EP3463302A1 - Lipoproteines chargees en complexes de platine pour le traitement du cancer - Google Patents
Lipoproteines chargees en complexes de platine pour le traitement du cancerInfo
- Publication number
- EP3463302A1 EP3463302A1 EP17730874.9A EP17730874A EP3463302A1 EP 3463302 A1 EP3463302 A1 EP 3463302A1 EP 17730874 A EP17730874 A EP 17730874A EP 3463302 A1 EP3463302 A1 EP 3463302A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cancer
- cisplatin
- loaded
- ldl
- platinum complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1275—Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors 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
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the use of anti-tumors for the treatment of cancer.
- Platinum complexes are commonly used in the treatment of cancers.
- cisplatin, carboplatin, oxaliplatin, tetraplatin, iproplatin, satraplatin, nedaplatin, lobaplatin, picoplatin Pt-based drugs.
- the spotlight will be proteins, O. Pinato, C.Musetti and C.Sissi, Metallomocis February 2014) or ProLindac (ProLindac TM (AP5346): A review of the development of an HPMA DACH platinum Polymer Therapeutic, David Nowotnika, Esteban Cvitkovic, Advanced Drug Delivery Reviews Volume 61, Issue 13, 12 November 2009, Pages 1214-1219).
- platinum complexes as currently used have the major disadvantage of forming adducts with proteins including albumin (Cisplatin Binding Sites on Human Albumin, Andrei Ivanov, John Christodoulou, John A. Parkinson, Kevin J Barnham, Alan Tucker, John Woodrowi, and Peter J. Sadler, The Journal of Biological Chemistry, Vol 273, No. 24, Issue of June 12, pp. 14721-14730, 1998).
- Cisplatin is one of the most used platinum complexes.
- CDDP complex cis-diaminedichloroplatinum
- II cisplatin
- CDDP complex cis-diaminedichloroplatinum
- cisplatin does not specifically target cancer cells.
- side effects such as nephrotoxicity, neurotoxicity, ototoxicity, bone marrow toxicity and other tissues, hemolysis, peripheral neuropathy and gastrointestinal irritation with nausea and vomiting.
- the present invention relates to a low density lipoprotein (LDL) loaded with platinum complex.
- Another object of the present invention is a platinum complex loaded high density lipoprotein (HDL) or a platinum complex loaded low density lipoprotein.
- Another object of the present invention is a kit comprising:
- HDL high density lipoprotein
- LDL low density lipoprotein
- the present invention also relates to a low density lipoprotein (LDL) loaded with a platinum complex for its use against cancer, characterized in that it is used in combination with a modified low density lipoprotein loaded with platinum complex.
- LDL low density lipoprotein
- the present invention relates to a high density lipoprotein (HDL) loaded with platinum complex for its use against cancer, characterized in that it is used in combination with a low density lipoprotein (LDL) loaded with platinum complex.
- the inventors of the present invention have demonstrated that the vectorization of a platinum complex, in particular cisplatin, makes it possible to increase the effectiveness of said complex in the treatment of cancer, while making it possible to reduce the toxicity associated with the use of the last.
- the inventors have also demonstrated that the combination of different types of platinum complex-loaded lipoproteins, in particular cisplatin, makes it possible to obtain a synergistic effect and therefore to further improve the efficacy of said complex in the treatment of cancer while decreasing its toxicity to the body.
- LDL Low density lipoproteins
- HDL high density lipoproteins
- high density lipoproteins are lipoproteins rich in cholesterol, phospholipids and including apolipoproteins AI, A-II, A-IV, CI, C-II, C-III, and E, with a density between 1.063 and 1,210 g / mL and diameter ranging between 5 and 12 nm.
- the native non-oxidized and non-acetylated low density lipoproteins are lipoproteins rich in cholesterol and including apo lipoprotein B-100, with a density of between 1.019 and 1.063 g / mL and diameter varying between 18 and 25 nm.
- the term "modified low-density lipoprotein” or "modified LDL lipoprotein” means an oxidized or acetylated low-density lipoprotein (LDL).
- HDL and LDL lipoproteins are obtained from donor plasma by an ultracentrifugation separation technique.
- the platinum complex is added to the lipoprotein in a physiological medium.
- the samples are incubated and then dialyzed.
- the concentration of said platinum complex is determined by graphite furnace atomic absorption spectrometry.
- the concentration of platinum complex found in lipoproteins is 0.1 to 1 mg / ml, preferably 0.2 to 0.8 mg / ml and even more preferably 0.3 to 0.6 mg / ml. of final solution, ie the solution obtained by addition of lipoproteins in a solution of phosphate buffered saline (PBS) containing cis-platinum. This concentration is measured for a cholesterol concentration of Immol / mL of said final solution.
- PBS phosphate buffered saline
- the concentration of platinum complex found in LDL lipoproteins is 0.3 mg / mL of said final solution. This concentration is measured for a cholesterol concentration of Immol / mL of said final solution.
- the concentration of platinum complex found in HDL lipoproteins is 0.5 mg / ml of said final solution. This concentration is measured for a cholesterol concentration of Immol / mL of said final solution.
- the present invention relates to a low density lipoprotein (LDL) loaded with platinum complex.
- said charged low density lipoprotein (LDL) is used as a medicament. More particularly, said loaded low density lipoprotein (LDL) is used to treat cancer.
- cancers for which platinum complexes are already commonly used colorectal cancer, colon cancer, stomach cancer, cancers of the otolaryngeal sphere (ENT), breast cancer, pancreatic cancer, liver cancer, lung cancer, brain cancer, prostate cancer, ovarian cancer, testicular cancer, cancer of the esophagus, bladder cancer, squamous cell cancers, cervical cancer, endometrial cancer, bone cancer, lymphomas, central nervous system tumors, sarcomas, leukemias and adenomas.
- ENT otolaryngeal sphere
- the cancer is colorectal cancer or breast cancer.
- said charged low density lipoprotein (LDL) is used in therapy to induce apoptotic death of tumor cells.
- the present invention also relates to a high density lipoprotein (HDL) loaded with platinum complex or a modified low density lipoprotein loaded with platinum complex.
- HDL high density lipoprotein
- Modified low density lipoproteins are known to those skilled in the art to be recognized by macrophage scavenger receptors. Typically, they can be obtained by incubation in the presence of copper sulphate or a generator of free radicals (oxidized LDL) or by acetylation (acetylated LDL) (see A Modification Method for Insulation and Acetylation of Low Density Lipoprotein of Human Plasma by Density Discontinuons Gradient Ultracentrifugation, JZ Reza et al., Journal of Biological Sciences 10 (8): 785-789, 2010 ISSN 1727-3048).
- said charged high density lipoprotein (HDL) or said charged modified low density lipoprotein is used as a medicament.
- said charged high density lipoprotein (HDL) or said charged modified low density lipoprotein is used to treat cancer.
- cancers for which platinum complexes are already commonly used colorectal cancer, colon cancer, stomach cancer, cancers of the otolaryngeal sphere (ENT), breast cancer, pancreatic cancer, liver cancer, lung cancer, brain cancer, prostate cancer, ovarian cancer, testicular cancer, cancer of the esophagus, bladder cancer, squamous cell cancers, cervical cancer, endometrial cancer, bone cancer, lymphomas, central nervous system tumors, sarcomas, leukemias and adenomas.
- the cancer is colorectal cancer or breast cancer.
- said charged high density lipoprotein (HDL) or said charged low density lipoprotein is used in therapy to activate macrophages.
- ROS reactive oxygen species
- enzymes proteases and lipases
- cytokines cytokines and coagulation components.
- kit comprising:
- HDL high density lipoprotein
- the kit is used to treat cancer.
- LDL low density lipoprotein
- cancers for which platinum complexes are already commonly used colorectal cancer, colon cancer, stomach cancer, cancers of the otolaryngeal sphere (ENT), breast cancer, pancreatic cancer, liver cancer, lung cancer, brain cancer, prostate cancer, ovarian cancer, testicular cancer, cancer of the esophagus, bladder cancer, squamous cell cancers, cervical cancer, endometrial cancer, bone cancer, lymphomas, central nervous system tumors, sarcomas, leukemias and adenomas.
- ENT otolaryngeal sphere
- the cancer is colorectal cancer or breast cancer.
- the present invention relates to a low density lipoprotein (LDL) loaded with a platinum complex for its use against cancer, characterized in that it is used in combination with a modified low density lipoprotein loaded with a complex of platinum.
- LDL low density lipoprotein
- the present invention relates to a high density lipoprotein (HDL) loaded with platinum complex for its use against cancer, characterized in that it is used in combination with a low density lipoprotein (LDL) loaded with platinum complex.
- HDL high density lipoprotein
- LDL low density lipoprotein
- cancers for which platinum complexes are already commonly used colorectal cancer, colon cancer, stomach cancer, cancers of the otolaryngeal sphere (ENT), breast cancer, pancreatic cancer, liver cancer, lung cancer, brain cancer, prostate cancer, ovarian cancer, testicular cancer, cancer of the esophagus, bladder cancer, squamous cell cancers, cervical cancer, endometrial cancer, bone cancer, lymphomas, central nervous system tumors, sarcomas, leukemias and adenomas.
- ENT otolaryngeal sphere
- the cancer is colorectal cancer or breast cancer.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a high density lipoprotein (HDL) loaded with platinum complex as defined above or a modified low density lipoprotein loaded with platinum complex as defined above.
- HDL high density lipoprotein
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a low density lipoprotein (LDL) loaded with a platinum complex as defined above.
- LDL low density lipoprotein
- the present invention also relates to the use of said platinum complex loaded lipoproteins as defined above or said kit as defined above for the manufacture of a medicament for the treatment of cancer.
- the present invention also relates to a method for the treatment of cancer which comprises administering to a patient a therapeutically effective amount of said platinum complex loaded lipoproteins as defined above.
- therapeutically effective amount any amount of loaded lipoproteins according to the present invention which is sufficient to induce an anti-tumor response or activate macrophages.
- platinum complexes are commonly used in the treatment of cancers.
- platinum complexes are cisplatin, carboplatin, oxaliplatin, tetraplatin, iproplatin, satraplatin, nedaplatin, lobaplatin, picoplatin or ProLindac (polymer-platinate-DACH AP5346).
- ProLindac is understood to mean a diaminocyclohexane complex (DACH) -platinum (Pt) coupled to the co-polymer hydroxypropylmethacrylamide (HPMA) (NCI Drug Dictionary, National Cancer Institute).
- DACH diaminocyclohexane complex
- Pt platinum
- HPMA co-polymer hydroxypropylmethacrylamide
- the platinum complex is chosen from the group comprising cisplatin, carboplatin, oxaliplatin, tetraplatin, iproplatin, satraplatin, nedaplatin, lobaplatin, picoplatin and ProLindac. (polymer-platinate-DACH AP5346).
- the platinum complex is cisplatin.
- the inventors have demonstrated that the targeting of platinum complexes, in particular cisplatin, is possible via high density lipoproteins (HDL) but also via low density lipoproteins (LDL).
- HDL high density lipoproteins
- LDL low density lipoproteins
- the targeting of platinum complexes, in particular cisplatin, by lipoproteins makes it possible to improve the efficacy of the anti-tumor response while reducing the toxicity associated with the use of the complexes. platinum.
- Platinum complex-loaded lipoproteins make it possible to effectively target different cell types.
- the modified HDL and LDL-type lipoproteins make it possible to target the macrophages and the lipoproteins of the charged LDL type make it possible to target the tumor cells.
- the targeting of platinum complexes, in particular cisplatin, by lipoproteins makes it possible to activate the macrophages more and to target the tumor cells in comparison with non-vectorized platinum complexes.
- the use of both platinum-complex-loaded LDL lipoproteins and the use of platinum complex-loaded HDL lipoproteins or modified platinum-complex-loaded LDL lipoproteins or their mixture makes it possible to provide a synergistic effect. and thus to improve anti-tumor efficacy by specifically and simultaneously targeting two cell types.
- the combined use of cisplatin-loaded LDL lipoproteins and the use of platinum complex-loaded HDL lipoproteins or modified platinum-complex-loaded LDL lipoproteins or their mixture makes it possible to specifically target both tumor cells and macrophages. This use therefore makes it possible to exert a more potent cytotoxic effect and to reinforce the immune response via the activation of macrophages while decreasing the toxicity associated with the use of the platinum complex alone.
- FIG. 1A Vectorization of cisplatin
- Figure 1B Evaluation of cisplatin exchange between charged LDL / HDL and native LDL / HDL
- Figure 2A Effect of vectorization of cisplatin on tumor cells
- Figure 2C Effect of vectorization of cisplatin on macrophages (with oxidized LDL)
- Figure 3 Study of the activity of LDLs loaded with cisplatin and HDLs loaded with cisplatin on cancer cells and on macrophages in tumor extracts
- Figure 4 Vectorization of cisplatin by LDL - improvement of tumor efficiency - in vivo
- Figure 4A Evolution of tumor size as a function of time
- Figure 5 Vectorisation of cisplatin by LDL - reduction of in vivo toxicity
- Figure 5A Effect of cisplatin vectorization by LDL - tumor volume
- Low density lipoproteins and high density lipoproteins were isolated from healthy donor plasma by a potassium bromide differential density gradient centrifugation separation technique (KBr) (Redgrave Technique, 1975). After extraction, the lipoproteins were adjusted to a cholesterol concentration of 1 mM. ⁇ of a solution of cisplatin (at 10 mg / ml, in saline) was then added for an expected final concentration of 1 mg / ml. In order to allow the combination of cisplatin with lipoproteins and to eliminate the unbound fraction of cisplatin, the samples were incubated for 3 hours at 37 ° C. and then subjected to two successive dialyses (compared with 1000 times the volume of phosphate buffered saline).
- KBr potassium bromide differential density gradient centrifugation separation technique
- cisplatin concentration was determined by graphite furnace absorption spectrometry (GF-AAS) ( Figure 1A).
- the concentration of cisplatin in LDL is 0.3 mg / mL of final solution, ie the solution obtained by adding lipoproteins in a solution of phosphate buffered saline (PBS) containing cisplatin.
- the cisplatin concentration in HDL is 0.5 mg / mL of said final solution.
- LDL containing vectorized cisplatin (LDL-C18) were incubated for 18 hours at 37 ° C with native HDL (HDL 0). Similarly, HDL containing vectorized cisplatin (HDL-C18) were therefore incubated for 18 hours at 37 ° C. with native LDL (LDL 0).
- lipoprotein fractions were extracted by a potassium bromide (KBr) differential density gradient ultracentrifugation separation technique.
- KBr potassium bromide
- the amount of cisplatin bound to the different fractions was then determined by graphite furnace absorption spectrometry (GF-AAS).
- Adenocarcinoma cells and macrophages are mostly found in colon tumors.
- SW480 colorectal cancer lines were treated for 48 hours with native LDL (LDL 0), native HDL (HDL 0), non-vectorized cisplatin, LDL-Cis or HDL-Cis (final concentration of cisplatin: 25 ⁇ l).
- LDL 0 native LDL
- HDL 0 native HDL
- non-vectorized cisplatin LDL-Cis
- HDL-Cis final concentration of cisplatin
- human macrophages were differentiated from monocytes into macrophages of alternating phenotype M2 (pro-tumoral). These macrophages were then stimulated for 2 hours with native LDL (LDL 0), native HDL (HDL 0), non-vectorized cisplatin, LDL-Cis or HDL-Cis (final cisplatin concentration: 25 ⁇ ).
- ROS reactive oxygen species
- DHE Dihydroethidium
- LDLox + Cis oxidized LDL lipoproteins loaded with cisplatin
- LDLox + Cis induce a macrophage activation greater than that induced by HDL-Cis.
- the oxidized LDLs were obtained by incubation of native LDL (cholesterol, 1 mM) for 24 hours at 37 ° C in the presence of copper sulphate (5 ⁇ l). After oxidation, the oxidized LDLs are dialyzed in PBS buffer.
- This test aims to verify that the vectorization of cisplastin makes it possible to reduce the general and renal toxicity in comparison with non-vectorized cisplatin.
- cisplatin administered at a dose of 20 mg / kg for 3 days to our murine model previously described, ie the ectopic (subcutaneous) allograft model of CT-26 colonic tumors in the BALB-C mouse, (validated protocol for cisplatin-induced nephrotoxicity).
- non-vectorized cisplatin induced, on the one hand, a weight loss of nearly 15% compared to the control sample (CTL).
- CTL control sample
- histological analyzes not shown
- non-vectorized cisplatin induces a strong nephrotoxicity which is characterized by de-epithelializations, the presence of hyaline bodies and phenomena of necrosis and apoptosis.
- no weight loss or signs of nephrotoxicity were observed for the cisplatin group vectorized by LDL (see Figure 5B).
- the vectorization of cisplatin reduces the toxicity associated with the use of the latter in comparison with non-vectorized cisplatin.
- cisplatin vectorized by LDL causes apoptosis of the cells within the tumor but not that of the renal cells (histological analysis not shown).
- the use of vectorized cisplatin thus makes it possible to overcome the side effects associated with the use of non-vectorized cisplatin.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Optics & Photonics (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1654931A FR3051674B1 (fr) | 2016-05-31 | 2016-05-31 | Lipoproteines chargees en complexes de platine pour le traitement du cancer |
PCT/FR2017/051320 WO2017207897A1 (fr) | 2016-05-31 | 2017-05-29 | Lipoproteines chargees en complexes de platine pour le traitement du cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3463302A1 true EP3463302A1 (fr) | 2019-04-10 |
Family
ID=56511774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17730874.9A Withdrawn EP3463302A1 (fr) | 2016-05-31 | 2017-05-29 | Lipoproteines chargees en complexes de platine pour le traitement du cancer |
Country Status (4)
Country | Link |
---|---|
US (1) | US20190110990A1 (fr) |
EP (1) | EP3463302A1 (fr) |
FR (1) | FR3051674B1 (fr) |
WO (1) | WO2017207897A1 (fr) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001501173A (ja) * | 1996-08-23 | 2001-01-30 | アルザ コーポレイション | シスプラチン化合物を含有するリポソーム |
US6511676B1 (en) * | 1999-11-05 | 2003-01-28 | Teni Boulikas | Therapy for human cancers using cisplatin and other drugs or genes encapsulated into liposomes |
DE10117043A1 (de) * | 2001-04-05 | 2002-11-07 | Gerhard Puetz | Verfahren zur Eliminierung von potentiell toxischen und/oder schädlichen Stoffen |
US20090110739A1 (en) * | 2007-05-15 | 2009-04-30 | University Of North Texas Health Science Center At Forth Worth | Targeted cancer chemotherapy using synthetic nanoparticles |
US9889092B2 (en) * | 2013-03-13 | 2018-02-13 | The Board Of Regents Of The University Of Texas System | Low density lipoprotein nanocarriers for targeted delivery of omega-3 polyunsaturated fatty acids to cancer |
-
2016
- 2016-05-31 FR FR1654931A patent/FR3051674B1/fr not_active Expired - Fee Related
-
2017
- 2017-05-29 EP EP17730874.9A patent/EP3463302A1/fr not_active Withdrawn
- 2017-05-29 WO PCT/FR2017/051320 patent/WO2017207897A1/fr unknown
- 2017-05-29 US US16/305,999 patent/US20190110990A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20190110990A1 (en) | 2019-04-18 |
WO2017207897A1 (fr) | 2017-12-07 |
FR3051674A1 (fr) | 2017-12-01 |
FR3051674B1 (fr) | 2019-11-08 |
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