Development of Bio-Functional Molecules for Cancer Therapy

[1] Phthalocyanine-Based Fluorescence Probes for Detecting Ascorbic Acid

Ascorbic acid (Vitamin C) is a well-known and essential nutrient in relation to biological functions such as carnitine biosynthesis and scurvy prevention; moreover, it is also used in health care supplements as anti-oxidizing agents or anti-aging agents.

In particular, recently, ascorbic acid has attracted considerable attention for its uses in modern cancer therapy. Although it has become necessary to directly detect ascorbic acid today, no fluorescence bioimaging technique has been established thus far.

Recently, we have succeeded in developing a novel fluorescence probe for bioimaging of ascorbic acid in cancer cells. The molecular design of this fluorescence probe originates from the combination of three features: (i) unpaired electron spin, (ii) fluorescence quenching, and (iii) reaction with ascorbic acid. Due to the using of red light, which is highly transparent to biological tissues, this probe is expected to be a novel feasible tool to study the effects of vitamin C in living tissues.

T. Yokoi, T. Otani, and K. Ishii
"In vivo fluorescence bioimaging of ascorbic acid in mice: Development of an efficient probe consisting of phthalocyanine, TEMPO, and albumin"
Sci. Rep., 8, 1560 (2018).

K. Ishii, K. Kubo, T. Sakurada, K. Komori, and Y. Sakai
"Phthalocyanine-Based Fluorescence Probes for Detecting Ascorbic Acid: Phthalocyaninatosilicon Covalently Linked to TEMPO Radicals"
Chem. Commun., 47, 4932 (2011).

[2] Photosensitizers for Photodynamic Therapy

Molecules such as phthalocyanine and their derivatives have strong absorption at around 630 nm wavelength, the region of high permeability through biological tissues. Therefore, they are widely used as photosensitizers for singlet oxygen generation in photodynamic therapy (PDT: a method of cancer treatment in which singlet oxygen is produced by laser irradiation, then, this active singlet oxygen will attack and kill cancer cells). By increasing the light absorption coefficient of sensitizers, the singlet oxygen yield can be improved. However, the strong light absorption of photosensitizers in the tissues on the surface is suggested for the problem that light cannot reach to deep cancer tissues. Therefore, while the photosensitizers are desirable to stably generate singlet oxygen until the completion of treatment, there is a dilemma that they are hoped to decompose after the treatment, so that light can reach to deeper tissues.

Herein, we proposed ruthenium phthalocyanine (RuPc(CO)(Py)) and naphthalocyanine (RuNc(CO)(Py)) complexes as photosensitizers that satisfied the two above requirements. When a nanosecond-pulsed laser is used, the photodecarbonylation of our Ru complexes efficiently proceeds via stepwise two-photon excitation, while the reaction yields are negligibly small when a continuous-wave (CW) laser is employed. The pulsed laser selective photodecarbonylation decreases the Q-band absorbance, which satisfies what the photodynamic therapy (PDT) requires of the photobleaching. For RuPc(CO)(Py), the photochemical reactions including both the photodecarbonylation and just photobleaching occur in HeLa cells in vitro.

On the basis of these results, we propose a novel concept for achieving a greater depth of necrosis in PDT as follows:

(1) PDT of upper cellular layers using CW laser irradiation;

(2) efficient photobleaching in upper cellular layers using pulsed dye-laser irradiation, which results in an increase in the therapeutic depth of red light;

(3) PDT directed toward deeper tumor tissues using CW laser irradiation.

In addition, these Ru complexes are promising as CO release agents to investigative biochemistry.

Kazuyuki Ishii
"Efficient Singlet Oxygen Generation without Heavy-Atom Effect"
Seisan-Kenkyu, 60, 160-163 (2008).

K. Ishii, M. Shiine, Y. Shimizu, S. Hoshino, H. Abe, K. Sogawa, and N. Kobayashi
"Control of Photobleaching in Photodynamic Therapy Using Photodecarbonylation Reaction of Ruthenium Phthalocyanine Complexes via Stepwise Two-Photon Excitation"
J. Phys. Chem. B, 112, 3138 (2008).

K. Ishii, A. Takayanagi, S. Shimizu, H. Abe, K. Sogawa, and N. Kobayashi
"In vitro Photodynamic Effects of Phthalocyaninatosilicon Covalently Linked to 2,2,6,6-Tetramethyl-1-Piperidinyloxy Radicals on Cancer Cells"
Free Radical Biol. Med., 38, 920 (2005).

K. Ishii, H. Itoya, H. Miwa, M. Fujitsuka, O. Ito, and N. Kobayashi
"Relationship between Symmetry of Porphyrinic π-Conjugated Systems and Singlet Oxygen (1Δg) Yields: Low-Symmetrical Tetraazaporphyrin Derivatives"
J. Phys. Chem. A, 109, 5781 (2005).

K. Ishii, S. Takeuchi, S. Shimizu, and N. Kobayashi
"A Concept for Controlling Singlet Oxygen (1Δg) Yields by Nitroxide Radicals: Phthalocyaninatosilicon Covalently Linked to Nitroxide Radicals"
J. Am. Chem. Soc., 126, 2082 (2004).

H. Miwa, K. Ishii, and N. Kobayashi
"Electronic Structures of Zinc and Palladium Tetraazaporphyrin Derivatives Controlled by Fused Benzo-Rings"
Chem. Eur. J., 10, 4422 (2004).

K. Ishii, S. Hoshino, N. Kobayashi
"Photodecarbonylation of Ruthenium Carbonyl Octaethylporphyrin via Stepwise Two-Photon Absorption of Visible Light"
Inorg. Chem., 43, 7969 (2004).


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