RU2339414C1 - Method for suppression of tumours growth - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely, to oncology and can be used at treatment of malignant tumours. The essence of the declared method is the following: intravenously inject nanoparticles of phthalocyanines in a dose not below 5 mg/kg of weight and not above as much as possible tolerable dose with the subsequent irradiation of a tumour laser impulses with a wavelength in the field of intensive absorption nanoparticles at energy density in impulse not lower than 0.1 J/cm² and total density of energy not lower than 10 J/cm².

EFFECT: increase of treatment efficiency of malignant tumours in comparison with earlier applied nanoparticles of carbon due to higher absorption coefficient of nanoparticles of phthalocyanines.

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Description

The present invention relates to medicine, namely to oncology, and can be used in the treatment of malignant tumors.

A known method of inducing cell death in vitro by introducing gold nanoparticles (NPs) into them followed by irradiation with laser pulses (C. M. Pitsillides, E.K. Joe, X. Wei, RRAnderson, and CPLin, Selective Cell Targeting with Light Absorbing Microparticles and Nanoparticles, Biophysical Journal, 84, 4023-4032, 2003; VP Zharov, E.N. Galitovskaya, C. Johnson, and T. Kelly. Synergistic Enhancement of Selective Nanophotothermolysis with Gold Nanoclusters: Potential for Cancer Therapy, Lasers in Surgery and Medicine 37, 219-226, 2005; VPZharov, K.E. Mercer, E.N. Galitovskaya, and M.S.Smeltzery. Photothermal Nanotherapeutics and Nanodiagnostics for Selective Killing of Bacteria Targeted with Gold Nanoparticles, Biophysical Journal , 90, 619-627, 2006). However, experiments on the effectiveness of gold NPs in vitro have not been confirmed in in vivo experiments, which are closer to clinical use.

The idea of the method in in vivo experiments is as follows. NPs are introduced intravenously to the animal, which have intensive absorption in the red or near infrared region of the spectrum (in the wavelength range of 0.6-1.2 μm, in the so-called “therapeutic window of biological tissue transparency”). Then the tumor is irradiated with powerful laser pulses with a wavelength in the region of intense absorption of NPs. Under the action of each laser pulse, “microexplosions” of NPs occur, leading to damage to the surrounding structures of the biological tissue and subsequent death of tumor cells. The effectiveness of the impact is determined by the dose of the introduced low frequencies, the energy density of the laser pulse and the total energy density. Other things being equal, the absorption coefficient of the introduced NPs at the irradiation wavelength is of great importance, since the energy of the laser pulse absorbed by each particle (microexplosion energy) and, consequently, the amount of damage produced by it depends on it.

Closest to the proposed solution is a method of suppressing tumor growth in an experiment on animals (mice) by intravenous administration of carbon nanoparticles at a dose of 30 mg / kg, followed by irradiation of the tumor with laser pulses in the spectral region of absorption of nanoparticles with an energy density of 3 J / cm ² and total energy density of 180 J / cm ² (B.Ya. Kogan, RIYakubovskaya, AAPankratov, TNAndreeva, LDKvacheva, AATitov, VAPuchnova, RAFeysulova, GNVorozhtsov, Laser heating of sulphuretted carbon Danoparticles inhibits tumor growth. Technical Proc., 2006, NSTI Nanostonote tumors tumor growth. Technical Proc., 2006 , 2006, Vol. 2, Chapter 1, p. 71-74). The maximum tumor growth inhibition (TPO) for S-26 carcinoma and S-37 sarcoma reached 70-75%.

The disadvantage of this method is its low efficiency, because with a rather high energy density per pulse (3 J / cm ² ) and a total energy density (180 J / cm ² ) SRW is only 70-75%.

The objective of the present invention is to increase the effectiveness of this method, i.e. achieving the same or higher values of SRW at lower radiation energy densities. The problem is solved by intravenous administration of NPs of phthalocyanines, followed by irradiation of the tumor with laser pulses in the region of absorption of NPs. The dose of nanoparticles is chosen not lower than 5 mg / kg body weight (with a further decrease in dose, the effectiveness of the method significantly decreases) and not higher than the maximum tolerated dose (MTD). The pulse energy density is chosen not lower than 0.1 J / cm ² (with a further decrease, the efficiency of the method significantly decreases). The upper limit of the pulse energy density is related to the capabilities of the laser used. The total energy density is limited above by the permissible duration of the irradiation session, and below by a value of 10 J / cm ² (with a further decrease, the efficiency of the method significantly decreases).

Studies were performed on mice with transplantable solid tumors of various histogenesis. As thermosensitizers, NPs based on various phthalocyanines were used. LF was administered intravenously in doses from MTD (maximum tolerated dose) and below. Then the tumor was irradiated with Q-switched laser pulses on a ruby. The energy density in the pulse was not lower than 0.1 J / cm ² , the total energy density was not lower than 10 J / cm ² . Evaluation of the antitumor effect was carried out by inhibition of tumor growth (TPO,%), which was calculated by the formula: TPO (%) = [(RO _control -RO _experience ) / RO _control ] × 100,

where RO _control is the size of the tumor in the control group; RO _experience - the size of the tumor in the experimental group.

The invention is illustrated by the following examples.

Example 1. Low-level aluminum phthalocyanine (AlPc) as a thermosensitizer.

Studies were performed on mice with C-26 carcinoma. The data characterizing the antitumor efficacy of the AlPc NP method are presented in Table 1. As can be seen from Table 1, irradiation of the tumor site with pulsed laser radiation after preliminary administration of a thermosensitizer in doses from 30 mg / kg (close to MPD) to 7.5 mg / kg led to inhibition of tumor growth up to 90% with a significantly lower radiation energy density than in the prototype. The introduction of NP phthalocyanine aluminum in the studied doses without irradiation, as well as irradiation without the introduction of nanoparticles did not significantly affect tumor growth (TPO did not exceed 15%).

Table 1
Antitumor efficacy of the method with aluminum phthalocyanine nanoparticles in mice with C-26 carcinoma No. gr Dose AlPc, mg / kg Exposure parameters TPO in% on the day after treatment The energy density per pulse, J / cm ² Total energy density, j / cm ² 7 fourteen one thirty 0.1 twenty 75 51 2 fifteen 0.3 thirty 90 86 3 7.5 0.3 thirty 67 34 four thirty - - 10 3 5 fifteen - - 3 -5 6 7.5 - - 8 8 7 - 0.3 thirty 5 fifteen

Example 2. Lp of copper phthalocyanine (CuPc) as a thermosensitizer.

Studies were performed on mice with S-37 sarcoma. The data characterizing the antitumor efficacy of the method with CuPc NPs are presented in table 2.

table 2
Antitumor efficacy of the method with copper phthalocyanine nanoparticles in mice with S-37 sarcoma No. gr Dose of CuPc, mg / kg Exposure parameters The number of complete resorption of the tumor node,% TPO in% on the day after treatment The energy density per pulse, J / cm ³ Total energy density, j / cm ² 8 eleven one thirty 0.6 60 80 99 89 2 thirty - - 0 eleven eighteen 3 - 0.6 60 0 -2 2

As can be seen from table 2, the irradiation of the tumor node at significantly lower energy densities compared with the prototype after administration of CuPc NPs at a dose of 30 mg / kg had a pronounced therapeutic effect - in 80% of the animals, complete regression of the tumor node was observed. In some animals (20%) in which it was not possible to achieve complete tumor regression, TPO was observed at 99-89% (according to data on days 8 and 11 after treatment). The introduction of copper phthalocyanine nanoparticles in the same dose without irradiation, as well as irradiation without the introduction of nanoparticles, did not significantly affect tumor growth (TPO did not exceed 18%).

EXAMPLE 3 Cobalt octacarboxyphthalocyanine acid (CoPc) NP

Studies were performed on mice with S-37 sarcoma. The data characterizing the antitumor efficacy of the method with LF CoCs are presented in table 3. As can be seen from the data presented in table 3, the irradiation of the tumor node at significantly lower energy densities compared with the prototype after the administration of CoCs LF at a dose of only 5 mg / kg (close to MTD) had an antitumor effect comparable to the prototype, leading to inhibition of tumor growth by 65%. The administration of cobalt phthalocyanine NPs in the same dose without irradiation, as well as irradiation without the introduction of NPs, did not significantly affect tumor growth (SRW did not exceed 15%).

Table 3
Antitumor efficacy of the cobalt octacarboxyphthalocyanine acid nanoparticle method in mice with S-37 sarcoma No. gr Dose of CoPs, mg / kg Exposure parameters TPO in% on the day after treatment The energy density per pulse, J / cm ² Total energy density, j / cm ² 7 5 0.6 60 65 5 - - fifteen - 0.6 60 -2

Example 4. Zinc phthalocyanine zinc (ZnPc) as a thermosensitizer.

Studies were performed on mice with S-37 sarcoma. The data characterizing the antitumor efficacy of the method with ZnPc NPs are presented in table 4.

As can be seen from the data presented in table 4, the irradiation of the tumor site at significantly lower energy densities compared with the prototype after the introduction of ZnPc nanoparticles at a dose of 30 mg / kg led to inhibition of tumor growth up to 100%. Administration of zinc phthalocyanine NPs at the same dose without irradiation, as well as irradiation without nanoparticle administration, did not significantly affect tumor growth (TPO did not exceed 16%).

Table 4
Antitumor efficacy of the method with zinc phthalocyanine nanoparticles in mice with S-37 sarcoma No. gr House ZnPc, mg / kg Exposure parameters TPO in% on the day after treatment The energy density per pulse, J / cm ² Total energy density, j / cm ² 8 fifteen one thirty 0.6 60 one hundred 88 2 thirty - - 10 16 3 - 0.6 60 5 -3

The above examples show that pulsed laser irradiation of tumors after intravenous administration of NP phthalocyanines leads to more effective inhibition of tumor growth or even complete cure at lower doses of the drug and lower radiation energy densities compared to using carbon NPs. Thus, a method for inhibiting the growth of tumors by intravenous administration of phthalocyanine nanoparticles with subsequent irradiation of the tumor with laser pulses with a wavelength in the region of intensive absorption of nanoparticles is proposed, which has advantages over the known similar method using carbon nanoparticles. With lower doses of injected NPs and lower radiation energy densities, a better therapeutic effect is achieved up to a complete cure.

Claims (1)

A method of suppressing tumor growth by intravenous administration of nanoparticles followed by irradiation of the tumor with laser pulses with a wavelength in the region of intense absorption of nanoparticles, characterized in that for intravenous administration use phthalocyanine nanoparticles in a dose of not less than 5 mg / kg weight and not higher than the maximum tolerated dose at a density energy per pulse is not lower than 0.1 J / cm ² and the total energy density is not lower than 10 J / cm ² .