Poly (photosensitizers) Nanoparticles for Enhanced In Vivo

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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

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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)

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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


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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.



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.


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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



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


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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.



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).


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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



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


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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.



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


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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).



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


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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.



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Poly (photosensitizers) Nanoparticles for Enhanced In Vivo

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