WO2011110186A1 - Utilisation de nanoparticules cœur écorce de cobalt/argent dans un traitement de tumeurs solides - Google Patents

Utilisation de nanoparticules cœur écorce de cobalt/argent dans un traitement de tumeurs solides Download PDF

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Publication number
WO2011110186A1
WO2011110186A1 PCT/EG2010/000009 EG2010000009W WO2011110186A1 WO 2011110186 A1 WO2011110186 A1 WO 2011110186A1 EG 2010000009 W EG2010000009 W EG 2010000009W WO 2011110186 A1 WO2011110186 A1 WO 2011110186A1
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Prior art keywords
nanoparticles
tumor
silver
mice
cobalt
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PCT/EG2010/000009
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English (en)
Inventor
Tarek Abd Allah El-Tayeb
Iman Omar Gomaa
Mona Mohamed Bakr
Mohamed Ahmad Ghaly
Marwa Aii Ramdan
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El-Tayeb Tarek Abd Allah
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Priority to PCT/EG2010/000009 priority Critical patent/WO2011110186A1/fr
Publication of WO2011110186A1 publication Critical patent/WO2011110186A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention is related to the cancer treatment using novel models of photothermal drugs. It is includes in vivo study on mice as an animal model.
  • Nanotechnology is a multidisciplinary field, which covers enormous and diverse array of devices derived from engineering, biology, physics and chemistry (Ferrari, 2005).
  • Nanosciences and nanotechnology are transforming a wide array of products and services that have the potential to enhance the practice of medicine and improve public health (Walker and Mouton, 2006).
  • the potential impact of nanotechnology on the life sciences is one of the main motivations for the worldwide increase of government and private investment in this rapidly growing field of research and development (Kumar, 2007).
  • Nanoparticles are defined as microscopic particles between 1 nm and 100 nm, with some defining them up to 1 micron (Praetorius and Mandal, 2006).
  • One great feature of them that they are smaller than human cells which have a diameter of 10,000 -20,000 nm while they are similar in size to large biological macromolecules such as enzymes and receptors and as a result, nanoscale devices with diameter smaller than 50 nm can easily enter most cells, while those with smaller 20 nm diameter can transit out through blood vessels (McNeil, 2005).
  • Nanoparticles encounter great possibilities in biomedicine and bioanalysis. Owing to the advantage in their attractive size that places them at dimensions that are smaller than or comparable to those of biological macromolecules and the special physicochemical properties. There is great progress in their bioanalytical and medical applications such as multiplexed bioassays, biomedicine, ultrasensitive biodetection and bioimaging (Iida, 2008). From the biological applications of nanoparticles:
  • Solid tumors When abnormal mass of tissue formed and does not contain cysts or liquid areas, it is called solid tumor.
  • Solid tumors may benign when lacks the ability of ultimate growth, metastasis and invasion of the surroundings, or may be cancer (malignant) that has the preceding properties.
  • Different kinds of solid tumors are named according to the type of cells of which they are composed of (Ruddon, 2007). From the kinds of malignant: solid tumors are sarcomas, carcinomas and lymphomas.
  • Sarcomas are cancers arising from connective or supporting tissues such as bone or muscle.
  • Carcinomas are cancers arising from the body's glandular cells and epithelial cells, which line body tissues.
  • Lymphomas are cancers of the lymphoid organs such as the lymph nodes, spleen, and thymus, which produce and store infection-fighting cells. These cells also occur in almost all tissues of the body, and lymphomas therefore, may develop in a wide variety of organs.
  • the treatment of solid tumors includes surgery, chemotherapy and radio therapy (Gabriel, 2007). In surgery, most of the tumor or even the invaded organ is excised.
  • Chemotherapy includes the use of drugs to destroy cancer cells. Some cancers are curable by chemotherapy while others are not. Chemotherapeutic drugs can affect not only cancer cells but also other rapidly dividing normal cells such as those in the gastrointestinal tract, bone marrow, hair follicles, and reproductive system which result in several side effects.
  • Radiotherapy includes the use of x-rays to treat cancers (Gabriel, 2007). Some are curable by radiotherapy while others are not.
  • nanoparticles in the treatment of cancer especially solid tumors is a promising approach that is still under research. It involves two main principles which are hyperthermia using a magnetic field and photodynamic therapy.
  • Hyperthermia is a promising approach for cancer therapy. It involves the selective local rising of tumor cells temperature to intended temperature that damages these cells away from normal body tissues. The procedure involves dispersing magnetic nanoparticles throughout the target tissue and applying magnetic field with sufficient strength and frequency to cause the particles to emit heat (Iida, 2008).
  • This invention introduces novel modality for solid tumor treatment using silver and Cobalt/silver core shell nanoparticles. No one was using these types of nanoparticles in the treatment this type of cancer. Synthesis of these types of nanoparticles was done by certain method to be biologically applicable. 2.3. Methodology:
  • the Ag nanoparticles used is made completely of silver while the Co/Ag nanoparticles is made of cobalt core covered with a silver shell. They are prepared in the biotechnology laboratory at the National Institute of Laser Enhanced Sciences (NILES), Cairo University. Both Ag and Co/Ag nanoparticles are used in this study as photosensitizers that have cytotoxic thermal effect when activated with a monochromatic blue light source.
  • the Ag nanoparticles were synthesized by preparing NaBH4 of concentration (2* 10 3 M) followed by the addition of 1% PVA (polyvinyl alcohol) after freezing. AgN0 3 of concentration (10 "3 M) was added drop wise with stirring and rising the temperature gradually.
  • the Co/Ag nanoparticles were synthesized by placing pre-synthesized Cobalt nanoparticles in flask equipped with a small magnet bar for the sake of stirring followed by the addition of Ag precursor solution (aq. Soln. of AgN03, 1 mM with polyvinylpyrrolidone). The reaction mixture was allowed to boil under reflux.
  • Ehrlich tumor ascitis cells are transplantable, poorly differentiated malignant tumor cells that appeared originally as a spontaneous breast adenocarcinoma in albino mice.
  • Ehrlich tumor cells are grown in vivo in albino mouse by intraperitoneal injection forming ascitic cells. Upon subcutaneous injection, they form solid tumor mass (Giimushan and Musa, 2008).
  • mice normal laboratory albino mice with the age of 8 weeks and 20-25 gm body weight were obtained from the animal house of the National Cancer Institute in Cairo, Egypt (NCI). The mice were kept under standard conditions in the animal facility, Faculty of Pharmacy and Biotechnology, the German University in Cairo. All animal experiments were performed following the regulations of the "Research Ethics committee at the GUC”.
  • LED monochromatic light emitting diode
  • Ehrlich tumor cells were grown in vivo by intraperitoneal injection in albino mouse for two weeks.
  • the ascitic tumor cells were extracted from the abdomen using 20 cc syringe ( Figure 1). These cells were diluted with PBS, and about 2x l 0 6 cells we injected subcutaneously in the right hind limb of the mice belonging to groups 2 to 7.
  • the nanoparticles were prepared at the National Institute of Laser Enhanced Sciences (NILES) in water suspension. This was centrifuged at 20000 rpm for 1 hour and the pellet was then resuspended in phosphate buffered saline (PBS) at a concentration of 0.4g/lml referring to (Hou, et ai, 2009). Mice belonging to groups 4 to 7 were injected intratumoraly with ⁇ ⁇ of the nanoparticles suspension 15 days after tumor induction (Figure 2).
  • PBS phosphate buffered saline
  • mice in groups 3, 5 and 7 were intraperotenialy injected with 60mg/kg sodiumthiopentanal (EIPICO) for general anesthesia. After 15 minutes, each mouse was then fixed at a certain position that allows complete and direct exposure of the solid tumor to monochromatic blue LED (Photon LED DH48S) of 460 nm and 250 mW for 1 hour duration ( Figure 3). During light exposure, general body temperature of each mouse was monitored every 10 minutes by measuring rectal temperature using mercury thermometer ( Figure 4). Body temperature for normal mice with and without anaesthesia was also monitored as a control.
  • EIPICO sodiumthiopentanal
  • mice After the 30 days of monitoring the tumor volume, all the mice were anaesthetized using diethyl ether for being dissected. Blood samples were collected by cardiac puncture using 3 cc syringes for later biochemical analysis. Tissue biopsies were also taken from the tumors or what is left in case of treated mice and fixed in 10% buffered formol saline for histopathological examination.
  • Tumor biopsies were taken from all animal groups and fixed in 10% formol saline for 24 hour. Dehydration was then applied in ascending series of ethyl alcohol. Specimens were cleared in xylene then embedded in paraffin at 56°C at a hot air oven for 24 hour. Paraffin wax tissue blocks were prepared for sectioning at 4 ⁇ thickness by "Slidge" microtome. The obtained tissue sections were collected on glass slides, deparaffinized, stained by hematoxylin and eosin stains (Banchroft et ai, 1996). Tissue sections were finally examined under the light microscope for histopathological interpretation.
  • This study was performed to measure the efficacy of photodynamic therapy at solid tumor treatment in a mouse tumor model, using both Ag and Co/Ag nanoparticles.
  • Several parameters have been considered in this study including, reduction in tumor volume and histopathological modifications post-treatment.
  • the quality of this therapeutic modality has been evaluated by investigating the side effects that might appear during or after application of the therapeutic program, such as; influence on general body temperature, and/or limitations in the normal physiological processes.
  • One of the parameters that indicate the quality of the applied cancer therapeutic modality is the variation in general body temperature of the animals indicated by measuring the rectal temperature during exposure to the LED. Since the exposure was applied under general anesthesia for 1 h duration, body temperature of the anesthetized mice was monitored after 15 minutes from the onset of the intraperitoneal injection with sodium thiopentanal, and compared with that of the treated mice. Rectal temperature was also measured for normal mice without anesthesia and without exposure to LED as a reference for normal body temperature of the mice Table (2) shows the average variation in body temperature at different animal groups with 10 min. intervals for 1 h duration of light exposure. The normal control group includes the average body temperature of both the normal control and tumor control mice without anesthesia and without exposure to the LED.
  • the anesthetized control group of animals involves the average body temperature of both the normal control as well as the tumor control mice under general anesthesia with sodium thiopental but without being exposed to the LED. While the treated animal group, shows the average body temperature of the Ag-treated and Co/Ag-treated under general anesthesia for 1 h light exposure with 10 min intervals.
  • the anesthetized control mice showed gradual decrease in general body temperature from 37.5°C before injection to 35.5°C after 15 minutes post injection, then decreased to 34.5°C and finally became stable at 34°C throughout the 1 h light exposure.
  • the body temperature slightly rose from 35.5°C at the beginning of exposure and became stable around 36.5°C. Accordingly, comparison between variations in body temperature between the treated mice and the anesthetized control mice indicates only 2.5°C decrease which is still within the normal range of body temperature in the control mice.
  • Those treated mice did not show any signs of dehydration during light exposure and all mice survived for 30 days post treatment.
  • monochromatic light exposure is considered safe when operated under general anesthesia since the final stable elevated core body temperature is within the normal range.
  • liver functions was performed by quantitative determination of serum alanine aminotransferase "ALT" and serum direct bilirubin in order to investigate the effect of the applied therapeutic modality on normal physiological functions of the studied animals.
  • ALT serum alanine aminotransferase
  • serum direct bilirubin The following table presents the average activity of ALT in the serum and the serum direct bilirubin concentration of each group.
  • the level of necrosis in the treated tumors is higher in case of Co/Ag than Ag while in the dark control samples; the Co/Ag samples have more intact cells than in case of Ag injected tumors.
  • Co/Ag have less dark toxicity than the Ag nanoparticles, while the Co/Ag nanoparticles have more light toxicity than the Ag nanoparticles.
  • Co/Ag nanoparticles is less toxic to the unexposed tissues proposing specific tumor cells killing by maximizing tumor cells exposure to the LED and minimizing it to adjacent tissues in which nanoparticels might diffuse from the injected tumor mass.
  • Tumors injected with Co/Ag have large number of intact tumor cells "n” and lower degree of necrobiosis “nc” in the subcutaneous tissue.
  • Treated tumors with Co/Ag and lh light exposure have large necrotic areas "nc” with some necrobiosis "nb” in the subcutaneous tissue and few intact cancer cells.
  • Figure (1) Extraction of Ehrlich ascites tumor cells from the abdominal region of a mouse having Ehrlich ascites.
  • Figure (2) Intratumoral injection of nanoparticles using an insulin syringe.
  • Figure (3) Monitoring of the rectal temperature of the mouse while being exposed to monochromatic blue light of wave length 460 nm from the LED.
  • Figure (4) Graphical representation of the tumor volume (mm 3 ) with respect to the time (days) after exposure to LED for each group of the mice.
  • Figure 7 Skeletal muscle of group 1 "Normal control" showing normal histological structure of striated muscle where there are no tumor cells found.
  • Figure (8) Tumor cells of group 2 "Tumor control” showing giant cell formation "g", mitotic nuclei "m” and hyperchromatic nuclei "h”.
  • Figure (9) infiltration of inflammatory cells through the skeletal muscles"m” with the intact neplastic cells "n” in the adjacent area.
  • Figure (10) a shows the presence of necrobiosis "nc" in the tumor cells as well as intact cancer cells in the subcutaneous tissue of group 4 "Dark control".
  • Figure(ll, a) Shows the presence of high degree necrosis "nc" as well as some intact tumor cells "n” in the subcutaneous tissue of group 5
  • Table 1 Reduction in tumor volume (mm 3 ) with respect to the time (days) in each experimental group.
  • Table (2) Monitoring rectal temperature for 1 h duration with 10 minutes intervals of the normal control, anesthetized control and the treated mice groups.
  • Table (3) The average activity of serum ALT and the average concentration of the direct bilirubin level for all animal groups

Abstract

Cette invention concerne une application in vivo à l'aide d'un système de modèle de souris pour une recherche sur l'effet des nanoparticules d'argent (Ag) et des nanoparticules à cœur de cobalt et écorce d'argent (Co/Ag) sur des tumeurs solides lorsque celles-ci sont exposées à une diode électroluminescente (DEL) monochromatique d'une longueur d'onde de 460 nm et de 250 mW dans un procédé entier connu sous le nom de Thérapie photo-thermique de tumeurs solides. Seules les souris auxquelles ont été injectées des nanoparticules d'Ag ou de Co/Ag et qui ont été exposées à la diode électroluminescente (DEL) ont montré une réduction spectaculaire du volume tumoral durant les six premiers jours d'une période de surveillance d'un mois. Nos résultats ont montré une sécurité complète du programme thérapeutique réalisé comme indiqué par la plage normale de la température corporelle et l'absence de symptômes de déshydratation durant l'exposition à la lumière.
PCT/EG2010/000009 2010-03-07 2010-03-07 Utilisation de nanoparticules cœur écorce de cobalt/argent dans un traitement de tumeurs solides WO2011110186A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006244A2 (fr) * 1998-07-30 2000-02-10 Hainfeld James F Particules metalliques de chargement dans des vesicules membranaires cellulaires et particule metallique utilisee pour l'imagerie et la therapie
US20020068187A1 (en) * 2000-04-07 2002-06-06 O'connor Charles J. Sequential synthesis of core-shell nanoparticles using reverse micelles
EP1710811A2 (fr) * 2005-04-08 2006-10-11 Industrial Technology Research Institute Structure coeur-enveloppe ayant des charactérisiques magnétiques, thermiques et optiques, et procédé de fabrication assicié
KR20090000859A (ko) * 2007-06-28 2009-01-08 연세대학교 산학협력단 진단 및 치료용 자성 메탈 나노 복합체

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006244A2 (fr) * 1998-07-30 2000-02-10 Hainfeld James F Particules metalliques de chargement dans des vesicules membranaires cellulaires et particule metallique utilisee pour l'imagerie et la therapie
WO2004112590A2 (fr) * 1998-07-30 2004-12-29 Hainfeld James F Procedes permettant de renforcer les effets de rayonnements a l'aide de nanoparticules metalliques
US20020068187A1 (en) * 2000-04-07 2002-06-06 O'connor Charles J. Sequential synthesis of core-shell nanoparticles using reverse micelles
EP1710811A2 (fr) * 2005-04-08 2006-10-11 Industrial Technology Research Institute Structure coeur-enveloppe ayant des charactérisiques magnétiques, thermiques et optiques, et procédé de fabrication assicié
KR20090000859A (ko) * 2007-06-28 2009-01-08 연세대학교 산학협력단 진단 및 치료용 자성 메탈 나노 복합체

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