Hyperflav — perspective photosensitizer for PDT: cell studies
Present studies investigated the effectiveness in vitro of Hyperflav application as a photosensitizer for photodynamic therapy.
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| Date: | 2010 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2010
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| Cite this: | Hyperflav — perspective photosensitizer for PDT: cell studies / P.V. Yermak, N.F. Gamaleia, A.S. Shalamay, T.V. Saienko, V.V. Kholin // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 233–236. — Біліогр.: 24 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859651020799344640 |
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| author | Yermak, P.V. Gamaleia, N.F. Shalamay, A.S. Saienko, T.V. Kholin, V.V. |
| author_facet | Yermak, P.V. Gamaleia, N.F. Shalamay, A.S. Saienko, T.V. Kholin, V.V. |
| citation_txt | Hyperflav — perspective photosensitizer for PDT: cell studies / P.V. Yermak, N.F. Gamaleia, A.S. Shalamay, T.V. Saienko, V.V. Kholin // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 233–236. — Біліогр.: 24 назв. — англ. |
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| description | Present studies investigated the effectiveness in vitro of Hyperflav application as a photosensitizer for photodynamic therapy.
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| first_indexed | 2025-12-07T13:34:07Z |
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Experimental Oncology 32, 233–236, 2010 (December) 233
Antitumor photodynamic therapy (PDT) comprises
systemic administration of a photosensitizer and
subsequent visible light delivery to the tumor lesion.
Sufficient oxygenation of targeted tissue enables
photochemical reactions with generation of reactive
oxygen species and/or free radicals leading to oxida-
tive damage and destruction of sensitized cells [1].
Promising clinical results obtained with photodynamic
therapy stimulate searching of novel photosensitiz-
ers with better chemophysical properties. One of
such promising substances is hypericin, a natural
product which was found together with other naph-
thodianthrone derivatives such as pseudohypericin,
protohypericin, protopseudohypericin, in a number
of plants of the genus Hypericum, H.perforatum and
H.maculatum for instance [2].
Nowadays drugs based on Hypericum extract is
widely used for the treatment of mild and moderate
depression [3], although there is some evidence that
indicates that not hypericin but hyperforin is respon-
sible for the antidepressant activity. Also because of
antiviral activity of hypericin [4] its possible application
as photodependent blood sterilizer was investigated
[5]. Hypericin is under investigation as photoinhibitor
of the progression of proliferative vitreoretinopathy in
ophthalmology [6].
Due to comparatively high singlet oxygen and su-
peroxide anions generation rate, triplet quantum yield,
potent light-dependent antineoplastic and antiviral
activities hypericin is under investigation as a photosen-
sitizer for PDT treatment of superficial bladder tumor
[7], recurrent mesothelioma, basal and squamous cell
carcinoma [8] and for inhibition of the growth of malig-
nant glioma [9, 10], pituitary adenoma, and cutaneous
T-cell lymphoma. Moreover, hypericin is successfully
applied as a diagnostic tool for the fluorescent detection
of flat neoplastic lesions in bladder [8, 11, 12].
Hypericin is soluble in polar solvents such as
ethanol, methanol, acetonitrile, tetrahydrofuran, cy-
clohexane, acetone, dimethylsulfoxide and insoluble
in nonpolar solvents [13]. At physiological pH hypericin
forms organic and inorganic monobasic salts in organic
solvents. Dissolved in organic solvents sodium hyperici-
nate exhibits bright red fluorescence (absorption λmax =
592 nm, emission λmax = 594 nm in ethanolic solutions)
[14, 15]. Unfortunately hypericin is insoluble in water
under physiological conditions and becomes barely
soluble in pure water if pH rises above 8 [13]. But hyperi-
cin can be solubilized in biological media, if formation
of complexes with biomacromolecules is possible [14].
Nanoparticles being from several dozens to
hundreds nanometers in size and from about one
hundred to ten thousand times smaller than human
cells, possess unique abilities in interaction with bio-
molecules, what may be used to improve anticancer
drugs and diagnostic agents. Among the most studied
nanoparticles are colloid gold, quantum dots, carbon
nanotubes, silicon and paramagnetic nanoparticles
HYPERFLAV — PERSPECTIVE PHOTOSENSITIZER FOR PDT: CELL
STUDIES
P.V. Yermak1, N.F. Gamaleia1,*, A.S. Shalamay2, T.V. Saienko2, V.V. Kholin3
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine,
Vasylkivska str. 45, Kiev 03022, Ukraine
2SIC “Borshchahivskiy Chemical-Pharmaceutical Plant” CJSC, Mira str. 17, Kiev 03680, Ukraine
3SME “Photonika Plus”, Odesska str. 8, Cherkassy 18023, Ukraine
Background: Application of hypericin (an alkaloid from Hypericum perforatum plants) as photodynamic agent may become the
next successful step in photodynamic therapy of malignant tumors. Hyperflav — is a purified Hypericum extract designed for
the purpose of photodynamic diagnosis. Aim: Present studies investigated the effectiveness in vitro of Hyperflav application as
a photosensitizer for photodynamic therapy. Methods: Hyperflav photodynamic activity was assessed in phototoxic cell tests on
Jurkat, MT-4 and Namalwa leukemic cell lines. Spectroscopic measurements of Hyperflav solutions were performed. Results:
Hyperflav aqueous solubility was maintained in presence of polyvinylpyrrolidone with the most pronounced photodynamic activity
at 1:5 (w/w) Hyperflav-PVP ratio. Hyperflav fluorescence spectrum in ethanol exhibits two main peaks around 597 and 647 nm,
in accordance with the spectrum of pure hypericin. Fluorescence spectrum of aqueous solution exhibits peaks at 604 and 655 nm
and indicates decreasing in fluorescence intensity. Hyperflav at drug dose range of 5 –25 μg/ml and light dose 15 J/cm2 showed
a dose-dependent cytotoxicity on tested cell cultures, while dark cytotoxicity was not observed. Light irradiation of cell samples
preincubated with 15 μg/ml Hyperflav resulted in 69.9, 76.0 and 78.3% cell death of Jurkat, MT-4 and Namalwa cultures, re-
spectively. Combined preparation of Hyperflav with gold nanoparticles showed low photocytotoxicity (24.2%) in comparison with
Hyperflav alone (99.6%) on Namalwa cells. Conclusion: Hyperflav being solubilized in nontoxic aqueous media exhibits in vitro
photodynamic activity at doses that do not have dark toxicity, and therefore it meets requirements as a perspective photosensitizer.
Further studies, particularly in vivo, are warranted to fully evaluate photodynamic potential of Hyperflav.
Key Words: photodynamic therapy (PDT), Hypericum extract, hypericin, gold nanoparticles, antitumor effect.
Received: October 25, 2010.
*Correspondence: Fax: +380442581656;
E-mail: gamaleia@onconet.kiev.ua
Abbreviations used: PDT — photodynamic therapy; PVP — polyvi-
nylpyrrolidone.
Exp Oncol 2010
32, 4, 233–236
ORIGINAL CONTRIBUTIONS
234 Experimental Oncology 32, 233–236, 2010 (December)
[16, 17]. Main fields of gold nanoparticles application
in biomedicine are drug delivery, photothermal and
photodynamic therapy, diagnostics.
MATERIALS AND METHODS
Cell lines. In our studies we used MT-4 and Jurkat
T-cell leukemic lines and B-cell Burkitt lymphoma cell
line Namalwa obtained from the Bank of Cell Lines from
Human and Animal Tissue NAS of Ukraine. Cells were
cultured in RPMI-1640 medium (FarmBiotek, Ukraine)
supplemented with 10% fetal cow serum (Sigma,
Germany) at 37 °C in presence of 5% CO2. Cells were
reseeded three times a week.
Hyperflav preparations. Hyperflav was provided
by SIC “Borshchahivskiy Chemical-Pharmaceutical
Plant”. Hyperflav dried powder was dissolved in 0.9%
sodium chloride with addition of various concentra-
tions (0.5; 1.25; 2.5; 5 and 10%) of polyvinylpyrrol-
idone and then diluted with sodium chloride to final
concentration of 500 μg/ml. Hyperflav solutions were
prepared ex tempore for every experiment.
Nanocomposite Hyperflav-colloid gold was pre-
pared in Scientific Research Institute of Nanotech-
nological Industry by conjugation of commercial of
commercial Hyperflav with gold nanoparticles. Dried
substance was dissolved in 0.9% sodium chloride with
2.5% polyvinylpyrrolidone and further diluted with so-
dium chloride to obtain the concentration of 500 μg/ml.
K-30 polyvinylpyrrolidone (BASF, China) with ap-
proximate molecular weight of 40 kDa was used to
prepare Hyperflav solutions.
Fluorescence measurements. Fluorescence
emission spectra of Hyperflav solutions were recorded
with ND-3300 cuvetteless spectrofluorometr (Nano-
drop Technologies, USA) connected to PC. Measure-
ments were conducted in 1 mm fluid column formed be-
tween surfaces of pedestal and receiving optical fiber.
Radiation sources. As the light source for irradia-
tion of cell samples we used an experimental device
(Photonika Plus, Ukraine) based on incandescent lamp
(Philips, USA) equipped with appropriate broadband
filter. The device emitted light in spectral range of
560–700 nm. Light beam was delivered to test tubes
with cells by a fiber-optical probe.
Photodynamic procedure. Each experimental
sample contained 2 ml of 2 x 106 cells/ml suspension.
Cell samples were preincubated in Hanks solution
with addition of appropriate Hyperflav preparations in
sodium cloride for 1 hour and then washed once to re-
move non-absorbed photosensitizer. After subsequent
resuspending in Hanks solution, samples were irradi-
ated with a power density of 150 mW/cm2 and a dose
of 15 J/cm2. Irradiation dose was controlled with the
help of energy and power meter (3A-p thermal head,
Ophir Optronics, USA). Irradiated cells were incubated
in RPMI-1640 media for 24 h, and then a phototoxic
effect was assessed by trypan blue dye exclusion test.
Statistical analysis. Per cent values of dead cells
was determined by counting of 200 cells five times for
each sample, and were presented as a mean ± stan-
dard deviation. One-way ANOVA analysis was used to
determine significance of difference between means.
RESULTS AND DISCUSSION
The first part of the study was devoted to elabora-
tion of the preparation dissolved forms which would be
suitable for biological investigations. Several reports
on photodynamic properties of Hypericum extracts
have been published earlier [18, 19]. Hyperflav, that is
actually a dried St. Johns wort (H. perforatum) extract,
proposed as a photodiagnostic agent, contains about
2% of hypericin and pseudohypericin. Hyperflav like
other similar extracts and pure hypericin, is insoluble
in water, being well soluble in ethanol and other polar
solvents. It is known that hypericin in aqueous buffers
is present in a form of colloidal high molecular weight
aggregates. In such aggregated form hypericin loses
its photodynamic activity as well as suffers decrease in
fluorescence yield [14]. Due to its lipophilic properties
it is possible to prevent aggregation of hypericin by ad-
dition of albumin and plasma lipoproteins that adsorb
hypericin in aqueous environment [14]. Some macro-
molecular substances such as polyethyleneglycol [14],
N-methylpyrrolidone [20] and polyvinylpyrrolidone [21,
22] can be used instead of serum proteins to solubilize
hypericin in aqueous media.
Thus, to obtain aqueous solutions of Hyperflav for
cell tests, we used polyvinylpyrrolidone (PVP). A cor-
relation exists between the amount of nonaggregated
hypericin and its fluorescence yield in a solution [14].
Fluorescence emission profile of Hyperflav solubilied in
water with PVP is almost similar (except its much lower
intensity) to that in ethanol and specifies hypericin as
the major photoactive constituent (Fig. 1). Results of
fluorescent spectroscopy measurements show signifi-
cant decrease in fluorescence intensity of water-PVP
solubilized Hyperflav compared to ethanolic solution.
Nevertheless they show presence of some nonaggre-
gated, thus bioavailable and photodynamically active
hypericin in solution.
0
5000
10000
15000
20000
25000
30000
49
9
51
9
53
9
55
9
57
9
59
9
61
9
63
9
65
9
67
9
69
9
Fl
uo
re
sc
en
ce
in
te
ns
ity
, R
FU
Ethanol
Water+PVP
Fig. 1. Fluorescence emission spectra of ethanolic and polyvi-
nylpyrrolidone-aqueous Hyperflav solutions. Concentration of
Hyperflav 500 μg/ml. Peak fluorescence emission at 597 nm in
ethanolic solution, and 604 nm in water-PVP solution
In the next stage of the study cytotoxicity cell tests
were performed to determine influence of Hyperflav to
PVP ratio on photodynamic activity of solutions (Fig. 2).
Samples containing Hyperflav in concentration of 10 μg/
ml with 20, 50, 100, 200 or 400 μg/ml of PVP in 0.9%
Experimental Oncology 32, 233–236, 2010 (December) 235
sodium chloride were tested. Maximal activity under
light irradiation was shown by the solution with 1:5 ratio
(10 μg/ml Hyperflav and 50 μg/ml PVP). No statistically
significant cytotoxicity in dark conditions was observed.
0
10
20
30
40
50
60
70
80
90
100
Intact cells 1:2 1:5 1:10 1:20 1:40
Ce
ll
de
at
h,
%
Dark conditions
PDT
*
*
*
*
*
Fig. 2. Photodynamic treatment of Jurkat cells. Hyperflav-
polyvinylpyrrolidone (w/w) ratios 1:2, 1:5, 1:10, 1:20 and 1:40.
*Significantly different from control at p < 0.05
Next, using the most effective Hyperflav: polyvi-
nylpyrrolidone ratio 1:5, we assessed photodynamic
activity of Hyperflav on three different cell cultures.
Under light irradiation Hyperflav showed dose de-
pendent cytotoxicity. Data obtained in tests with
Jurkat, Namalwa and MT-4 cell lines are presented
in Fig. 3–5. As it follows from the figures, 69.9, 78.3
and 76% cell death was observed in respective culture
samples preincubated with Hyperflav in concentration
of 15 μg/ml, and the preparation in concentration of
20–25 μg/ml was able to induce near total death of
tested cells. No significant cytotoxicity was observed
in dark conditions.
0
10
20
30
40
50
60
70
80
90
100
Intact
cells
Irradiated
cells 5 μg/ml 10 μg/ml 15 μg/ml 20 μg/ml
Ce
ll
de
at
h,
%
Dark conditions
PDT
*
*
*
*
Fig. 3. Photodynamic treatment of Jurkat cells with Hyperflav
in different concentrations. *Significantly different from control
at p < 0.05
0
10
20
30
40
50
60
70
80
90
100
Intact
cells
Irradiatied
cells 5 μg/ml 10 μg/ml15 μg/ml 20 μg/ml25 μg/ml
Ce
ll
de
at
h,
%
* *
*
*
*
Fig. 4. Photodynamic treatment of MT-4 cells with Hyperflav
in different concentrations. *Significantly different from control
at p < 0.05
0
10
20
30
40
50
60
70
80
90
100
Intact cells 5 μg/ml 10 μg/ml 15 μg/ml 20 μg/ml 25 μg/ml
Ce
ll
de
at
h,
%
*
*
*
*
*
Fig. 5. Photodynamic treatment of Namalwa cells with Hyperflav
in different concentrations. *Significantly different from control
at p < 0.05
Among different nanotechnology products gold
nanoparticles draw a special attention as perspective
drug delivery agents for cancer therapy [16, 17, 23].
Similar to the Hyperflav solubility problem, nanopar-
ticles can be stabilized in colloidal state by biocompa-
tible polymers which are able to inhibit colloid aggrega-
tion in physiological conditions [16].
Therefore a conjugated preparation of Hyperflav
with nanogold, stabilized by PVP, was obtained and
preliminarily tested using Namalwa cell culture. Con-
trary to expectations phototoxic tests revealed de-
crease in phototoxicity of nanocomposite preparation
in comparison with Hyperflav alone (Fig. 6).
0
10
20
30
40
50
60
70
80
90
100
Intact cells 15 μg/ml 20 μg/ml
Ce
ll
de
at
h,
%
Hyperflav
Hyperflav-nanogold
*
*
*
*
Fig. 6. Effect of photodynamic treatment with Hyperflav and
Hyperflav-nanogold on Namalwa cells. *Significantly different
from control at p < 0.05
The preliminary results obtained may be explained
by the fact that Hyperflav is polycomponent substance
containing not only the prooxidant constituent (hyperi-
cin) but antioxidative ones (flavonoids, quercetin) as
well [24]. It could interfere with the cell oxidative da-
mage by PDT. Also, the influence of gold nanoparticles
on bioavailability and distribution of prooxidative and
antioxidative components of the preparation in cell
culture system is still to be studied.
CONCLUSION
Hyperflav can be maintained in aqueous solution
in presence of polyvinylpyrrolidone. Hyperflav in dose
of 15 μg/ml shows photodynamic activity in tests with
leukemic cell cultures Jurkat, Namalwa and MT-4,
inducing approximately 70% cell death and does not
show dark toxicity. Conjugation with gold nanoparticles
causes decrease in phototoxic activity of Hyperflav.
236 Experimental Oncology 32, 233–236, 2010 (December)
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|
| id | nasplib_isofts_kiev_ua-123456789-32301 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T13:34:07Z |
| publishDate | 2010 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Yermak, P.V. Gamaleia, N.F. Shalamay, A.S. Saienko, T.V. Kholin, V.V. 2012-04-16T16:37:30Z 2012-04-16T16:37:30Z 2010 Hyperflav — perspective photosensitizer for PDT: cell studies / P.V. Yermak, N.F. Gamaleia, A.S. Shalamay, T.V. Saienko, V.V. Kholin // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 233–236. — Біліогр.: 24 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/32301 Present studies investigated the effectiveness in vitro of Hyperflav application as a photosensitizer for photodynamic therapy. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Hyperflav — perspective photosensitizer for PDT: cell studies Article published earlier |
| spellingShingle | Hyperflav — perspective photosensitizer for PDT: cell studies Yermak, P.V. Gamaleia, N.F. Shalamay, A.S. Saienko, T.V. Kholin, V.V. Original contributions |
| title | Hyperflav — perspective photosensitizer for PDT: cell studies |
| title_full | Hyperflav — perspective photosensitizer for PDT: cell studies |
| title_fullStr | Hyperflav — perspective photosensitizer for PDT: cell studies |
| title_full_unstemmed | Hyperflav — perspective photosensitizer for PDT: cell studies |
| title_short | Hyperflav — perspective photosensitizer for PDT: cell studies |
| title_sort | hyperflav — perspective photosensitizer for pdt: cell studies |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/32301 |
| work_keys_str_mv | AT yermakpv hyperflavperspectivephotosensitizerforpdtcellstudies AT gamaleianf hyperflavperspectivephotosensitizerforpdtcellstudies AT shalamayas hyperflavperspectivephotosensitizerforpdtcellstudies AT saienkotv hyperflavperspectivephotosensitizerforpdtcellstudies AT kholinvv hyperflavperspectivephotosensitizerforpdtcellstudies |