WO2008026224A2 - Nouvelles nanoparticules d'apotransferrine/transferrine, composition pharmaceutique contenant ces nanoparticules et procédés de préparation de celles-ci - Google Patents

Nouvelles nanoparticules d'apotransferrine/transferrine, composition pharmaceutique contenant ces nanoparticules et procédés de préparation de celles-ci Download PDF

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WO2008026224A2
WO2008026224A2 PCT/IN2007/000369 IN2007000369W WO2008026224A2 WO 2008026224 A2 WO2008026224 A2 WO 2008026224A2 IN 2007000369 W IN2007000369 W IN 2007000369W WO 2008026224 A2 WO2008026224 A2 WO 2008026224A2
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apotransferrin
transferrin
drug
nanoparticles
pharmaceutical composition
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PCT/IN2007/000369
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WO2008026224A3 (fr
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Anand Kumar Kondapi
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University Of Hyderabad
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • 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
    • 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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • A61K9/5192—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This invention relates to novel nanoparticles of apotransferrin / transferrin useful for preparing a pharmaceutical composition facilitating easy delivery of the drug contained therein, a process for producing said nanoparticles, a pharmaceutical composition containing a drug and said nanoparticles and processes for its preparation.
  • the nano particles of apotransferrin / transferrin can be conjugated with any reporter like Fluorescein isothiocyante or Rhodamine isothiocyante or any other (fluorescent agents) and can be used as probes for monitoring their cellular localisation.
  • the Composition is useful for the delivery ⁇ of drugs especially cancer drugs and neurq-active/agents-
  • transferrin receptors Binding of the proteins apotransferrin / transferrin with cells requires transferrin receptors.
  • the amount of transferrin receptors present on the surface of the cells is regulated by two factors (i) the concentration of iron in the cell and (i ⁇ ) cell growth. These receptors are highly expressed by tissues having high metabolic activity such as brain as well as those which are in .active growth such as in cancer cells. Hence, transferrin receptors are widely tested and accepted target for delivery of drugs to cancer, brain and other infected and disease demanding iron metabolism.
  • the ligands that have been well tested as carriers' of drug through transferrin receptor mediated endocytosis are soluble Transferrin, apotransferrin, anti-transferrin receptor antibody (OX-26). ' , •
  • US patent no 4,886,780 describes a process for conjugating apotransferrin with antitumour agents. This process deals with chemical conjugation of antitumour agents with apotransferrin by cross linking employing glutaraldehyde. The problem with this method is the kinetics of release of the drug from covalently linked apotransferrin.Thus efficiency of drug delivery is low as chemical bond has to be broken to release the adriamycin (drug).
  • US patent no 7,001,991 describes a process for target delivery of bioaffecting compounds for the treatment of cancer.
  • the process deals with glutaraldehyde conjugation of anticancer agents with bioaffecting materials such as transferrin a homogenous conjugates comprising a target agent linked to bio effecting material via a glutaraldehyde linker, where in said bio effecting material is doxorubicin and said targeting agent is transferrin where in said homogenous conjugate is free of dimmers, trimers and aggregates where in said conjugate has a doxorubicin: transferrin ration is i
  • the antibody / transferrin / apotransferrin specifically binds to transferrin receptor and receptor mediated endocytosis lead to the internalization of the drug conjugates.
  • drug which is directly conjugated to the antibody/. transferrin / apotransferrin
  • the conjugated chemical linkage required to be cleaved for the release of the drug Such cleavage takes place in liposomes in a pH dependent manner.
  • the release of drug through this mode is dependent on the proportion of the drug entered into the pell, proportion of the drug conjugates incorporated into the liposomes and the kinetics of drug cleavage from the chemically conjugated carrier comprising antibody and transferrin/apotransferrin
  • Some drugs may undergo inactivation/ degradation due to hydrolysis conditions of liposomes leading toudecrease in effective drug concentration. Conjugate part of the drug delivery system ⁇ remains in the cells and if it is not metabolized, may form burden to the cells and may induce toxicity. Due to irreversible binding of the conjugated antibody/ transferrin/ apotransferrin to drug, they compete out soluble transferrin binding, thus the iron transport is drastically inhibited, which would lead to iron depletion and anemia.
  • U.S patent no 6,576,221 describes a process for making iron containing nanoparticles with double coating and their use in diagnosis and therapy.
  • a method for diagnosing atherosclerosis comprising MR imaging of a patient having been administered nano particles comprising an iron- containing cores a primary synthesis polymer coat and a targeting polymer secondary coat. These nano particles having an iron-containing core of magnetite or maghemite, a primary coat of a synthesis polymer of dextrans or dextran derivatives and a secondary coat of a targeting polymer non-covalently bonded to the synthesis polymer, wherein the targeting polymer is not exposed to synthesis conditions.
  • Iron containing core is layered by a primary synthetic layer of polymer and then by second layer of apotransferrin and a pharmaceutical adjuvant.
  • the drawback of the process is that the polymer and the iron core will remain in the cell and form a source of toxicity which is not advisable
  • TrR antibodies transferrin / apotransferrin chemical conjugated to liposomes or polymers or micro spheres loaded with drug (Refer to Zhang H, Mardyani S, Chan WC, Kumacheva E. Design of biocompatible chitosan microgels for targeted pH-mediated intracellular release of cancer therapeutics. Biomacromolecules. 2006 May;7(5):1568-72. and Olivier JC, Huertas R, Lee HJ, Calon F, Pardridge WM. Synthesis of pegylated immunonanoparticles.,. Pharm Res. 2002 Aug;19(8):1137-43)
  • TrR antibody (0X26) / transferrin / apotransferrin were conjugated directly or through biotin /avidin coupling to liposome/ polymer micro spheres composing PEG or carbohydrates (Gosk S, Verioloen C, Storm G, Moos T. Targeting anti-transferrin receptor antibody (0X26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion,.,/ Cereb Blood Flow Metah. 2004 Nov;24(11):1193-204).
  • the conjugated TrR antibody/ transferrin/ apotransferrin can mediate the binding of liposome/ microspheres to transferrin receptor and intake occurs through receptor-mediated endocytosis (Dass CR, Choong PF . Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: Lessons from gene therapy,. Cancer Cell Int. 2006 Jun 23;6(1):17).
  • the drug can be released into cytosol directly.
  • the left over compounds of delivery system such as TrR antibody (0X26) / transferrin / apotransferrin conjugated liposome/ micro spheres will remain in the cell and degradation is slow and they form potential cytotoxicity to the cells due to 1 high metabolic stress on the cell for their degradation.
  • the extent of drug release from such liposome may not also be efficient. Due to irreversible binding o ⁇ me . conjugated aniiDo ⁇ yr transferrin / apotransferrin to liposome/ micro spheres, they compete out soluble transferrin binding, thus the iron transport is drastically inhibited, which would lead to iron depletion and anaemia.
  • Apotransferrin is highly abundant protein present in the cells and its receptors are ' abundant in cells having high metabolic activity since cancer, infectious, cells expresses high proportion transferrin receptors hence drugs targeting to the cells can be highly localized in the cells.
  • the cells in brain also over expresses transferrin receptors, in view of importance of apotransferrin/ transferrin in drug targeting led us to choose the protein as a targeting agent.
  • the prior art uses the cross linking of apotransferrin with the bioactive compound since cross li ⁇ kihglmits the activity of drug and removal of cross linking is rate limiting-an the present- invention-- provides to form apotransferrin complexes such complex formation was enhanced through formation of a insoluble particles.
  • Series of studies and investigations on the conditions to form such particles has lead to the production of homogenous particles containing apotransferrin and bioactive material. Since the apotransferrin has not cross linked with bioactive material the release of bioactive material may not be rate limiting and become instantaneous and release into the cell.
  • novel nano particles of apotransferrin / transferrin provided by the present invention would help providing a non-toxic delivery system.
  • the main objective of the present invention is to provide novel nanoparticles of apotransferrin / transferrin which are useful for preparing a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • Another objective of the present invention is to provide novel nanoparticles of apotransferrin / transferrin having sizes, in diameter, in the range of 20 to 30 nanometers which are useful for preparing a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • Yet another objective of the present invention is to provide a process for the preparation of the novel nanoparticles of apotransferrin / transferrin which are useful for preparing a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • Still another objective of the present invention is to provide novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin which is useful for preparing a pharmaceutical composition facilitating easy delivery of the drug contained in the composition.
  • Yet another objective of the present invention is to provide a novel pharmaceutical composition in which apotransferrin / transferrin is readily available after the delivery of the drug contained in the composition.
  • Another objective of the present invention is to provide a novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin which do not induce any cytotoxicity on the patients.
  • Another objective the present invention is to provide a process for the preparation of novel pharmaceutical compositiofi " ⁇ containing a drug- and the novel- nanoparticles'of-apotransferrirW- transferrin which is useful for the preparation of a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • the present invention is to provide a process for the preparation of novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin which is useful for target delivery of the drug without employing chemical conjugation of the drug and apotransferrin / transferrin.
  • the nanoparticles of apotransferrin / transferrin present in the composition can bind to transferrin receptors and drug enters all transferrin receptor expressing cells, the extent of localization of particles (along with the drug) is high in transferrin receptor over expressing cells such as cancer cells, brain and other infections and diseases where iron transport is very active.
  • the drug can be selectively targeted to cancer, brain and other infections /diseases through these novel nano particles of apotransferrin / transferrin.
  • nanoparticles of apotransferrin / transferrin is not hitherto known and we are the first to prepare such nanoparticles and our above mentioned findings are disclosed for the first time.
  • the invention disclosed in this application is novel
  • the present invention provides novel nanoparticles of apotransferrin / transferrin useful for the preparation of a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • novel nanoparticles of apotransferrin / transferrin having sizes in diameter in the range of 20 to 30 nanometers useful for the preparation of a pharmaceutical composition facilitating easy delivery of the drug contained in the composition
  • step (i) dissolving apotransferrin / transferrin in a solvent
  • step (ii. dispersing the solution obtained in step (i) in an oil at a temperature in the range of 4°C to 8°C
  • step (iii. sonicating the solution obtained in step (ii) in a sonicator using a probe by passing the pulse for 5-15 times with a gap of 1-5 minutes with each pulse of 15-45 seconds at 4°C to 8 0 C, iv. freezing the sonicated solution obtained in step (iii) for at least 10 minutes below minus) -
  • the invention ratio of the solution obtained and the oil used in step (ii) is at least 1 : 75.
  • the oil which can be used in step (ii) may be selected from olive oil and any vegetable oil such as olive oil, castor oil, peanut oil.
  • the solvent for dissolving apotransferrin/transferrin is selected from, Phosphate buffer saline or Tris buffer saline
  • the pulse amplitude of sonication used in step (iii) ranges from 2-6 microns and the probe used is medium short probe (1 cm diameter probe supplied by MSE Instruments, UK cat No PG43301).
  • the time period of sonication pulse is preferably 30 seconds.
  • step (iv) the sonicated solution is freezed immediately.
  • the centrifugation in step (v) may be carried out at least 5000 rpm.
  • step (v) The dispersion of the particles in step (v) may be done immediately after washing in ice cold ether or any oil miscible solvent. * '
  • a novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin facilitating easy delivery of the drug contained in the composition
  • a novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin in which apotransferrin /transferrin is readily available after the delivery of the drug
  • a novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin, which do not induce any cytotoxicity to the patients.
  • drugs can be used in the pharmaceutical composition of the present invention, in particular, the drugs selected from Antibiotics, anti cancer agents, neuroactive agents, Proteins, Antibodies, DNA and the like may be used.
  • Another embodiment of the present invention is to provide a process for the preparation of novel pharmaceutical composition containing a drug and the novel nanoparticles of apotransferrin / transferrin which is useful for preparing a pharmaceutical composition facilitating easy delivery of the drug which comprises, (i) dissolving apotransferrin / transferrin in a solvent, (ii) dissolving the desired drug in a solvent,
  • step (iii) mixing the solutions obtained in steps (i) and (ii) gradually at a temperature in the range of 4°C-8°C, (iv) dispersing the mixture obtained in step (Hi) , in an oil at a temperature in the range of 4°C to
  • step (v) sonicating the solution obtained in step (iv) in a sonicator using a probe by passing the pulse for 5-15 times with a gap of 1-5 minutes with each pulse of 15-45 seconds at 4°C to 8 0 C 1 '
  • step (vi) freezing the sonicated solution obtained in step (v) for atleast Klminutes below -20 0 C and incubating in ice for a period in the range of 4-8 hours, ' (vii) separating the drug encapsulated nano particles of apotransferrin / transferrin from free protein and free drug and oil by centrifugation for a period in the range of 10-20 minutes, (viii) discarding the supernatant- and' washing the drug encapsulated in nanoparticles of apotransferrin / transferrin repeatedly with ice cold diethyl ether or any oil miscible solvent- and (ixp dispersing " the dr ⁇ crencapsulated in nanoparticles of apotransferrin / transferrin in- saline or buffer and filtering.
  • the solvent for dissolving apotransferrin/transferrin is selected from, Phosphate buffer saline or Tris buffer saline
  • the drug in step (ii) may be dissolved preferably in which it is soluble in the same volume of the solvent used in step (i).
  • the solvent used in step (ii) may be selected from water, DMSO (dimethyl sulphoxide) etc.
  • the ratio of the solution obtained in step (iv) and the oil used is at least 1:75.
  • the oil used in step (iv) may be selected from olive oil or any vegetable oil such as olive oil / castor oil / peanut oil.
  • step (v) the pulse amplitude of sonication used ranges from 2-6 microns and the probe used in sonication is medium short probe (1 cm diameter probe supplied by MSE Instruments, UK cat No PG43301 or its equivalents in specification), the time period' of sonication pulse used is preferably 30 seconds. . . , '
  • step (vi) the sonicated is freezed immediately and the centrifugation in step (vii) is carried out at atleast 5000 rpm.
  • step (viii) the dispersion of the drug encapsulated in nanoparticles of apotransferrin/transferrin may be done immediately after washing in ice cold ether or any oil miscible solvent.
  • Figure 1 Apotransferrin Nanoparticles: Characterization of apotransferrin nanoparticles by scanning electron microscope.
  • Figure 2 Apotransferrin Nanoparticles stimulates cellular proliferation.
  • Figure 3 Apotransferrin Nanoparticles: red fluorescent color fluorescent apotransferrin 1 nanoparticles localized into the cells. ,
  • FIG. 4 Transferrin Nanoparticles: 1 Characterization of transferrin nanoparticles by scanning electron microscope.
  • TTaff ⁇ particles localized into the cells.
  • Figure 7 Doxorubicin Nanoparticles: Characterization of apotransferrin Doxorubicin ⁇ nanoparticles by scanning electron microscope.
  • Figure 7A Doxorubicin Nanoparticles: Characterization of apotransferrin Doxorubicin , nanoparticles by atomic force field ' microscope.
  • Figure 8 Action of Doxorubicin Nanoparticles on cell proliferation.
  • Figure 9 Doxorubicin apotransferrin nanoparticles treated rat.
  • Figure 10 Azalactone Ferrocene Nanoparticles: Characterization of apotransferrin
  • Azalactone Ferrobene nanoparticles by scanning electron microscope.
  • Figure 11 Action of Azalactone Ferrocene Nanoparticles on cell proliferation.
  • Figure 12 Rat 2 of 6 Aza treated. ,
  • Figure 14 Action of apotransferrin Mitomycin Nanoparticles on pell proliferation.
  • Figure 15 lriotecan hydrochloride trihydrate loaded Nanoparticles: Characterization of apotransferrin lriotecan hydrochloride trihydrate nanoparticles by scanning electron microscope.
  • Figure 16 Action of apotransferrin lriotecan hydrochloride. trihydrate Nanoparticles on cell proliferation.
  • Figure 17 Paclitaxel loaded Nanoparticles: Characterization of apotransferrin Paclitaxel nanoparticles by scanning electron microscope.
  • Figure 18 Action of apotransferrin Paclitaxel Nanoparticles on cell proliferation
  • Figure 19 Gemcitabine hydrochloride loaded Nanoparticles: Characterization of , apotransferrin Gemcitabine hydrochloride nanoparticles by scanning electron microscope. T/IN2007/000369
  • Figure 20 Action of apotransferrin Gemcitabine hydrochloride Nanoparticles on cell proliferation.
  • Figure 21 Bleomycin loaded Nanoparticles: Characterization of apotransferrin Bleomycin , nanoparticles by scanning electron microscope,
  • Figure 22 Action of apotransferrin Bleomycin Nanoparticles on cell proliferation.
  • FIG. 23 Etoposide Nanoparticles: Characterization of apotransferrin Etoposide nanoparticles by scanning electron .microscope.
  • Figure 24 Action of apotransferrin Etoposide Nanoparticles on cell proliferation.
  • Figure 25 Etoposide Apotransferrin Nanoparticles treated rat.
  • Figure 27 Transferrin Doxorubicin Nanoparticles: Characterization of Transferrin doxorubicin nanoparticles by scanning electron microscope.
  • Apotransferrin/transferrin is very stable protein and is present in high concentrations in human serum. It can be easily isolated. According to the process of the present invention, no chemical modification of the drug is required.
  • Thei scholar can be directly incorporated into the nanoparticles of apotransferrin/ transferrin through adsorption, absorption and occlusion during the particle formation.
  • the resulting composition can be used to for the delivery of the drug contained in the composition to treat diseases due to cancer, brain and other infectious and diseases in which transferrin receptor is over expressed .
  • nanoparticles apotransferrin/ transferrin can bind to' transferrin receptors and the cpmposition of the present invention enters all transferrin receptor expressing cells.
  • the extent of localization of particles (along with drug) is high in transferrin receptor overexpressing cells such as cancer cells, brain and other infections and diseases where iron transport is very active.
  • active ingredient can be selectively targeted to cancer, brain and other infections/diseases through these particles. . . •
  • the process of the apotransferrin/transferrin nano particle entry involves binding of the particle to transferrin receptors followed by entry through receptor mediated endocytosis.
  • the protein in the particle is undergoes molecular changes leading to the release of the active ingredient into the cytosol.
  • the apotransferrin/transferrin is converted to soluble from and the soluble apotransferrin/transferrin undergoes recycling.
  • the apotransferrin/transferrin is recycled, it does not possess any toxicity unlike in other delivery systems tested for transferrin receptor specific targeting rather the present delivery system will be supportive to cell.
  • the particles are not required to enter sub-organelles forrelease of active ingredient.
  • the drug After the release of the drug rest of apotransferrin/transferrin is available for recycling for iron 5 transport for the cell, thus increase iron intake and associated metabolic activation and associated active ingredient action. Thus the risk of iron depletion and activation resistance mechanism can be avoided by using the, composition of the present invention. If use is made of soluble apotransferrin/transferrin method, the drug requires iron or iron like center for binding to the active site of apotransferrin/transferrin and soluble drug bound to apotransferrin/transferrin may undergo
  • the nanoparticles of apotransferrin/transferrin present in the ⁇ composition is insbl ⁇ blerhence, " it cannot " participate- in- soluble -apotransferrin and- free iron- equilibria, hence cannot be destabilized in vivo.
  • apotransferrin 25 mg was prepared in 100 ⁇ l of phosphate buffer saline and incubated on ice for 5 min. Cold apotransferrin solution is slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • FITC fluoresceine isothiocyanate
  • transferrin nano particle — - 25 mg of a solution of transferrin was prepared in 10O ⁇ l of phosphate buffer saline and incubated on ice for 5 rhin. Cold transferrin solution is slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • transferrin in oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap. After sonication of the ojive ' oil containing transferrin, the resulting mixture was immediately frozen in liquid nitrogen at -
  • particles of transferrin obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained transferrin nano particles. These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • the nano particles of transferrin are characterized as 40 to 50 nano meters as shown in Fig 4. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles stimulate cellular proliferation as shown in Fig 5 and helps in tissue regeneration.
  • Fluorescence analysis for the presence of transferrin Protein was done using FITC (fluoresceine isothiocyanate).
  • FITC fluoresceine isothiocyanate
  • the FITC labeled protein was used to prepare transferrin protein particles and such particles were used to monitor the localization of drug in cells and organelles using the laser confocal microscope with the FITC excitation and emission.
  • the results of these studies show that the transferrin nanopartciles are localized in cytosol of the cells (Fig 6).
  • Example-3 COMPOSITION CONTAINING DOXORUBICIN HYDROCHLORIDE-AND APOTRANSFERRIN NANO PARTICLES:-
  • Doxorubicin hydrochloride in 100 ⁇ l of solvent in which it is soluble in this case the solvents used was phosphate buffer saline and incubated in ice for 5 min. the mixture of apotransferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with, continuous dispersion by
  • ThlTpafticle formationl)f ⁇ apo " transferrin-Doxorubicin " hydrochloride in- oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 , seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap ⁇
  • the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The 1 Particles formed were pelleted by spinning at 6000 rpm for 10 minutes. The.
  • pellets of the composition of nano particles of apotransferrin and Doxorubicin hydrochloride obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline .
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- Doxorubicin hydrochloride nano particles. These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below 0°C temperature.
  • the nano particles of apotransferrin- Doxorubicin hydrochloride were characterized as 68 to 75 nano meters as shown in fig 7 & 7 A . These nano particles were stable in water and got dissociated in acidic conditions (less than pH 3). These particles inhibited proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell line as shown in fig 8. And these particles upon injecting into the hepatoma bearing rat intra peritonially regressed cancer in rat ascetic hepatoma model as shown in Fig 9. The regression was complete, rat did not show any reappearance of cancer out of 12 rats tested in contrast to the results of soluble apotransferrin mediated drug delivery as shown in Fig 9.
  • the particles of the apotransferrin-AZALACTONE FERROCENE in oil phase was initiated by sonication using a medium short probe at pulse_with amplititude of 5 microns and time period for 30 seconds wltrra " ⁇ gap ⁇ of ⁇ 1 " minute at-4°Cr ⁇ This-step ⁇ s repeated-15-times to allow-15 pulses with 1 minute gap.
  • the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • the pellets of the composition of nano particles of apotransferrin and v obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- AZALACTONE FERROCENE nano particles.
  • These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • the nano particles of apotransferrin- AZALACTONE FERROCENE were characterized as ⁇ 68 nanometers as shown in Fig 10. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell line as shown in fig 11A, 11B, 11C, & 11 D. These particles upon injecting into the hepatoma bearing rat intra peritonially regressed cancer in rat ascetic hepatoma model as shown in fig 12. The regression was complete, rat did not show any reappearance of cancer out of 12 rats tested in contrast to the results of soluble apotransferrin mediated drug delivery
  • Example 5 COMPOSITION CONTAINING MITOMYCIN NANO PARTICLES: AND APOTRANSFERRIN NANOPARTICLES - 25 mg of apotransferrin in 100 ⁇ l of phosphate buffer saline was slowly mixed with the 3.34 mg of MITOCMYCIN in 100 ⁇ l of solvent in which it is soluble, in this case the solvents used was in phosphate buffered saline or DMSO and incubated in ice for 5 min. the mixture of apotransferrin • and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the apotransferrin-MITOCMYCIN in oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap. After sonication of the olive oil containing apotransferrin- MITOCMYCIN the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • ThT ⁇ peirets ⁇ of the composition " of Tia " nxrparticles ⁇ of " apotransferrin-and-MIT ⁇ GMYGIN-obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline .
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- MITOCMYCIN nano particles. These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature:
  • nano particles of apotransferrin- MITOCMYCIN were characterized as 88 to 95 nano meters as shown in Fig 13. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell line as shown in Fig 14.
  • the particle of the apotransferrin- IRINOTECAN HYDROCHLORIDE IN oil phase was initiated by sonication using a maximrfr short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap.
  • the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • pellets of the composition of nano particles of apotransferrin and IRINOTECAN HYDROCHLORIDE obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether. The pellets are immediately dispersed thoroughly by manual
  • micron filter and the filtrate obtained contained apotransferrin- IRINOTECAN HYDROCHLORIDE nano particles. These nano particles can be stored for, one week at 4 0 C and can be stored for more than a month at below 0 0 C temperature.
  • nano particles of apotransferrin- IRINOTECAN HYDROCHLORIDE ARE characterized as -81 nano meters as shown in Fig 15. These nano particles are stable in water and get dissociated in acidic conditions(less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma,
  • apotransferrin in 100 ⁇ l of phosphate buffer saline was slowly mixed with the 8.53 mg of PACLITAXEL in 100 ⁇ l of solvent in which it is soluble, in this case .the solvents used was in 20 DMSO and incubated in ice for 5 min. the mixture of apotransferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the apotransferrin-PACLITAXEL in oil phase was initiated by sonication using a 25 medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap.
  • the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 rhin. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • the pellets of the composition of nano particles of apotransferrin and PACLITAXEL obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether. The pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline . The dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- PACLITAXEL nano particles. These nano particles can be stored for one week at 4 0 C and can be 35 stored for more than a month at below O 0 C temperature.
  • the nano particles of apotransferrin- PACLITAXEL ARE characterized as 74 to 82 nano meters as shown in Rg 17. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell line as shown in Fig 18.
  • GEMCITABINE HYDROCHLORIDE AND APOTRANSFERRIN NANO PARTICLES 25 mg of apotransferrin in 100 ⁇ l of phosphate buffer saline was slowly mixed with the 2.99mg of GEMCITABINE HYDROCHLORIDE in 100 ⁇ l of solvent in which it is soluble, in this case the solvents used was in phosphate buffered saline or DMSO and incubated in ice for 5 min. the mixture of apotransferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the apotransferrin- GEMCITABINE HYDROCHLORIDE in oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap. After sonication of the olive oil containing apotransferrin- GEMCITABINE
  • HYDROCHLORIDE the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes. The pellets of the composition of nano particles of apotransferrin and GEMCITABINE HYDROCHLORIDE obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- GEMCITABINE HYDROCHLORIDE nano particles. These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • nano particles of apotransferrin- GEMCITABINE HYDROCHLORIDE are characterized as 74 to 88 nano meters as shown in Fig 19. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell line as shown in Fig 20.
  • the particle of the apotransferrin- BLEOMYCIN in oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 1 minute gap. After sonication of the olive oil containing apotransferrin- BLEOMYCIN the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • pellets of the composition of nano particles of apotransferrin and BLEOMYCIN obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline The dispersed
  • BLEOMYCIN nano particles These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • nano particles of apotransferrin- BLEOMYCIN are characterized as ⁇ 81 nano meters as shown in Fig 21. These nano particles are stable in water and get dissociated in acidic conditions(less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, SupT1 T cell lymphoma cell lines as shown in Fig 22.
  • apotransferrin in 100 ⁇ l of phosphate buffer saline was slowly mixed with the 5.88 mg of ETOPOSIDE in 100 ⁇ l of solvent in which it is soluble, in this case the 'solvents used was in r phosphate buffered saline or DMSO and incubated in ice for 5 min. the mixture of apotransferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the apotransferrin- ETOPOSIDE in oil phase was initiated by sonication using a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 times to allow 15 pulses with 'i minute gap. After sonication of the olive oil containing apotransferrin- ETOPOSIDE the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • the pellets of the composition of nano particles of apotransferrin and ETOPOSIDE obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin- ETOPOSIDE nano particles. These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • the nano particles of apotransferrin- ETOPOSIDE are characterized as ⁇ 34 nano meters as shown in Rg 23. These nano particles are stable in, water and get dissociated in acidic conditions(less than pH 3). these particles inhibit proliferation of SKNSH neuroblastoma; SupT1 T cell lymphoma cell lines Fig 24. These particles upon injecting into the hepatoma bearing rat intra peritonially, regressed cancer in rat ascetic hepatoma model. The regression was complete, rat did not show any reappearance of cancer out of 12 rats tested in contrast to the results of soluble apotransferrin mediated drug delivery a shown in Fig 25.
  • apotransferrin in 100 ⁇ l of phosphate buffer saline was slowly mixed with the 3.71 mg of carboplatin in 100 ⁇ l of solvent in which it is soluble, in this case the solvents used was in phosphate buffered saline or DMSO and incubated in ice for 5 min. the mixture of apotransferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the apotransferrin- carboplatin in oil phase was initiated by sonication using, a medium short probe at pulse with amplititude of 5 microns and time period for 30 seconds with a gap of 1 minute at 4 0 C. This step is repeated 15 ' times to allow 15 pulses with 1 minute gap.
  • the resulting mixture was immediately frozen in liquid nitrogen at -196 0 C for 10 min. Then it was transferred to ice and incubated for 4 hours. The Particles formed were pelleted by spinning at 6000 rpm for 10 minutes.
  • the pellets of the composition of nano particles of apotransferrin and carboplatin obtained is decanted and was washed twice using 15 ml of ice cold diethyl ether.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained apotransferrin - carboplatin nano particles.
  • These nano particles can be stored for one week at 4 0 C and can be stored for more than a month at below O 0 C temperature.
  • These nano particles are stable in water and get dissociated in acidic conditions(less than pH 3).
  • These particles inhibit proliferation of S ⁇ pT1 T cell lymphoma cell lines Fig 26, showing that this method applicable to platinum containing drugs like carboplatin, oxaliplatin and cisplatin.
  • transferrin fn 100 ⁇ l of phosphate buffer saline was slowly mixed with the .5.3 mg of Doxorubicin hydrochloride in 100 ⁇ l of solvent in which it is soluble, in this case the solvents used was in phosphate buffered saline or DMSO and incubated in ice for 5 min. the mixture of transferrin and the drug was slowly added in steps of 0.01 ml to 15 ml of olive oil at 4 0 C with continuous dispersion by gentle manual vortexing.
  • the particle of the transferrin-Doxorubicin hydrochloride in oil phase was initiated by sonication using a medium short probe at pulse with amplititud&of 5 microns and time period for 30 seconds with a gap.of 1 minute at 4 0 C. This step is repeated 15 times to allow 15. pulses with 1 minute gap.
  • the pellets are immediately dispersed thoroughly by manual vortexing in 1 ml of phosphate buffered saline
  • the dispersed pellets were passed through the 0.2 micron filter and the filtrate obtained contained transferrin- Doxorubicin hydrochloride nano particles.
  • These nano particles can be stored , for one week at 4 0 C and can be stored for more than a month at below 0 0 C temperature.
  • the nano particles of transferrin- Doxorubicin hydrochloride are characterized as ⁇ 61 to 74 nano meters as shown in Fig 27. These nano particles are stable in water and get dissociated in acidic conditions (less than pH 3). These particles inhibit proliferation of SKNSH neuroblastoma, S SupT1 T cell lymphoma cell line as shown in Fig 28.
  • the procedure also applicable to drugs paclitaxal, irinotecan and etoposide etc..
  • Rat 1 control rat
  • Rat 1 untreated saline injected
  • Rat 2 (control nano particle)- azalactone loaded BSA particles are made and given dose to rat
  • Rat 3 control drug azalactone ferrocene ⁇ doxorubicin ⁇ etoposide
  • Rat 3 azalactone ferrocene ⁇ doxorubicin ⁇ etoposide alone treated 1 mg/ kg body weight
  • Rat 4 (experimental Drug (azalactone ferrocene ⁇ doxorubicin ⁇ etoposide)-apotransferrin nanoparticle treated) - azalactone ferrocene ⁇ doxorubicin ⁇ etoposide loaded apotransferrin nano particles are treated to rat
  • Effective dose ⁇ 0.5 mg of protein-azalactone ferrocene/doxorubicin/etoposide nano particles referred in Examples 3,4 and10, contain 125 microgram of a azalactone ferrocene/ doxorubicin/ etoposide containing particles are dispersed in-0.5 ml of PBS or TBS to 120-140 gmWistar rat.
  • Dosage schedule ⁇ one dose per day 10 days treated. Dose is given by intraperitoneally with insulin syringe
  • Effective dose 0.5 mg of protein-azalactone ferrocene /doxorubicin /etoposide nano particles referred in Examples 3,4 and 10, contain 125 microgram of a azalactone ferrocene/ doxorubicin/ etoposide containing particles are dispersed in 0.5 ml of PBS or TBS to 120-140 gm Wistar rat Advantages of the invention
  • the invention provides novel nanoparticles of apotransferrin / transferrin which are useful for incorporation into a pharmaceutical composition
  • the novel pharmaceutical composition containing a drug and the novel nanoparticles of0 ' apotransferrin / transferrin facilitates easy delivery of the drug at the specified target cell and helps localization of the drug in that cell. Since cancer cells are highly abundant in transferrin receptors, the drug get localized in these cells thus effecting their function and - . regressibn ' ⁇ f cancer: " ⁇ - - -• ⁇ . — -- • -- 5 4.
  • the protein apotransferrin / transferrin is readily available after the delivery of the drug contained in the composition, the available apotransferrin supports the cellular iron uptake and increases the metabolic activity of the cell.
  • the pharmaceutical composition does not induce any cytotoxicity on the patients. 0
  • composition is prepared without employing chemical conjugation of the drug and apotransferrin / transferrin.
  • the apotransferrin from blood of a cancer patient can be isolated and drug-apotransferrin5 ' nano particles can be- made and administered to the same patient to avoid any immunological problems.
  • This nano particle preparative method can also be applied to other protein or peptide ligands for which corresponding receptors are expressed on the surface of target cells.0 These proteins or peptide nano particles can be loaded with a specific drug for targeting to these cells.

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Abstract

La présente invention concerne de nouvelles nanoparticules d'apotransferrine/transferrine utilisées pour préparer une composition pharmaceutique permettant de faciliter l'administration du médicament qu'elle contient. Cette invention concerne également un procédé de production de ces nanoparticules et la composition pharmaceutique contenant ces nanoparticules. Les nanoparticules d'apotransferrine/transferrine peuvent être conjuguées à n'importe quel rapporteur, tel que l'isothiocyanate de fluorescéine ou l'isothiocyanate de rhodamine ou autres (agents fluorescents) et peuvent servir de sondes pour surveiller leur localisation cellulaire. La composition est utilisée pour administrer des médicaments, en particulier des médicaments anticancéreux et des agents neuroactifs.
PCT/IN2007/000369 2006-08-31 2007-08-28 Nouvelles nanoparticules d'apotransferrine/transferrine, composition pharmaceutique contenant ces nanoparticules et procédés de préparation de celles-ci WO2008026224A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103080129A (zh) * 2010-04-08 2013-05-01 巴塞尔大学医院 用于治疗和预防免疫重建炎症综合征（iris）的血浆衍生的免疫球蛋白
EP3252068A2 (fr) 2009-10-12 2017-12-06 Larry J. Smith Procédés et compositions permettant de moduler l'expression génique à l'aide de médicaments à base d'oligonucléotides administrés in vivo ou in vitro
CN112675149A (zh) * 2021-01-04 2021-04-20 中国人民解放军空军军医大学 负载环孢菌素a的高效脑靶向递药***的制备方法和应用
CN113456832A (zh) * 2021-06-28 2021-10-01 重庆医科大学国际体外诊断研究院 一种转铁蛋白修饰的包载抗体的纳米粒及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BELLOCQ, N.C. ET AL.: 'Transferrin-Containing, Cyclodextrin Polymer-Based Particles for Tumor-Targeted Gene Delivery' BIOCONJUAGET CHEMISTRY vol. 14, no. 6, November 2003, pages 1122 - 1132 *
SAHOO, S. K ET AL.: 'Efficacy of Transferrin-conjuagted Paclitxel-loaded Nanoparticles in a Murine Model of Prostate Cancer' INT. J. CANCER vol. 112, June 2004, pages 335 - 340 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3252068A2 (fr) 2009-10-12 2017-12-06 Larry J. Smith Procédés et compositions permettant de moduler l'expression génique à l'aide de médicaments à base d'oligonucléotides administrés in vivo ou in vitro
EP4089169A1 (fr) 2009-10-12 2022-11-16 Larry J. Smith Procédés et compositions permettant de moduler l'expression génique à l'aide de médicaments à base d'oligonucléotides administrés in vivo ou in vitro
CN103080129A (zh) * 2010-04-08 2013-05-01 巴塞尔大学医院 用于治疗和预防免疫重建炎症综合征（iris）的血浆衍生的免疫球蛋白
CN112675149A (zh) * 2021-01-04 2021-04-20 中国人民解放军空军军医大学 负载环孢菌素a的高效脑靶向递药***的制备方法和应用
CN112675149B (zh) * 2021-01-04 2022-09-16 中国人民解放军空军军医大学 负载环孢菌素a的脑靶向递药***的制备方法和应用
CN113456832A (zh) * 2021-06-28 2021-10-01 重庆医科大学国际体外诊断研究院 一种转铁蛋白修饰的包载抗体的纳米粒及其应用
CN113456832B (zh) * 2021-06-28 2023-06-30 重庆医科大学国际体外诊断研究院 一种转铁蛋白修饰的包载抗体的纳米粒及其应用

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