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Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 5, Iss. 5 — May. 1, 2014
  • pp: 1355–1362
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Photo-induced processes in collagen-hypericin system revealed by fluorescence spectroscopy and multiphoton microscopy

V. Hovhannisyan, H. W. Guo, A. Hovhannisyan, V. Ghukasyan, T. Buryakina, Y. F. Chen, and C. Y. Dong  »View Author Affiliations


Biomedical Optics Express, Vol. 5, Issue 5, pp. 1355-1362 (2014)
http://dx.doi.org/10.1364/BOE.5.001355


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Abstract

Collagen is the main structural protein and the key determinant of mechanical and functional properties of tissues and organs. Proper balance between synthesis and degradation of collagen molecules is critical for maintaining normal physiological functions. In addition, collagen influences tumor development and drug delivery, which makes it a potential cancer therapy target. Using second harmonic generation, two-photon excited fluorescence microscopy, and spectrofluorimetry, we show that the natural pigment hypericin induces photosensitized destruction of collagen-based tissues. We demonstrate that hypericin–mediated processes in collagen fibers are irreversible and may be used for the treatment of cancer and collagen-related disorders.

© 2014 Optical Society of America

1. Introduction

Hypericin (Hyp) is a natural pigment synthesized by plants of the Hypericum genus, insects, fungi, and protozoa. Hyp has recently received increasing attention due to its high phototoxicity against viruses [1

1. S. Carpenter and G. A. Kraus, “Photosensitization is required for inactivation of equine infectious anemia virus by hypericin,” Photochem. Photobiol. 53(2), 169–174 (1991). [CrossRef] [PubMed]

3

3. N. D. Weber, B. K. Murray, J. A. North, and S. G. Wood, “The antiviral agent hypericin has in vitro activity against HSV-1 through non-specific association with viral and cellular membranes,” AntiViral Chem. Chemother. 5(2), 83–90 (1994).

] and anti-tumor photoactivity, which was explained by a combination of different mechanisms, such as singlet oxygen production, superoxide anion formation [4

4. H. Koren, G. M. Schenk, R. H. Jindra, G. Alth, R. Ebermann, A. Kubin, G. Koderhold, and M. Kreitner, “Hypericin in phototherapy,” J. Photochem. Photobiol. B 36(2), 113–119 (1996). [CrossRef] [PubMed]

6

6. J. M. Fernandez, M. D. Bilgin, and L. I. Grossweiner, “Singlet oxygen generation by photodynamic agents,” J. Photochem. Photobiol. B 37(1–2), 131–140 (1997). [CrossRef]

], and energy/charge transfer from excited states [7

7. D. S. English, K. Das, K. D. Ashby, J. Park, J. W. Petrich, and E. W. Castner, “Confirmation of excited-state proton transfer and ground-state heterogeneity in hypericin by fluorescence upconversion,” J. Am. Chem. Soc. 119(48), 11585–11590 (1997). [CrossRef]

,8

8. T. A. Wells, A. Losi, R. Dai, P. Scott, S. M. Park, J. Golbeck, and P. S. Song, “Electron transfer quenching and photoinduced EPR of hypericin and the ciliate photoreceptor stentorian,” J. Phys. Chem. A 101(4), 366–372 (1997). [CrossRef]

]. Photophysical and photochemical properties of Hyp (absorption peak around 590 nm, fluorescence peak ~600 nm [2

2. D. Meruelo, G. Lavie, and D. Lavie, “Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin,” Proc. Natl. Acad. Sci. U.S.A. 85(14), 5230–5234 (1988). [CrossRef] [PubMed]

]) make this pigment a potent photosensitizer and fluorescent marker for photodynamic therapy (PDT) and clinical tumor diagnosis, respectively. The PDT effect of Hyp has been demonstrated both in vitro and in vivo [9

9. G. Seitz, R. Krause, J. Fuchs, H. Heitmann, S. Armeanu, P. Ruck, and S. W. Warmann, “In vitro photodynamic therapy in pediatric epithelial liver tumors promoted by hypericin,” Oncol. Rep. 20(5), 1277–1282 (2008). [PubMed]

,10

10. W. T. Couldwell, A. A. Surnock, A. J. Tobia, B. E. Cabana, C. B. Stillerman, P. A. Forsyth, A. J. Appley, A. M. Spence, D. R. Hinton, and T. C. Chen, “A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas,” Cancer 117(21), 4905–4915 (2011). [CrossRef] [PubMed]

]. Furthermore, Hyp exhibited a stronger affinity to collagen than chlorine e6, a commercial photodynamic agent [11

11. D. Yova, V. Hovhannisyan, and T. Theodossiou, “Photochemical effects and hypericin photosensitized processes in collagen,” J. Biomed. Opt. 6(1), 52–57 (2001). [CrossRef] [PubMed]

], and might be an effective photosensitizer in collagen-rich tissues, such as cornea or skin.

Collagen is the major structural component of the extracellular matrix in tissues such as skin, tendon, cartilage, cornea, sclera, and bone. Proper balance between synthesis and degradation of collagen molecules is critical for maintaining normal physiological functions. Recently, it was demonstrated that collagen is involved in different stages of tumorigenesis including vascularization [12

12. A. L. Maas, S. L. Carter, E. P. Wileyto, J. Miller, M. Yuan, G. Yu, A. C. Durham, and T. M. Busch, “Tumor vascular microenvironment determines responsiveness to photodynamic therapy,” Cancer Res. 72(8), 2079–2088 (2012). [CrossRef] [PubMed]

] and metastases formation [13

13. Y. Shintani, M. Maeda, N. Chaika, K. R. Johnson, and M. J. Wheelock, “Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-β signaling,” Am. J. Respir. Cell Mol. Biol. 38(1), 95–104 (2008). [CrossRef] [PubMed]

]. These results identify collagen as a potential target for cancer treatment. Specifically, damage and alteration of collagen in blood vessels can change the delivery of a photosensitizer and molecular oxygen to tumor tissue, therefore affecting the outcome of PDT procedures. Furthermore, alterating tissue’s collagen content can affect the penetration depth of the photosensitizer and excitation light thereby affecting the effectiveness of PDT in treating superficial malignant tumors such as skin and oral cancer. Thus, the ability to modulate and visualize collagen organization can be important to optimize the treatment strategy of PDT and therapy in collagen-containing tissues.

The goal of this study was to investigate photo-induced interaction of Hyp with collagen using fluorescence spectroscopy and multiphoton microscopy. The change of fluorescence spectra and signal intensity in Hyp-collagen system was measured under UV and visible light illumination, which can provide information on the destruction and alteration of Hyp-sensitized collagen. For spatially-resolved investigation of Hyp-collagen interaction, two-photon excited fluorescence (TPEF) and SHG images of purified and native collagen tissues were further acquired by multiphoton microscopy.

2. Materials and methods

2.1. Spectrofluorimetry

The experimental setup shown in Fig. 1
Fig. 1 Experimental setup for spectrofluorimetric measurement of laser-induced photoprocesses.
was used to detect fluorescence from the treated collagen samples. Illumination and excitation of the samples were performed with a Q-switched pulsed Nd:YAG laser (Quanta-Ray GRC-16, 1064 nm, 100 mJ/pulse and 532 nm, 20 mJ/pulse, 8-10 ns pulse duration, 10 Hz repetition rate) and a pulsed N2 laser (LSI VSL-337 NDS, 337 nm, 4 ns pulse duration, 1-20 Hz repetition rate, 0.3 mJ/pulse). Fluorescence of the samples with and without Hyp sensitization was probed under excitation with the N2 laser at 337 nm. Illumination for Hyp-induced phototoxicity was carried out at 337 nm (N2 laser) and 532 nm (second harmonic of the Nd:YAG laser) or unfiltered light of a halogen lamp (2 W). Elliptically shaped laser beam spot of about 2 mm by 3.5 mm was focused on the collagen samples of approximately 3 × 6 mm2. All samples were placed between two thin quartz slides with non-detectable fluorescence at 330- 400 nm excitation. The scattered light from the samples was collected with a 3.5-cm focal length lens 4 cm in diameter. Spectra of collagen samples were recorded through the use of a grating spectrometer coupled to a CCD array at the spectral resolution of less than 4 nm.

2.2 TPEF and SHG imaging

TPEF and SHG imaging were performed with the LSM 510 META microscope (Carl Zeiss, Jena, Germany) coupled to a femtosecond titanium-sapphire (Ti:sapphire) Tsunami laser operating at 780 nm (Spectra-Physics, Mountain View, CA). The average power of the laser beam on the sample surface was between 5 - 30 mW. Detection bandwidths of SHG and TPEF signals were 380-400 nm and 435-700 nm, respectively. Effects of Hyp-mediated modification were observed using Plan-Neofluar 20 × /NA 0.5 with the working distance of 1.3 mm, and Plan-Neofluar 10 × /NA 0.3 with the working distance of 3.6 mm (Carl Zeiss, Germany).

2.3 Samples and hypericin preparation

Type I collagen from bovine Achilles tendon (BAT) and gelatin (Fluka Biochemica 27662 and 48724, respectively), as well as from chicken tendon, was used in this study. We performed experiments on normal and denatured collagen in dry form and in aqueous environment. Denatured collagen samples were obtained by heating the BAT sample in water at about 65°C for roughly 3 min. Collagen and gelatin samples were treated in phosphate buffer saline (PBS) and 2 to 80 μM solution of Hyp in 75% EtOH of PBS solution.

Hypericin was derived from Hypericum Perforatum according to the standard gel column chromatography procedure [2

2. D. Meruelo, G. Lavie, and D. Lavie, “Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin,” Proc. Natl. Acad. Sci. U.S.A. 85(14), 5230–5234 (1988). [CrossRef] [PubMed]

] and used as a sensitizer in the 75% EtOH in PBS solution.

3. Results

3.1 Spectrofluorimetric analysis of the hypericin interaction with collagen

The same samples were then sensitized with the application of Hyp solution in 75% EtOH-PBS (at various concentrations) and incubated for 2.5 h in dark environment. New fluorescence peaks at around 600 nm and 650 nm were found in the spectra of Hyp-sensitized samples (Fig. 2), which is in good agreement to the fluorescence spectrum of Hyp in biological tissues [28

28. B. S. P. Miskovsky, “Hypericin--a new antiviral and antitumor photosensitizer: mechanism of action and interaction with biological macromolecules,” Curr. Drug Targets 3(1), 55–84 (2002). [CrossRef] [PubMed]

]. Furthermore, there was no significant change in the spectral profile of collagen, except for the minor shift of the maximum from 390 nm to 397 nm and the intensity quenching by 18% indicating the possibility of dark reactivity of Hyp (Fig. 2(a)). Illumination of the sensitized collagen samples with UV or visible light caused a change of the fluorescence spectrum. The photo-induced effect correlated with the illumination dose, and the signal intensity of collagen fluorescence decreased at about 15 min after illumination. In Fig. 2(a), one can see the effect of the 15 min-long UV (337 nm) and green (532 nm) laser illumination of the collagen fibers sensitized by 2 μM and 8 μM Hyp concentrations. Specifically, UV illumination of 8 μM Hyp-sensitized collagen resulted in the broadening of collagen fluorescence spectral profile, red-shift of the maximum wavelength to 435 nm, and approximately 50% decrease in fluorescence peak intensity. The extent of these effects increased with higher concentrations of Hyp (Fig. 2(a)). For comparison, the fluorescence spectrum of denatured collagen is also shown in Fig. 2(a) (dotted line). It can be seen that fluorescence maximum of denatured collagen (426 nm) is localized close to that of 8 μM Hyp-sensitized and UV illuminated collagen (435 nm), and spectral profile of the fluorescence of heated collagen is very close to that of Hyp-sensitized and laser-irradiated collagen. In contrast to collagen, only a slight change in the fluorescence spectrum of sensitized and illuminated gelatin was observed (Fig. 2(b)).

Fluorescence spectra of native collagen tissues contains two peaks. In addition to the 390 nm-peak observed for BAT, a second peak positioned near 450 nm can be seen on the spectra plots (Fig. 3
Fig. 3 Fluorescence spectra of chicken tendon, before and after 8μM Hyp sensitization and UV (337 nm) illumination. The sample was illuminated at the intensity of 15 mW/cm2 for 30 minutes. Excitation was carried out at 337 nm at the intensity of 0.5 mW/cm2.
). In the case of chicken leg tendon (CLT), long-wavelength maximum was comparably weak, and the effect of Hyp photosensitization was similar to that of pure BAT (i.e. quenching of the fluorescence intensity and long-wavelength shift of the 390 nm maximum by 10 nm). A minor increase in intensity was observed in the fluorescence region of the 450 nm-maximum, which can be associated with the red-shift of the first peak.

3.2. Multiphoton imaging of collagen-hypericin system

Illumination of the Hyp-sensitized native collagen-based CLT for a longer, 55 min period resulted not only in the reduced SHG and increased TPEF intensity, but also in morphological change in collagen structure (Fig. 5). Treatment with PBS or 75% EtOH-PBS solutions did not affect CLT morphology and SHG intensity.

The dynamics of the photosensitized destruction of the CLT under irradiation with the halogen lamp is shown in Fig. 5(e).

In order to investigate the possible recovery of collagen structure in the absence of Hyp, we continued multiphoton imaging after elution of Hyp + EtOH(75%)–PBS solution and application of pure EtOH/PBS to the sample solvent (time point 55 min in Fig. 5(e)). We found that that SHG and TPEF intensities did not change substantially for 30 min after Hyp elution. As the SHG imaging is sensitive to structural changes of collagen, it may be concluded that Hyp-mediated modification of collagen is irreversible.

4. Discussion

In this study, we presented the photosensitizing effect of Hyp on collagen via monitoring of photo-induced destruction of collagen fibers with spectrofluorimetric measurements and multiphoton imaging. Spectrofluorimetric measurements revealed that UV and visible light can induce irreversible changes in Hyp-sensitized purified collagen from BAT. Dose-dependent decay and shift of the spectral maximum from 390 nm to 435 nm in collagen fluorescence indicated a photo-induced damage in the Hyp-collagen system. Furthermore, we demonstrated that the spectral profile of Hyp-photosensitized collagen was similar to that of gelatin and denatured collagen (Fig. 2), indicative of structural modifications in collagen. Furthermore, 523 nm-illumination of pure collagen had no influence on the fluorescence spectral profile. No significant difference between the fluorescence spectra of pure and sensitized gelatin was found at the Hyp concentration of 40 μM. A comparison of the spectra of pure and Hyp-sensitized gelatin specimens allow us to exclude the reabsorption of sample fluorescence by Hyp as a possible explanation for the change of the collagen spectral profile after photosensitization. Spectral alteration of Hyp-photosensitized collagen is believed to take place due to the strong interaction between the light-activated Hyp and collagen.

Figures 2-3 clearly show that the UV- and 532 nm-irradiation of Hyp sensitized BAT and CLT decreased fluorescence intensity in the spectral range of 350-425 nm. However, increase in fluorescence intensity was observed for the collagen tissues in the spectral range of 450-670 nm. Increase in long-wavelength (435-700 nm) fluorescence intensity was also observed in TPEF microscopy of BAT and CLT (Figs. 4-5). These results can be interpreted as photodestruction of collagen fluorophores and formation of new ones. Note that the fluorescence increase was observed only within collagen fibers (Fig. 4), suggesting that the fluorescence increase in 450-670 nm range (including Hyp fluorescence band 590-670 nm) (see Fig. 2(a)) can be explained by collagen photo-products formed upon light illumination. The increase in TPEF intensity in the photo-modified collagen was previously observed from femtosecond laser illumination, and attributed to the formation of autofluorescent molecules (most likely, tyrosine dimers) [18

18. V. Hovhannisyan, W. Lo, C. Hu, S. J. Chen, and C. Y. Dong, “Dynamics of femtosecond laser photo-modification of collagen fibers,” Opt. Express 16(11), 7958–7968 (2008). [CrossRef] [PubMed]

,19

19. E. J. Gualda, J. R. Vázquez de Aldana, M. C. Martínez-García, P. Moreno, J. Hernández-Toro, L. Roso, P. Artal, and J. M. Bueno, “Femtosecond infrared intrastromal ablation and backscattering-mode adaptive-optics multiphoton microscopy in chicken corneas,” Biomed. Opt. Express 2(11), 2950–2960 (2011). [CrossRef] [PubMed]

].

Acknowledgments

This study was financially supported by the National Science Council, Taiwan (NSC 101-2112-M-002-003-MY3), National Taiwan University (NTU-102R7804), Center for Quantum Science and Engineering (CQSE-102R891401), National Health Research Institutes (NHRI-EX101-10041EI).

References and links

1.

S. Carpenter and G. A. Kraus, “Photosensitization is required for inactivation of equine infectious anemia virus by hypericin,” Photochem. Photobiol. 53(2), 169–174 (1991). [CrossRef] [PubMed]

2.

D. Meruelo, G. Lavie, and D. Lavie, “Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin,” Proc. Natl. Acad. Sci. U.S.A. 85(14), 5230–5234 (1988). [CrossRef] [PubMed]

3.

N. D. Weber, B. K. Murray, J. A. North, and S. G. Wood, “The antiviral agent hypericin has in vitro activity against HSV-1 through non-specific association with viral and cellular membranes,” AntiViral Chem. Chemother. 5(2), 83–90 (1994).

4.

H. Koren, G. M. Schenk, R. H. Jindra, G. Alth, R. Ebermann, A. Kubin, G. Koderhold, and M. Kreitner, “Hypericin in phototherapy,” J. Photochem. Photobiol. B 36(2), 113–119 (1996). [CrossRef] [PubMed]

5.

L. M. Davids, B. Kleemann, D. Kacerovská, K. Pizinger, and S. H. Kidson, “Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells,” J. Photochem. Photobiol. B 91(2-3), 67–76 (2008). [CrossRef] [PubMed]

6.

J. M. Fernandez, M. D. Bilgin, and L. I. Grossweiner, “Singlet oxygen generation by photodynamic agents,” J. Photochem. Photobiol. B 37(1–2), 131–140 (1997). [CrossRef]

7.

D. S. English, K. Das, K. D. Ashby, J. Park, J. W. Petrich, and E. W. Castner, “Confirmation of excited-state proton transfer and ground-state heterogeneity in hypericin by fluorescence upconversion,” J. Am. Chem. Soc. 119(48), 11585–11590 (1997). [CrossRef]

8.

T. A. Wells, A. Losi, R. Dai, P. Scott, S. M. Park, J. Golbeck, and P. S. Song, “Electron transfer quenching and photoinduced EPR of hypericin and the ciliate photoreceptor stentorian,” J. Phys. Chem. A 101(4), 366–372 (1997). [CrossRef]

9.

G. Seitz, R. Krause, J. Fuchs, H. Heitmann, S. Armeanu, P. Ruck, and S. W. Warmann, “In vitro photodynamic therapy in pediatric epithelial liver tumors promoted by hypericin,” Oncol. Rep. 20(5), 1277–1282 (2008). [PubMed]

10.

W. T. Couldwell, A. A. Surnock, A. J. Tobia, B. E. Cabana, C. B. Stillerman, P. A. Forsyth, A. J. Appley, A. M. Spence, D. R. Hinton, and T. C. Chen, “A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas,” Cancer 117(21), 4905–4915 (2011). [CrossRef] [PubMed]

11.

D. Yova, V. Hovhannisyan, and T. Theodossiou, “Photochemical effects and hypericin photosensitized processes in collagen,” J. Biomed. Opt. 6(1), 52–57 (2001). [CrossRef] [PubMed]

12.

A. L. Maas, S. L. Carter, E. P. Wileyto, J. Miller, M. Yuan, G. Yu, A. C. Durham, and T. M. Busch, “Tumor vascular microenvironment determines responsiveness to photodynamic therapy,” Cancer Res. 72(8), 2079–2088 (2012). [CrossRef] [PubMed]

13.

Y. Shintani, M. Maeda, N. Chaika, K. R. Johnson, and M. J. Wheelock, “Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-β signaling,” Am. J. Respir. Cell Mol. Biol. 38(1), 95–104 (2008). [CrossRef] [PubMed]

14.

S. Fine and W. P. Hansen, “Optical second harmonic generation in biological systems,” Appl. Opt. 10(10), 2350–2353 (1971). [CrossRef] [PubMed]

15.

T. Hayashi, “Time-dependent increase in the stability of collagen fibrils formed in vitro. I. Effects of pH and salt concentration on the dissolution of the fibrils,” J. Biochem. 84(2), 245–249 (1978). [PubMed]

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S. J. Lin, C. Y. Hsiao, Y. Sun, W. Lo, W. C. Lin, G. J. Jan, S. H. Jee, and C. Y. Dong, “Monitoring the thermally induced structural transitions of collagen by use of second-harmonic generation microscopy,” Opt. Lett. 30(6), 622–624 (2005). [CrossRef] [PubMed]

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V. Hovhannisyan, W. Lo, C. Hu, S. J. Chen, and C. Y. Dong, “Dynamics of femtosecond laser photo-modification of collagen fibers,” Opt. Express 16(11), 7958–7968 (2008). [CrossRef] [PubMed]

19.

E. J. Gualda, J. R. Vázquez de Aldana, M. C. Martínez-García, P. Moreno, J. Hernández-Toro, L. Roso, P. Artal, and J. M. Bueno, “Femtosecond infrared intrastromal ablation and backscattering-mode adaptive-optics multiphoton microscopy in chicken corneas,” Biomed. Opt. Express 2(11), 2950–2960 (2011). [CrossRef] [PubMed]

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M. Bueeler, E. Spoerl, T. Seiler, and M. Mrochen, “UV collagen cross-linking of the cornea: safety aspects and design of a UV illumination system,” in Proc. SPIE 6844, Ophthalmic Technologies XVIII (2008), p. 68440Z.

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C. Thrasivoulou, G. Virich, T. Krenacs, I. Korom, and D. L. Becker, “Optical delineation of human malignant melanoma using second harmonic imaging of collagen,” Biomed. Opt. Express 2(5), 1282–1295 (2011). [CrossRef] [PubMed]

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I. Georgakoudi, B. C. Jacobson, M. G. Müller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, and M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62(3), 682–687 (2002). [PubMed]

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P. Pande, B. E. Applegate, and J. A. Jo, “Application of non-negative matrix factorization to multispectral FLIM data analysis,” Biomed. Opt. Express 3(9), 2244–2262 (2012). [CrossRef] [PubMed]

28.

B. S. P. Miskovsky, “Hypericin--a new antiviral and antitumor photosensitizer: mechanism of action and interaction with biological macromolecules,” Curr. Drug Targets 3(1), 55–84 (2002). [CrossRef] [PubMed]

OCIS Codes
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(190.1900) Nonlinear optics : Diagnostic applications of nonlinear optics
(180.4315) Microscopy : Nonlinear microscopy

ToC Category:
Optical Therapies and Photomodificaton

History
Original Manuscript: December 24, 2013
Revised Manuscript: January 20, 2014
Manuscript Accepted: January 20, 2014
Published: April 2, 2014

Citation
V. Hovhannisyan, H. W. Guo, A. Hovhannisyan, V. Ghukasyan, T. Buryakina, Y. F. Chen, and C. Y. Dong, "Photo-induced processes in collagen-hypericin system revealed by fluorescence spectroscopy and multiphoton microscopy," Biomed. Opt. Express 5, 1355-1362 (2014)
http://www.opticsinfobase.org/boe/abstract.cfm?URI=boe-5-5-1355


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References

  1. S. Carpenter and G. A. Kraus, “Photosensitization is required for inactivation of equine infectious anemia virus by hypericin,” Photochem. Photobiol.53(2), 169–174 (1991). [CrossRef] [PubMed]
  2. D. Meruelo, G. Lavie, and D. Lavie, “Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin,” Proc. Natl. Acad. Sci. U.S.A.85(14), 5230–5234 (1988). [CrossRef] [PubMed]
  3. N. D. Weber, B. K. Murray, J. A. North, and S. G. Wood, “The antiviral agent hypericin has in vitro activity against HSV-1 through non-specific association with viral and cellular membranes,” AntiViral Chem. Chemother.5(2), 83–90 (1994).
  4. H. Koren, G. M. Schenk, R. H. Jindra, G. Alth, R. Ebermann, A. Kubin, G. Koderhold, and M. Kreitner, “Hypericin in phototherapy,” J. Photochem. Photobiol. B36(2), 113–119 (1996). [CrossRef] [PubMed]
  5. L. M. Davids, B. Kleemann, D. Kacerovská, K. Pizinger, and S. H. Kidson, “Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells,” J. Photochem. Photobiol. B91(2-3), 67–76 (2008). [CrossRef] [PubMed]
  6. J. M. Fernandez, M. D. Bilgin, and L. I. Grossweiner, “Singlet oxygen generation by photodynamic agents,” J. Photochem. Photobiol. B37(1–2), 131–140 (1997). [CrossRef]
  7. D. S. English, K. Das, K. D. Ashby, J. Park, J. W. Petrich, and E. W. Castner, “Confirmation of excited-state proton transfer and ground-state heterogeneity in hypericin by fluorescence upconversion,” J. Am. Chem. Soc.119(48), 11585–11590 (1997). [CrossRef]
  8. T. A. Wells, A. Losi, R. Dai, P. Scott, S. M. Park, J. Golbeck, and P. S. Song, “Electron transfer quenching and photoinduced EPR of hypericin and the ciliate photoreceptor stentorian,” J. Phys. Chem. A101(4), 366–372 (1997). [CrossRef]
  9. G. Seitz, R. Krause, J. Fuchs, H. Heitmann, S. Armeanu, P. Ruck, and S. W. Warmann, “In vitro photodynamic therapy in pediatric epithelial liver tumors promoted by hypericin,” Oncol. Rep.20(5), 1277–1282 (2008). [PubMed]
  10. W. T. Couldwell, A. A. Surnock, A. J. Tobia, B. E. Cabana, C. B. Stillerman, P. A. Forsyth, A. J. Appley, A. M. Spence, D. R. Hinton, and T. C. Chen, “A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas,” Cancer117(21), 4905–4915 (2011). [CrossRef] [PubMed]
  11. D. Yova, V. Hovhannisyan, and T. Theodossiou, “Photochemical effects and hypericin photosensitized processes in collagen,” J. Biomed. Opt.6(1), 52–57 (2001). [CrossRef] [PubMed]
  12. A. L. Maas, S. L. Carter, E. P. Wileyto, J. Miller, M. Yuan, G. Yu, A. C. Durham, and T. M. Busch, “Tumor vascular microenvironment determines responsiveness to photodynamic therapy,” Cancer Res.72(8), 2079–2088 (2012). [CrossRef] [PubMed]
  13. Y. Shintani, M. Maeda, N. Chaika, K. R. Johnson, and M. J. Wheelock, “Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-β signaling,” Am. J. Respir. Cell Mol. Biol.38(1), 95–104 (2008). [CrossRef] [PubMed]
  14. S. Fine and W. P. Hansen, “Optical second harmonic generation in biological systems,” Appl. Opt.10(10), 2350–2353 (1971). [CrossRef] [PubMed]
  15. T. Hayashi, “Time-dependent increase in the stability of collagen fibrils formed in vitro. I. Effects of pH and salt concentration on the dissolution of the fibrils,” J. Biochem.84(2), 245–249 (1978). [PubMed]
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