WO2009138806A1 - Nouvelles formulations de cocktail de liposomes contenant de la doxorubicine et de l’amiodarone, puissant inhibiteur de la résistance à plusieurs médicaments - Google Patents

Nouvelles formulations de cocktail de liposomes contenant de la doxorubicine et de l’amiodarone, puissant inhibiteur de la résistance à plusieurs médicaments Download PDF

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WO2009138806A1
WO2009138806A1 PCT/GR2008/000037 GR2008000037W WO2009138806A1 WO 2009138806 A1 WO2009138806 A1 WO 2009138806A1 GR 2008000037 W GR2008000037 W GR 2008000037W WO 2009138806 A1 WO2009138806 A1 WO 2009138806A1
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liposomes
amiodarone
doxorubicin
dox
cells
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PCT/GR2008/000037
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English (en)
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Theodossis Theodossiou
Maria Galanou
Constantinos Paleos
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Dendrigen S.A.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • This invention relates to the fields of biochemistry and medicine, and in particular to a novel liposomal formulation and process. More specifically, it relates to a liposomal cocktail formulation containing the multidrug resistance inhibitor amiodarone in the lipid bilayers and the chemotherapeutic agent doxorubicin in the aqueous cores and to its process of manufacture. This invention also relates to a liposomal amiodarone0 formulation having reduced toxicity enhanced ability to defeat MDR mechanisms in cells (in vitro) as well as in vivo.
  • MDR multidrug resistance
  • Pgp is not the only cause of MDR; many drug resistant cell lines do not exhibit elevated levels of Pgp and yet manage to withstand lethal doses of a wide range of5 natural product drugs (9-1 1). Some of these cell lines express upregulated levels of a second protein - member of the ABC superfamily- the MDR associated protein (MRP) (12-16). Much like Pgp, MRP seems to also act as a drug efflux pump (17), is mainly present in the plasma membrane too (17, 18) and has the ability to diminish intracellular drug levels against a concentration gradient (17).
  • MRP MDR associated protein
  • GSH reduced glutathione
  • glutathione S-transferase (19- 25) occurring in two steps: (a) formation of GSH S-conjugate with the drug and (b) removal of the toxic complex from the cell interior via a GSH S-conjugate export carrier, the GS-X pump (26) also known as multispecific organic anion transporter (MOAT) (27, 28).
  • MOAT multispecific organic anion transporter
  • doxorubicin which is a natural anthracycline glycoside antineoplastic antibiotic isolated from streptomyces peucetius. Its principle mode of action is through DNA intercalation and inhibition of both DNA and RNA synthesis (29-31) by the stabilization of topoisomerase II. (32).
  • MDR inhibitors such as cyclosporine A, verapamil, PSC 833 and amiodarone both in vitro and in vivo (36-39).
  • amiodarone originally an anti- arrythmic drug, has also been found to possess anti-inflammatory and anti-oxidative properties (40).
  • a pilot clinical study performed with the coadministration of amiodarone and infusional DOX has been performed (41), however it was inconclusive with respect to Pgp blocking due to the need of an alternative treatment plan design.
  • the therapeutic index of DOX was greatly increased with liposomal encapsulation.
  • Doxorubicin-loaded liposomes exhibit enhanced efficiency in some forms of cancer in comparison to free drug administration, as liposomes accumulate in the extracellular space of the target tumours through the enhanced permeability and retention effect (EPR) (42, 43), resulting in increased drug payloads delivered to the neoplastic formations.
  • EPR is attributed to the leaky vascular endothelial linings of growing neoplasias, leaving gaps in the endothelium of up to 800 nm in diameter, large enough to permit the extravasation of liposomes with diameters in the range of 100 nm (44).
  • liposome refers to unilamellar vesicles or multilamellar vesicles.
  • encapsulation refers to the incorporation of the amiodarone into the liposome membrane and of the doxorubicin to the aqueous cores.
  • the process of preparing the formulation embodied in the present invention is initiated with the preparation of a solution from which the liposomes are formed. This is done by weighing out a quantity of phosphatidylcholine, cholesterol , guanidinylated lipids and amiodarone, and dissolving them into an organic solvent, preferably chloroform and methanol in a 2:1 mixture.
  • the solution is evaporated to form a solid lipid phase such as a film or powder, for example, with a rotary evaporator, spray dryer or other means.
  • the film or powder is then hydrated with an aqueous solution containing doxorubicin having a pH ranging from about 4.5 to about 9.5 to form a liposome dispersion.
  • the preferred aqueous solution for purposes of hydration is a buffered solution such as 10 mM phosphate buffer, pH 7.4.
  • the lipid film or powder dispersed in buffer is heated from about 25° C. to about 65° C.
  • Multilamellar liposomes are formed by agitation of the dispersion, preferably through the use of a thin-film evaporator apparatus or through shaking or vortex mixing.
  • Unilamellar vesicles are formed by the application of an shearing force to an aqueous dispersion of the lipid solid phase, e.g., by sonication or the use of a homogenizing apparatus or an extruder such as a LiposoFast-Pneumatic extruder, Avestin Inc..
  • Shearing force can also be applied using ether injection, freezing and thawing, dialyzing away a detergent solution from lipids, or other known methods used to prepare liposomes.
  • the size of the liposomes can be controlled using a variety of known techniques including the duration of shearing force. Methods for the agitation or shearing of lipids to form multilamellar or unilamellar vesicles are known in the art and are not part of this invention per se.
  • Distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine (egg PC), hydrogenated egg phoshatidylcholine (HEPC) and hydrogenated soy phosphatidylcholine (HSPC) are the preferred phosphatidylcholines for use in the invention.
  • Other suitable phosphatidylcholines include those obtained from soy beans or other plant sources, or those that are partially or wholly synthetic, such as dipalmitoylphosphatidylcholine. All of these are commercially available.
  • Octadecylguanidine hydrochloride (ODG) and N-[3-(octadecylamino)propyl] guanidine hydrochloride (ODPG) are the preferred positively charged lipids for use in the invention.
  • Other positively charged lipids may be suitable for use either custom made or commercially available.
  • the preferred MDR inhibitor for use in the invention is amiodarone.
  • the preferred molar ratios for use with this invention are 0.076 mmol (3.8 x 10 "2 M) of PC, 0.038 mmol of cholesterol (1.9 x 10 "2 M) (molar ratio PC:CHOL 2: 1) and 0.0058 mmol (1.45 x 10 "3 M) ODG or ODPG.
  • Amiodarone may be added to the solution in 100, 200, 500 and 1000 ⁇ M final concentrations. The above concentrations are indicative and are by no means limiting.
  • Encapsulation of DOX into the liposomal core is performed during hydration of the lipid films with the buffer of choice (e.g. Phosphate Buffer Saline) containing DOX in 250, 500 and 1000 ⁇ M final concentrations preferably, without these concentrations being limiting. Removal of non-encapsulated DOX is achieved by size exclusion chromatography (e.g. Sephadex G-50). The elution is performed with phosphate buffer saline. The encapsulated DOX concentration can be determined by fluorescence or absorbance spectroscopy.
  • the buffer of choice e.g. Phosphate Buffer Saline
  • the preferred size of the liposomes is approximately 50 nm (radius).
  • the preferred percent entrapped amiodarone is 66% or greater, while the preffered DOX encapsulation percentage is 3.5% or higher.
  • Soybean hydrogenated phosphatidylcholine; nucleopore filters of 100 nm pore size were employed for liposome extrusion.
  • Octadecylguanidine hydrochloride (ODG) was prepared by the method reported in our previous study (54).
  • Cell culture Cells used in this study were the human prostate carcinoma cell line DU145. The cells were grown in RPMI 1640 with 10% fetal bovine serum (FBS), penicillin/streptomycin at 37 0 C in a 5% CO 2 humidified atmosphere. Cells were inoculated into either 96-well plates (3 ⁇ 10 4 cells/100 ⁇ l media/well) or 35mm dishes (0.5 ⁇ 10 5 cells/2 ml media /dish) 24 h before experiments.
  • FBS fetal bovine serum
  • PBS penicillin/streptomycin
  • amiodarone was also added to the solution in 100, 200, 500 and 1000 ⁇ M final concentrations.
  • the suspension obtained was extruded through two-stacked polycarbonate filters of 100 nm pore size. Twenty-seven cycles were applied at 60 0 C.
  • the encapsulated amiodarone concentration was determined by absorbance (vide infra).
  • Encapsulation of DOX into the liposomal core was performed during hydration of the lipid films with 4ml PBS containing DOX in 250, 500 and 1000 ⁇ M final concentrations. Removal of non-encapsulated DOX was achieved by size exclusion chromatography (Sephadex G-50). The elution was performed with PBS. The encapsulated DOX concentration was determined by fluorescence spectroscopy (vide infra). The DOX-amiodarone containing liposomal dispersions were diluted 1 :20 and filter-sterilized through 0.22 ⁇ m cellulose acetate filters prior to cell application.
  • Liposome size characterization Liposomes were characterized by dynamic light scattering (DLS). For the size determination of liposomes an AXIOS-150/EX (Triton Hellas) with a 30 mW He-Ne laser emitting at 658 nm and an Avalanche detector at right angles was employed. Ten microliters of liposomal dispersion were each time diluted to 0.99 mL of PBS. Ten measurements were collected per sample and the results were averaged.
  • DLS dynamic light scattering
  • Amiodarone encapsulation determination For the determination of amiodarone encapsulated in liposome lipid bilayers, a calibration absorbance curve of various amiodarone concentrations (0 to 50 ⁇ M) in methanol containing an amount of lipids and chloroform equivalent to that of 60 ⁇ l liposome dispersion, was constructed using a Cary 100 CONC UV-Visible spectrophotometer (Varian Inc) by each time registering absorbance at 240 nm. Aliquots (60 ⁇ l) of undetermined amiodarone encapsulation liposome dispersions were diluted to 3 ml of methanol to ensure complete liposomal membrane disruption and amiodarone release. The absorbance at 240 nm was registered at the same conditions applied to the calibration curve measurements and amiodarone concentration was each time extrapolated by fitting to the calibration curve.
  • DOX encapsulation determination For the determination of DOX encapsulated in liposome hydrophilic cores, the same procedure as with amiodarone was applied, employing however, fluorescence instead of absorbance. A calibration curve for various DOX concentrations (0 to 10 ⁇ M) was constructed using a Cary Eclipse fluorescence spectrophotometer (Varian Inc) by each time registering fluorescence intensity at 585 nm, following 490 nm excitation. DOX liposome encapsulation concentrations were each time extrapolated as per the protocol described for amiodarone (vide supra), adapted to the fluorimetric settings.
  • Calcein AM assay The effect of liposomal amiodarone on the multidrug resistance of DU 145 cells was initially assayed using calcein acetoxumethyl ester (calcein AM) as a substrate for MDR efflux activity.
  • calcein AM is a non fluorescent lipid soluble dye with the ability to rapidly permeate cellular plasma membranes. Once inside the cells the ester bonds are cleaved by endogenous esterases transforming calcein AM into hydrophilic and intensely fluorescent calcein.
  • MDR mechanisms extrude calcein AM from the plasma membrane reducing cytosolic accumulation of fluorescent calcein, while upon MDR defeat, calcein is well retained in the cytoplasm.
  • the assay was performed in two modes: (a) fluorescence microplate and (b) laser scanning confocal fluorescence microscopy imaging.
  • Amiodarone-DOX confocal microscopy Cells were prepared for confocal microscopy as above. On the day of the experiment, three cell groups were incubated for four hours with (i) control liposomes, (ii) liposomes containing DOX encapsulated in their cores (equivalent DOX incubation concentration ⁇ 3 ⁇ M) and (iii) liposomes with amiodarone encapsulated in their lipid bilayers and DOX in their aqueous centres (equivalent incubation concentrations: DOX ⁇ 3 ⁇ M and amiodarone -45 ⁇ M).
  • the cells were in all cases imaged with the ⁇ 63 oil immersion quartz objective of the same confocal system used for calcein imaging , in physiological saline. Excitation was facilitated by the 488 nm line of an argon-krypton laser (3% of total laser power) while DOX fluorescence was collected with the use of a dichroic filter centred at 585 nm (585 EFLP).
  • Mitochondrial redox function (translating directly to cytotoxicity) was assessed in all cell groups at 24, 48 and 72h following incubation via a standard XTT assay. This relies on the reduction of the tetrazolium salt to a formazan by mitochondrial matrix reductive enzymes. In non-redox competent mitochondria, e.g. uncoupled mitochondria or dead cells no formazan formation occurs.
  • the assay was carried out by adding 150 ⁇ l of complete media containing 50 ⁇ l XTT salts (1 mg/ml) and 1 ⁇ l phenazine methosulphate (0.383 mg/ml) to cells and incubating at 37 °C in a 5% CO2 atmosphere for 2 h.
  • Liposome characterization The liposomes produced were of similar sizes. More specifically their mean hydrodynamic radii as measured by DLS range from 40-55nm (80 - 1 10 nm diameter). The concentrations of encapsulated amiodarone in the lipid bilayer and DOX in the aqueous cores of the liposomes were determined as described earlier. A useful parameter regarding drug encapsulation in the liposomes under investigation is the encapsulation fraction:
  • f ENC is the encapsulation fraction
  • C E NC is the concentration of the drugs encapsulated in liposomes
  • Q NC is the concentration of amiodarone or DOX used to make the lipid films.
  • the average encapsulation fractions for DOX and amiodarone were found to be fTM « 3.5% and f r f" c « 66.5% respectively.
  • Fig. 2 A representative confocal image of a DU145 cell incubated with control liposomes for 4h and calcein AM during the final (fourth) incubation hour.
  • the image in Fig. 2B is characteristic of a cell incubated with amiodarone loaded liposomes (equivalent incubation concentration 17 ⁇ M).
  • cytosolic calcein fluorescence intensity There is a considerable difference in cytosolic calcein fluorescence intensity between the two images.
  • results of the microplate fluorometric assay are shown for cells incubated with liposomes of varying amiodarone content (equivalent incubation concentrations 0-17 ⁇ M) for one and a half hours, while 50 ⁇ l of 1 ⁇ M calcein AM were added to each well during the final half hour of incubation.
  • the results show a monotonous increase in calcein fluorescence for increasing liposomal amiodarone concentrations.
  • Liposomal amiodarone-DOX confocal microscopy Typical images of cells incubated with DOX loaded liposomes (equivalent incubation concentration 3 ⁇ M) for 4h are shown in Fig. 3 A (zoom 1) and 3C (zoom T).
  • the confocal images in Fig. 3B and C are representative of cells incubated with DOX-amiodarone loaded liposomes (equivalent incubation concentrations 3 and 45 ⁇ M respectively) for 4h (zoom 1 and 2 correspondingly).
  • DOX-amiodarone loaded liposomes equivalent incubation concentrations 3 and 45 ⁇ M respectively
  • Liposomal amiodarone-DOX cytotoxicity results on cell groups incubated with liposomes loaded with DOX, amiodarone or DOX and amiodarone for 5h and 19h incubation as assayed by XTT at 24, 48 and 72h following incubation are presented in Fig 4 and Fig. 5. More specifically the data in Fig. 4 were obtained using liposomes bearing DOX in their cores (equivalent free drug concentration 1.4 ⁇ M), amiodarone in their lipid bilayers (equivalent free drug concentration 15 ⁇ M) or DOX and amiodarone (equivalent incubation concentrations 1.4 and 15 ⁇ M respectively). From Fig.
  • the results are summarised in Fig. 5.
  • the toxicity assay at 24h revealed minimal cell death for 5h incubation with amiodarone liposomes and approximately 30-40% toxicity for 19 h incubation.
  • the respective values of dox toxicity were ca. 20% while the cytotoxicity of cocktail liposomes was largely increased (-55% for 5h incubation and -80% for 19h incubation).
  • the cocktail liposome treatment for 19h caused approximately 97% cell death.
  • the toxicity values further increased 72h following incubation for all groups apart for the 19h incubation cocktail liposome group where cell death was already maximal (complete cell death within experimental errors).
  • the above results suggest a profound enhancement in DOX cytotoxicity by use of cocktail DOX-amiodarone liposomes and especially for longer times of incubation ( 19h).
  • Liposomal DOX formulations such as Doxil are clinically approved for a multitude of ailments such as AIDS associated Kaposi sarcoma, refractory ovarian cancer, and metastatic breast cancer (45-49), greatly enhancing the therapeutic index of DOX through the EPR effect (42-44) and alleviating DOX associated side effects such as collateral cardiotoxicity (49).
  • the present work aimed to assess the in vitro efficacy of novel cocktail liposomes, bearing DOX in their aqueous centres and amiodarone, a potent MDR inhibitor in their lipid bilayers, to further increase the therapeutic index of DOX via defeat of MDR mechanisms. This research was triggered by the well documented synergistic effects of parallel administration of non liposomal DOX and amiodarone in vitro and in vivo (37-39, 41).
  • DOX was encapsulated in liposomes by a passive core encapsulation method through hydration of the films prior to liposome extrusion.
  • the DOX encapsulation yield although as a percentage is quite low (-3.5%) was sufficient to confer the cytotoxic effects required (Fig. 4 and 5).
  • there are other active loading techniques such as for example the pH gradient technique (58) affording higher encapsulation yields.
  • amiodarone encapsulation was very efficient since it localized in the liposome lipid bilayer and was directly mixed with the lipids during lipid film preparation allowing small losses.
  • Tsogas I Sideratou Z
  • Tsiourvas D Theodossiou TA
  • Paleos CM Interactive transport of guanidinylated poly(propylene imine)-based dendrimers through liposomal and cellular membranes. Chembiochem 2007;8( 15): 1865-76.
  • Tsogas I Theodossiou T, Sideratou Z, et al. Interaction and transport of poly(L-lysine) dendrigrafts through liposomal and cellular membranes: the role of generation and surface functionalization. Biomacromolecules 2007;8(10):3263-70.
  • MacDonald RC MacDonald RI
  • Menco BP Takeshita K
  • Subbarao NK Hu LR.
  • Small-volume extrusion apparatus for preparation of large, unilamellar vesicles.
  • Fig. 1 Liposomal encapsulation of A. Doxorubicin.
  • Encapsulation concentrations are expressed as equivalent free drug concentrations in the liposomal dispersion and are plotted against drug concentrations added to the lipid films during liposome preparation. The mean encapsulation fractions are obtained from the slopes of the linear regressions.
  • Fig. 2 Calcein AM retention studies.
  • Fig. 3 DOX fluorescence cell confocal images.
  • a and C cells incubated with DOX loaded liposomes (equivalent free drug concentration 3 ⁇ M) for 4h - zoom 1 and 2 respectively.
  • B and D Cells incubated with DOX-amiodarone loaded liposomes (equivalent incubation concentrations 3 and 45 ⁇ M correspondingly) for 4h zoom 1 and 2 respectively.
  • the presence of amiodarone in the liposomes incurred enhanced accumulation of DOX in the cell nuclei (white arrows).
  • DOX fluorescence was excited at 488nm and imaged through a 585 nm dichroic filter (585 EFLP).
  • a 3 step Kalman smoothing filter was in all cases applied for image acquisition.
  • Fig 4 Liposomal DOX cytotoxicity on DU 145 cells with/without amiodarone encapsulated in the liposome lipid bilayer (equivalent free drug concentrations DOX: 1.4 ⁇ M and amiodarone: 15 ⁇ M).
  • the toxicity was determined by a standard XTT assay performed at 24, 48 and 72h following incubation. Two incubation times were studied: 5h (light gray columns and 19h black columns). Student paired t-tests were performed between the cell groups incubated with DOX and amiodarone-DOX liposomes in all cases (ns p>0.05, * p ⁇ 0.05, ** pO.Ol, *** p ⁇ 0.001 and **** pO.OOOl).
  • Fig. 5 Liposomal DOX cytotoxicity on DU145 cells with/without amiodarone encapsulated in the liposome lipid bilayer (equivalent incubation concentrations DOX: 3 ⁇ M and amiodarone: 45 ⁇ M). The toxicity was again determined by a standard XTT assay performed at 24, 48 and 72h following incubation. Two incubation times were studied: 5h (light gray columns and 19h black columns). Student paired t-tests were performed between the cell groups incubated with DOX and amiodarone-DOX liposomes in all cases (**** pO.OOOl).
  • FIG. 6 Schematic representation of the ODG lipid inserted into the liposomal lipid bilayer.
  • FIG. 7 Schematic representation of the invention.

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Abstract

La présente invention concerne une nouvelle formulation de cocktail à base d’amiodarone et de doxorubicine encapsulée dans un liposome qui augmenterait l’indice thérapeutique de la doxorubicine liposomique par la mise en échec de la résistance à plusieurs médicaments médiée par l’amiodarone. L’invention concerne également de l’amiodarone encapsulée dans un liposome dans des liposomes portant des lipides guanidinylés qui peuvent favoriser la liaison cellulaire par reconnaissance moléculaire. Les liposomes ayant ces propriétés sont composés de phosphatidylcholine, de cholestérol, des lipides guanidinylés chlorhydrate d’octadécyl guanidine (ODG) ou chlorhydrate de  N- [3- (octadécylamino) propyl] guanidine (ODPG), d’amiodarone et de doxorubicine encapsulés dans leurs noyaux aqueux. Ces liposomes sont unilamellaires et ont une taille approximative de 100 nanomètres et seraient stables dans le sang total de mammifère, après introduction de polyéthylène glycol (PEG) ou autres groupes équivalents.
PCT/GR2008/000037 2008-05-13 2008-05-13 Nouvelles formulations de cocktail de liposomes contenant de la doxorubicine et de l’amiodarone, puissant inhibiteur de la résistance à plusieurs médicaments WO2009138806A1 (fr)

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WO2014144421A1 (fr) * 2013-03-15 2014-09-18 Memorial Sloan-Kettering Cancer Center Inversion de céramide de la résistance à plusieurs médicaments
US9065392B2 (en) 2013-02-28 2015-06-23 Dialog Semiconductor Gmbh Divide by 2 and 3 charge pump methods
CN104983681A (zh) * 2015-06-10 2015-10-21 上海市第一人民医院 一种胺碘酮脂质体的制备方法及其应用

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