Lutetium-177-labeled bombesin analogs for radiotherapy

A technology of bombesin and conjugates, applied in the field of bombesin analogs, can solve the problems of influence, cognitive function of dementia, treatment failure, etc.

Inactive Publication Date: 2013-12-25
PIRAMAL IMAGING SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the main problem is that cancer cells are difficult to eradicate successfully in conventional radiation therapy and tumor recurrence occurs, which leads to treatment failure
In addition, normal tissue is also considerably affected, producing radiation toxicity
Side effects such as inflammation at the irradiation site are common and there may be toxic necrosis and gliosis in the brain with dementia and cognitive decline, a serious side effect of radiation therapy in neuro-oncology

Method used

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  • Lutetium-177-labeled bombesin analogs for radiotherapy
  • Lutetium-177-labeled bombesin analogs for radiotherapy
  • Lutetium-177-labeled bombesin analogs for radiotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Example 1: Binding affinity and serum stability to GRPr

[0143] Binding affinity assay

[0144] Compound 2 was used at increasing concentrations ranging from 0.1 to 1.000 nmol / L [ 177 / nat Lu] and compound 3[ 111 / nat In], binding saturation experiments were performed. For blocking experiments, 0.8 mmol / L blocker was used. For each radioligand, triplicate samples were prepared for each concentration for both total and non-specific binding. Plates were kept on ice for 30 min before adding radioligand to the wells. After the addition of specific blockers and radioligands, plates were incubated at 4°C for 2h. After this time interval, the binding buffer was aspirated and the wells were washed twice with ice-cold phosphate-buffered saline (PBS, pH 7.4); this represents the free fraction. Cells were then harvested using 1 N NaOH; this corresponds to the bound fraction. At each radioligand concentration, specific binding was calculated by subtracting non-specific bindin...

Embodiment 2

[0150] Example 2: Biodistribution of compound 2 in PC-3 bearing mice at 1 h, 4h, 24h, 48h and 72h

[0151] Biodistribution at different time points was studied in NMRI nude mice bearing subcutaneous PC-3 tumors in the right hindlimb. Male mice weighed approximately 30 g, and 3 animals were studied per time point. After intravenous dose injection into the tail vein, mice were sacrificed at indicated time points and dissected organs were analyzed by radioactivity counts. An administered dose of 100 [mu]L per animal gave an average activity of 86 kBq.

[0152] At indicated time points, urine and feces were collected quantitatively. At the same time point, the animals were sacrificed and bled under isoflurane anesthesia, and the following organs and tissues were removed and performed using a γ-counter[ 177 Lu] Determination: spleen, liver, gallbladder, kidney, lung, femur, heart, brain, fat, thyroid, muscle, skin, blood, tail, stomach (without inclusions), prostate, intestine (...

Embodiment 3

[0166] Example 3: Radiation Dosimetry

[0167] The biodistribution data of compound 2 in PC-3 tumor bearing mice (see Example 2) were used in the radiation dosimetry calculations, estimating the mice by the MIRD (Medical Internal Radiation Dosimetry) method The organ's own dose ratio. Time activity (kinetic) data were modeled to generate residence times for compound 2.

[0168] Radiation dosimetry calculated by the Medical Internal Radiation Dose (MIRD) method shows an excellent therapeutic window (for kidney and pancreas) in mice. Considering a maximal activity of 450MBq injected per animal, a dose of 150-200Gy can be achieved in the tumor. The kidneys are not critical, instead the pancreas becomes the dose limiting organ. (In contrast to rodent pancreas, human pancreas expresses only very small amounts of GRPr).

[0169] See Figure 3.

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Abstract

The invention is directed to novel Lutetium-177-labeled bombesin analogs for treatment of tumor by radiotherapy.

Description

technical field [0001] The present invention relates to novel lutetium-177 labeled bombesin analogues for use in the treatment of tumors by radiotherapy. Background technique [0002] Radiation therapy is the most commonly used form of cancer treatment; worldwide, 50% of cancer patients receive radiation administration each year. Malignant tissue is typically treated using photons (x-rays / gamma-rays) or electrons using particle beams that produce a low linear energy transfer to the tissue. These particle beams are usually produced by linear accelerators or radioactive sources. These types of radiation therapy or radiosurgery equipment are widely used in clinics and hospitals. However, the main problem is that it is difficult to successfully eradicate cancer cells in conventional radiation therapy and tumor recurrence occurs, which leads to treatment failure. In addition, normal tissue is also considerably affected, resulting in radiation toxicity. Side effects such as in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61P35/00
CPCA61K51/08A61K51/088A61P11/00A61P13/08A61P15/00A61P35/00A61P35/04A61P43/00C07K7/06C07K14/575C07K1/13
Inventor 桑德拉·博尔科斯基洛萨尔巴·曼西赫尔马特·梅克
Owner PIRAMAL IMAGING SA
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