.; Galoppini, E. Tetrachelate porphyrin chromophores for metal oxide semiconductor sensitization:  effect of the spacer length and anchoring group position. J. Am. Chem. Soc. 2007, 129, 4655-4665. [37] Xu, D.; You, Y.; Zeng, F.; Wang, Y.; Liang, C.; Feng, H.; Ma, X. Disassembly of hydrophobic photosensitizer by biodegradable zeolitic imidazolate framework-8 for photodynamic cancer therapy. ACS Appl. Mater. Interfaces, 2018, 10, 15517-15523. [38] Liu, L.; Qiu, W.; Li, B.; Zhang, C.; Sun, L.; Wan, S.; Rong, L.; Zhang, X. A red light activatable multifunctional prodrug for image-guided photodynamic therapy and cascaded chemotherapy. Adv. Funct. Mater. 2016, 26, 6257-6269. [39] Wang, J.; He, H.; Xu, X.; Wang, X.; Chen, Y.; Yin, L. Far-red light-mediated programmable anti-cancer gene delivery in cooperation with photodynamic therapy. Biomaterials 2018, 171, 72-82. [40] Shim, M.; Xia, Y. A reactive oxygen species (ROS)-responsive polymer for safe, efficient, and targeted gene delivery in cancer cell. Angew. Chem. Int. Ed. 2013, 52, 6926-6929. [41] He, H.; Chen, Y.; Li, Y.; Song, Z.; Zhong, Y.; Zhu, R.; Cheng, J.; Yin, L. Effective and selective anti-Cancer protein delivery via all-function-in-one nanocarriers coupled with visible light-responsive, reversible protein engineering. Adv Funct Mater, 2018, 28, 1706710.

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[42] Guo, B.; Cai, X.; Xu, S.; Fateminia, S.; Liu, J.; Liang, J.; Feng, G.; Wu, W.; Liu, B. Decoration of porphyrin with tetraphenylethene: converting a fluorophore with aggregation-caused quenching to aggregation-induced emission enhancement. J. Mater. Chem. B, 2016, 4, 4690-4695. [43]Tong. R.; Yala, L.; Fan, T.; Cheng, J. The formulation of aptamer-coated paclitaxel-polylactide nanoconjugates and their targeting to cancer cells. Biomaterials 2010, 31, 3043-3053. [44]Ozdemir, T.; Bila, J.; Sozmen, F.; Yildirim, L.; Akkaya, E. Orthogonal bodipy trimers as photosensitizers for photodynamic action. Org.Lett. 2016, 18, 4821-4823. [45] Liu, F.; Ma, Y.; Xu, L.; Liu, L.; Zhang, W. Redox-responsive supramolecular amphiphiles constructed via host–guest interactions for photodynamic therapy. Biomater. Sci. 2015, 3, 1218-1227. [46] Ter-Avetisyan, G.; Tuennemann, G.; Nowak, D.; Nitschke, M.; Herrmann, A.; Drab, M.; Cardoso, M. C. J Biol Chem 2009, 284, 3370-3378.

ACS Paragon Plus Environment

Page 40 of 41

Page 41 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Table of contents (TOC) graphic

ACS Paragon Plus Environment