Cyclic tetrapyrrole derivatives which can self-assemble

Abstract

The present invention relates to a cyclic tetrapyrrole derivative, which can self-assemble, of formula (I), or one of the salts or conjugated acids or bases of this derivative.

Description

[0001] DESCRIPTION

[0002] TITLE: Self-assembling cyclic tetrapyrrole derivatives

[0003] The present invention relates to a self-assembling cyclic tetrapyrrole derivative, as well as a porphysome resulting from the self-assembly of this derivative.

[0004] The therapeutic effects of light are known and implemented in different therapeutic methods, including dynamic phototherapy and thermal phototherapy.

[0005] Photodynamic therapy consists of administering a photosensitizing molecule to a target tissue, i.e. one capable of generating reactive oxygen species (ROS) when illuminated by light of the appropriate wavelength in the presence of oxygen, and then irradiating the target tissue with light of the appropriate wavelength.

[0006] Irradiation causes the photosensitizing molecule to transition into an electronically excited state. Subsequent de-excitation of the photosensitizing molecule results in the formation of ROS in the target tissue, which in turn react with the target tissue and / or an infectious agent present in that target tissue to destroy it.

[0007] ROS have a very short lifespan and, as a result, a limited spatial effect. The effectiveness of phototherapy therefore depends greatly on the ability of photosensitizing molecules to reach the target tissue and then be incorporated into the cells present in this target tissue.

[0008] Tetrapyrrolic macrocycles, including porphyrin, chlorin, or phthalocyanine derivatives, are known for their photosensitizing properties. However, these molecules are highly hydrophobic, and their therapeutic effect is therefore highly dependent on their formulation.

[0009] It has been proposed to formulate tetrapyrrolic macrocycles with a co-solvent such as ethylene glycol or to incorporate them into liposomes. However, these strategies have not achieved satisfactory therapeutic efficacy to date.

[0010] It has also been considered to utilize the ability of tetrapyrrolic macrocycles, when conjugated to phospholipids, to self-assemble to form liposomal supramolecular assemblies, called porphysomes. Lovell, JF et al., 2011, Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nature Materials, 10(4), 324-332, and Bronstein, LG, et al., 2022, Phospholipid-porphyrin conjugates: deciphering the driving forces behind their supramolecular assemblies. Nanoscale, 14(19), 7387-7407, describe such porphysomes, formed by tetrapyrrolic macrocycle-phospholipid conjugates in which conjugation is mediated by either an ester or an amide bond, respectively.

[0011] However, while these porphysomes have interesting bioavailability, their effect on the target tissue is more photothermal than photodynamic. The risk of collateral damage linked to excessive heating of the target tissue is therefore not negligible.

[0012] Therefore, there is still a need to propose a cyclic tetrapyrrole derivative with improved bioavailability, and in particular allowing the preparation of porphysomes whose balance between photodynamic and photothermal properties is better controlled.

[0013] For this purpose, the invention relates to a self-assembling cyclic tetrapyrrole derivative of formula (I): in which R1 is selected from a hydroxyl group, a glycerol group, an ethanolamine group, a serine group and a choline group, and characterized in that:

[0014] - R2 is chosen from a fatty acid and a fragment sensitive to reactive oxygen species of formula (II) or (III):

[0015] - R3 is selected from an aliphatic chain and a hydrogen atom; and - R5 is selected from a hydrogen atom, an aliphatic chain, and a fragment sensitive to reactive oxygen species of formula (IV):

[0016] LP designating a fragment comprising a functional group sensitive to reactive oxygen species and R4 designating a group of atoms comprising at least one tetrapyrrolic macrocycle, at least one of R2 and R5 comprising an LP fragment sensitive to reactive oxygen species, or one of the salts or conjugate acids or bases of this derivative.

[0017] The presence of at least one LP fragment comprising a functional group sensitive to reactive oxygen species between the tetrapyrrolic macrocyclyl and the rest of the molecule makes the molecule labile in the presence of ROS. The self-assembling cyclic tetrapyrrole derivative according to the invention is therefore itself the generator of ROS following illumination.

[0018] Without wishing to be bound by any theory, when the derivative is illuminated in the presence of oxygen with light of appropriate wavelength, a photothermal effect is always observed but the ROS generated by the cyclic tetrapyrrole derivative in parallel with this photothermal effect, even if few in number, can also react with the LP fragment to cause the dissociation of the derivative into a fragment comprising the macrocycle and a second lipid fragment which could act as a detergent-like molecule. The derivatives thus released are then able to act by photodynamic effect more efficiently than in their assembled form.

[0019] In other words, the initial photodynamic effect is at least partially used on the derivative itself to cause its dissociation into two fragments at the LP fragment level, and consequently the destabilization of any self-assemblies of the derivatives, so as to obtain a subsequent more intense photodynamic effect and to extinguish the photothermal effect before reaching high temperatures capable of causing collateral damage to the treated tissues.

[0020] It is therefore understood that the presence of the LP fragment makes it possible to limit the duration during which the effect is predominantly photothermal and to quickly switch to a predominant photodynamic effect. Collateral damage such as burns is thus limited and the therapeutic effect is better controlled. According to other advantageous aspects of the invention, the cyclic tetrapyrrole derivative comprises one or more of the following characteristics, taken individually or in all technically possible combinations:

[0021] - R4 is chosen from porphyrin and its derivatives, phthalocyanine and its derivatives, and chlorine and its derivatives;

[0022] - the at least one LP fragment sensitive to reactive oxygen species comprises a functional group selected from a thioether group, a thioacetal group, a dithioacetal group, a disulfide group, a diselenide group and an enol ether group;

[0023] - the at least one LP fragment sensitive to reactive oxygen species is linked to the R4 group by a peptide bond;

[0024] - R2 is a fatty acid chosen from natural fatty acids, and / or R3 and / or R5 is (are each) an aliphatic chain which is that of a natural fatty acid;

[0025] - R2 is a fatty acid and R3 is a hydrogen atom;

[0026] R3 is an aliphatic chain of formula (V)

[0027] (V) and R5 is a hydrogen atom;

[0028] - the cyclic tetrapyrrole derivative of formula (I) is chosen from:

[0029]

[0030] The invention also relates to the cyclic tetrapyrrole derivative according to any of the preceding embodiments for its use as a medicament.

[0031] According to an advantageous aspect of the invention, the cyclic tetrapyrrole derivative is used in the treatment of cancer or in the treatment of bacterial infections.

[0032] The invention also relates to a porphysome formed by the self-assembly of at least two cyclic tetrapyrrole derivatives, or their salts, conjugate acids or bases, as described above.

[0033] Without wishing to be bound by any theory, when the porphysome is illuminated in the presence of oxygen with light of appropriate wavelength, due to the compactness of the self-assembly, the initial photodynamic effect is weak and mainly a photothermal effect is observed. However, the few EORs generated locally can react with the LP fragments of the derivatives forming the porphysome, causing their fragmentation into two sub-parts. This fragmentation leads to a destabilization of the porphysome and causes its "active" disaggregation, i.e. in an anticipated manner compared to a passive or equivalently spontaneous disaggregation. This puts an end to the quenching of the photodynamic effect due to the compactness of the assembly initially observed, so that the photodynamic effect quickly becomes predominant over the photothermal effect.

[0034] Collateral damage such as burns is thus limited and the therapeutic effect is better controlled. According to other advantageous aspects of the invention, the porphysome comprises one or more of the following characteristics, taken individually or in all technically possible combinations:

[0035] - cyclic tetrapyrrole derivatives, or their salts, conjugate acids or bases, are all identical;

[0036] - the porphysome comprises an equimolar percentage of cholesterol and cyclic tetrapyrrole derivative;

[0037] - the porphysome further comprises the compound of formula (XVIII):

[0038] (XVIII).

[0039] The invention also relates to a porphysome according to any of the preceding embodiments for its use as a medicament, in particular for its use in the treatment of cancer or in the treatment of bacterial infections.

[0040] The invention further relates to a pharmaceutical composition comprising a cyclic tetrapyrrole derivative according to any of the preceding embodiments or a porphysome according to any of the preceding embodiments in a pharmaceutically acceptable medium.

[0041] The invention therefore relates to a self-assembling cyclic tetrapyrrole derivative of formula (I):

[0042] [Chem 1] in which R1 is selected from a hydroxyl group, a glycerol group, an ethanolamine group, a serine group and a choline group, and characterized in that:

[0043] - R2 is chosen from a fatty acid and a fragment sensitive to reactive oxygen species of formula (II) or (III):

[0044] - R3 is chosen from an aliphatic chain and a hydrogen atom; and

[0045] - R5 is chosen from a hydrogen atom, an aliphatic chain, and a fragment sensitive to reactive oxygen species of formula (IV):

[0046] (IV);

[0047] LP designating a fragment comprising a functional group sensitive to reactive oxygen species and R4 designating a group of atoms comprising at least one tetrapyrrolic macrocycle, at least one of R2 and R5 comprising an LP fragment sensitive to reactive oxygen species, or one of the salts or conjugate acids or bases of this derivative.

[0048] Conjugate acids or bases of compounds of formula (I) are understood to mean compounds which have an acidic character and / or a basic character in the sense of Brônsted.

[0049] The derivative of formula (I) is organized around a basic skeleton with three carbon atoms, carrying at one end a phosphate group of which one of the oxygen atoms carries an R1 group.

[0050] The R1 group is a hydrophilic group. Specifically, the R1 group is selected from a hydroxyl group, a glycerol group, an ethanolamine group, a serine group, and a choline group.

[0051] The R2 group is selected from a fatty acid and a reactive oxygen species-sensitive moiety of formula (II) or formula (III):

[0052] [Chem 2]

[0053] [Chem 3]

[0054] (III).

[0055] Fatty acid means a chemical compound comprising a linear aliphatic chain, saturated or unsaturated, one end of which carries a carboxylic acid function.

[0056] The fatty acid is advantageously C4 to C36, advantageously C12 to C22, advantageously C16 to C20, advantageously C16.

[0057] Advantageously, the fatty acid is chosen from natural fatty acids, advantageously saturated or unsaturated natural fatty acids. These include, for example, myristic, palmitic, stearic, palmitoleic or oleic acid.

[0058] The fatty acid is linked to the basic three-carbon skeleton by an ester function, the carboxylic acid function of the isolated fatty acid therefore being replaced by an ester function in the cyclic tetrapyrrole derivative according to the invention.

[0059] It is therefore understood that in the case where the R2 group is a group of formula (III) or a fatty acid, the basic skeleton with three carbon atoms is derived from glycerol, and that in the case where the R2 group is a group of formula (II), the basic skeleton with three carbon atoms is derived from 2-amino-1,3-propanediol.

[0060] In all cases, the R2 group is linked by an ester bond or a peptide bond to the basic three-carbon skeleton.

[0061] In formulas (II) and (III) of the R2 group, the LP fragment is configured to connect the R4 group of atoms to the remainder of the cyclic tetrapyrrole derivative by a bond that can be broken in the presence of a reactive oxygen species. The LP fragment is therefore a fragment comprising a functional group of which at least one covalent bond can be broken, in particular homolytically, in the presence of a reactive oxygen species.

[0062] In this application, reactive oxygen species means an oxygen-containing chemical compound having at least one unpaired electron. A reactive oxygen species is designated in this application by the acronym ERO (in English “reactive oxygen species” or ROS), but it is also commonly designated by the acronym DOR (for reactive oxygen derivative).

[0063] For example, superoxide anion, singlet oxygen, ozone or hydrogen peroxide are reactive oxygen species.

[0064] Breaking the covalent bond of the LP fragment by reaction with an ERO results in the formation of two fragments of the cyclic tetrapyrrole derivative according to the invention, one of which comprises the R4 group initially linked to the LP fragment, and the other of which comprises the basic three-carbon skeleton.

[0065] The LP fragment comprises, for example, at least one covalent bond whose dissociation energy is relatively low, typically lower than the average dissociation energy of a single CC bond or a CH bond. This is, for example, an SC bond, an SS bond, etc.

[0066] The LP fragment advantageously comprises a functional group selected from a thioether group, a thioacetal group, a dithioacetal group, a disulfide group, a diselenide group and an enol ether group. Particularly advantageously, the LP fragment comprises a functional group selected from a thioacetal group and a dithioacetal group.

[0067] Advantageously, the LP fragment comprises the group of formula (XV):

[0068] [Chem 15]

[0069] Advantageously, the LP fragment is of formula (XVI) or (XVII): [Chem 16]

[0070] The R4 group denotes a group comprising at least one tetrapyrrolic macrocycle.

[0071] In the present application, the expression "tetrapyrrolic macrocycle" is used to designate not only the macrocycle common to porphyrins, namely a cycle formed by four pyrrole nuclei linked together by methine bridges, of formula (XII) represented below:

[0072] [Chem 12]

[0073] (XII), but also related macrocycles, such as: i) the macrocycles of monobenzoporphyrins or polybenzoporphyrins, in particular the macrocycle common to phthalocyanines, of formula (XIII) represented below:

[0074] [Chem 13] (ii) a cycle formed by four pyrrole and / or azoline rings, including at least one pyrrole ring and one azoline ring, linked together by methine groups, such as the macrocycle common to chlorins, of formula (XIV) represented below:

[0075] [Chem 14]

[0076] (XIV). The tetrapyrrolic macrocycle of the R4 group therefore always has an aromatic pi electron system which is responsible for the photosensitizing character of the derivative according to the invention. The type of macrocycle used in the R4 group is for example chosen according to the corresponding absorption band and / or the intensity of the photodynamic effect and / or its capacity to interact with another macrocycle by pi-pi stacking type interactions.

[0077] Notably, the absorption band of phthalocyanines corresponds to higher wavelengths than those of porphyrins, which allows a greater depth of penetration of light into tissues.

[0078] In the R4 group, the tetrapyrrolic macrocycle may have one or more substituents. By way of non-limiting example, the R4 group may be formed by the skeleton of a chlorophyll or a heme.

[0079] Advantageously, the R4 group and the LP fragment are linked by a peptide bond, formed during the reaction of a carboxylic acid function present on the precursor of the R4 group and an amine function present on one end of the precursor of the LP fragment.

[0080] The third atom of the basic skeleton of the cyclic tetrapyrrole derivative according to the invention is linked to a group R3 of atoms and to an oxygen atom carrying a group R5 of atoms.

[0081] The R3 group is selected from an aliphatic chain and a hydrogen atom.

[0082] If the R3 group is an aliphatic chain, this aliphatic chain is saturated or not. Advantageously, it is a C4 to C36 chain, advantageously C12 to C22, advantageously C16 to C20, advantageously C16.

[0083] Advantageously, the R3 group is in this case an aliphatic chain of a natural fatty acid, in particular palmitic acid.

[0084] The R5 group is selected from a hydrogen atom, an aliphatic chain, and a reactive oxygen species-sensitive moiety of formula (IV):

[0085] [Chem 4]

[0086] (IV).

[0087] LP and R4 denote in formula (IV) the same types of groups as in formulas (II) and (III).

[0088] If the R5 group is an aliphatic chain, this aliphatic chain is saturated or not. Advantageously, it is a C4 to C36 chain, advantageously C12 to C22, advantageously C16 to C20, advantageously C16. Advantageously, the R5 group is in this case an aliphatic chain of a natural fatty acid, in particular palmitic acid.

[0089] The cyclic tetrapyrrole derivative according to the invention comprises at least one LP fragment. In other words, if the R2 group is a fatty acid, the R5 group is necessarily a group of formula (IV), and if the R5 group is a hydrogen atom or an aliphatic chain, the R2 group is necessarily a group of formula (II) or formula (III).

[0090] Advantageously, if the R2 group is a fatty acid, the R3 group is a hydrogen atom. In this case, since the R5 group is a group of formula (IV), the cyclic tetrapyrrole derivative is a glycerophospholipid-cyclic tetrapyrrole conjugate. These are, for example, the derivatives of formulae (VI), (VII), (IX) and (X) described in the examples.

[0091] Advantageously, if the group R2 is a group of formula (II) or formula (III), R5 is a hydrogen atom and R3 is an aliphatic chain of formula (V):

[0092] [Chem 5]

[0093] In this case, the cyclic tetrapyrrole derivative is a sphingosine derivative. This includes the derivative of formula (VIII) described in the examples.

[0094] It is also possible that the R5 group is a group of formula (IV) and the R2 group is a group of formula (II) or (III), like the derivative of formula (XI) of the examples.

[0095] In all cases, the cyclic tetrapyrrole derivative according to the invention therefore comprises at least one tetrapyrrolic macrocycle linked to the basic skeleton with three carbon atoms via an LP fragment sensitive to reactive oxygen species.

[0096] When the cyclic tetrapyrrole derivative absorbs a photon of the appropriate wavelength, the macrocycle enters an excited state. In the presence of oxygen, its deexcitation results in the local formation of singlet oxygen. The singlet oxygen can react with the EOR-sensitive LP fragment of the cyclic tetrapyrrole derivative itself or that of a neighboring molecule of the same type to cause the breakage of the covalent bond with relatively low dissociation energy present in the LP fragment concerned. The R4 group is then freed from the rest of the molecule, in particular from a possible aliphatic chain or another R4 group, and available to absorb new photons and induce a more efficient photodynamic effect.

[0097] Furthermore, as can be seen in Example 7, the cyclic tetrapyrrole derivatives according to the invention can self-assemble to form porphysomes. Without wishing to be bound by any theory, in these porphysomes, the hydrophobic parts of the derivatives according to the invention form an annular lipid bilayer, in which the macrocycles are positioned next to each other, the lipid bilayer being bordered on either side by the hydrophilic parts of these derivatives.

[0098] A porphysome within the meaning of the present application is therefore a nanovesicular-type assembly formed by the self-assembly of at least two cyclic tetrapyrrole derivatives, or their salts, conjugated acids or bases, according to the invention.

[0099] The hydrophilic parts present on the surface of the porphysome typically give it very good biocompatibility and allow it to diffuse inside the target tissues.

[0100] In the absence of light of the appropriate wavelength, the porphysome is stable.

[0101] When the porphysome is irradiated with light of the appropriate wavelength, the compactness of the assembly causes a quenching of the photodynamic effect, with the photothermal effect predominating.

[0102] The self-assembling nature of cyclic tetrapyrrole derivatives therefore makes it possible to form biocompatible and biodegradable assemblies with satisfactory bioavailability, the LP fragment present in the cyclic tetrapyrrole derivatives making it possible in parallel to control the release of tetrapyrrole macrocycles at the level of a target tissue by the irradiation to which the target tissue is subjected. The therapeutic effect, and in particular the distribution between the photothermal effect and the photodynamic effect, is therefore well controlled.

[0103] The invention therefore also relates to a porphysome formed by the self-assembly of at least two cyclic tetrapyrrole derivatives according to the invention.

[0104] The number of cyclic tetrapyrrole derivatives contained in a porphysome depends on its size and the nature of the cyclic tetrapyrrole derivatives. A porphysome with a hydrodynamic diameter of 200 nm typically contains 1x10 5 at 2 x10 5 cyclic tetrapyrrole derivative molecules.

[0105] It is therefore a supramolecular assembly of nanometric dimension.

[0106] Advantageously, the porphysome is formed by the self-assembly of cyclic tetrapyrrole derivatives according to the invention which each comprise either an aliphatic chain and a tetrapyrrolic macrocycle, or two tetrapyrrolic macrocycles. This arrangement makes it possible to obtain porphysomes of particularly satisfactory stability but also a modulable tetrapyrrolic macrocycle loading rate.

[0107] Advantageously, the porphysome is formed by the self-assembly of cyclic tetrapyrrole derivatives according to the invention, all identical.

[0108] Advantageously, the porphysome comprises an additional phospholipid derivative, such as DSPE-PEG2000 of formula (XVIII):

[0109] [Chem 18]

[0110] (XVIII)

[0111] Advantageously, the porphysome comprises 5 mol% of additional phospholipid derivative.

[0112] Advantageously, the porphysome comprises an equimolar mixture of cyclic tetrapyrrole derivative and cholesterol.

[0113] The number of cyclic tetrapyrrole derivative molecules contained in the assemblies can be modulated, in particular by changing the hydrodynamic diameter of the assemblies and / or by changing the formulation of the porphysomes, for example by modifying the proportion of cholesterol or by using one or more different derivatives, in particular by modifying the proportion of derivative of formula XI which comprises two tetrapyrrole macrocycles.

[0114] The invention also relates to the use of a cyclic tetrapyrrole derivative according to the invention or a porphysome according to the invention as a medicament.

[0115] The cyclic tetrapyrrole derivative according to the invention or the porphysome according to the invention may be combined with pharmaceutically acceptable excipients to form a therapeutic composition.

[0116] The pharmaceutical composition may in particular be administered subcutaneously, intramuscularly, intravenously, intra-arterially, intrathecally, intraocularly, intracerebrally, transdermally, pulmonarily or locally. The active ingredient formed by the cyclic tetrapyrrole derivative or the porphysome according to the invention may then be administered in a mixture with conventional pharmaceutical carriers.

[0117] Preferably, the pharmaceutical composition contains a pharmaceutically acceptable carrier for an injectable formulation.

[0118] In the present description, the term “pharmaceutically acceptable vehicle” is intended to mean a compound or a combination of compounds included in a pharmaceutical composition which does not cause side reactions and which allows, for example, the facilitation of the administration of the active compound(s), the increase in its lifespan and / or its effectiveness in the body, the increase in its solubility in solution or even the improvement of its conservation.

[0119] These pharmaceutically acceptable vehicles are well known and will be adapted by those skilled in the art according to the nature and method of administration of the active compound(s) chosen. They may in particular be isotonic, sterile formulas, saline solutions (with monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like, or mixtures of such salts), or lyophilized compositions, which, upon addition of sterilized water or physiological serum as appropriate, allow the constitution of injectable solutions.

[0120] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be free-flowing since it is to be injected by syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0121] The dispersions according to the invention can be prepared in glycerol, liquid polyethylene glycols or mixtures thereof. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0122] The pharmaceutically acceptable carrier may be a solvent or dispersion medium containing, for example, water, a polyol (for example, glycerin, propylene glycol, polyethylene glycol, and the like), or suitable mixtures thereof. Prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

[0123] Sterile injectable solutions are prepared by incorporating the active ingredients in the required amount into the appropriate solvent with several of the other ingredients listed above, if any, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the other required ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization. In formulation, the solutions will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are readily administered in a variety of dosage forms, such as the injectable solutions described above.For parenteral administration in an aqueous solution, for example, the solution must be suitably buffered and the liquid diluent made isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous media that can be used are known to those skilled in the art. These are, in particular, sterile, pH-buffered and isotonic aqueous solutions.

[0124] The cyclic tetrapyrrole derivative according to the invention or the porphysome according to the invention, optionally in a pharmaceutically acceptable composition, can be used to treat different types of tumors in mammals, in particular humans. In particular, solid tumors, located in an area of ​​a human or animal body which can be irradiated, can be treated using the derivatives and porphysomes according to the invention. These include, for example, tumors of the prostate, the esophagus, adenocarcinomas of the lungs, basal cell carcinomas of the skin, cancers of the head or neck, sarcomas of the nasopharynx, colorectal neoplasms.

[0125] To do this, for example, an intravenous, subcutaneous injection near the site of the tumor or intra-tumoral injection of a pharmaceutical composition comprising a porphysome according to the invention is carried out, followed by irradiation of the tumor using light of an appropriate wavelength, typically of the order of 600 to 800 nm.

[0126] The cyclic tetrapyrrole derivative according to the invention or the porphysome according to the invention, optionally in a pharmaceutically acceptable composition, can also be used to treat bacterial infections in mammals, in particular humans. Advantageously, all local bacterial infections caused by bacteria in suspension and / or biofilms can be treated by the porphysomes according to the invention.

[0127] The invention is illustrated by the following examples and figures.

[0128] Figure 1 shows the absorbance and fluorescence spectra of the derivative of formula VII at a final concentration of 5 μM derivative.

[0129] Absorbance intensity (au) = absorbance intensity (au); Fluorescence intensity (au) = fluorescence intensity (au); Wavelength (nm) = wavelength (nm); before rupture = before rupture; after rupture = after rupture.

[0130] Figure 2 shows the absorbance and fluorescence spectra of the derivative of formula VI at a final concentration of 5 μM of derivative. Absorbance intensity (au) = absorbance intensity (au); Fluorescence intensity (au) = fluorescence intensity (au); Wavelength (nm) = wavelength (nm); before rupture = before rupture; after rupture = after rupture.

[0131] Figure 3 shows A: the temperature in the tank as a function of time for the control (10 mM HEPES buffer, 150 mM NaCl, pH 7.4 - curve with square markers), the porphysome of the derivative of formula VI (curve with white circle markers) and the porphysome of the derivative of formula VII (curve with black circle markers). The porphysomes are in all cases in a HEPES buffer (10 mM; pH 7.4, 150 mM NaCl); B: the absorbance spectra of each type of assembly, i.e. porphysome of the derivative of formula VI (B) before illumination (“before illumination”, solid curve) and after illumination (“after illumination”, dotted curve).

[0132] Time (min) = time (min); Absorbance (au) = absorbance (au); Wavelength (nm) = wavelength (nm); HEPES buffer = HEPES buffer.

[0133] Figure 4 shows C: the absorbance spectra of each type of assembly, i.e. porphysome of the derivative of formula VII (C) before illumination (“before illumination”; solid curve) and after illumination (“after illumination”; dotted curve). Absorbance (au) = absorbance (au); Wavelength (nm) = wavelength (nm); HEPES buffer = HEPES buffer.

[0134] Figure 5 represents the percentage of cell viability, A and B: in black: porphysome of the derivative of formula VI; in hatched: porphysome of the derivative of formula VII. % Bacteria survival = % bacterial survival; Control = 0 μM; Only light = 0 μM + light; Dark (20 μM) = 20 μM + no light.

[0135] Figure 6 represents the percentage of cell viability, C and D: in black: porphysome of the derivative of formula IX; in hatched: porphysome of the derivative of formula X.% Bacteria survival = % bacterial survival; Control = 0 μM; Only light = 0 μM + light; Dark (20 μM) = 20 μM + no light.

[0136] Figure 7 represents the median inhibitory concentration (IC50) on a PC3 cell line as a function of the light surface energy received (0, 2, 4 and 6 J / cm 2 ), A: in black: Pheophorbide-a in DMSO, in gray: derivative of formula VII in DMSO, in hatched: porphysome of the derivative of formula VII in DMSO; B: in black: Pyropheophorbide-a in DMSO, in gray: derivative of formula VI in DMSO, in hatched: porphysome of the derivative of formula VI in DMSO.

[0137] Figure 8 represents the median inhibitory concentration (IC50) on a PC3 cell line as a function of the surface light energy received, C: control liposomes of the Pyr3LPC compound of formula (XX) in DMSO. Figure 9 represents the median inhibitory concentration (IC50, μM) on a PC3 cell line as a function of the surface light energy received. In black: porphysomes from Lovell, JF et al, (called “Pyrolipid”) in HEPES buffer; in gray: porphysomes of the derivative of formula VI of the invention, in white: porphysomes of the derivative of formula VII; in diagonal hatching porphysomes of the derivative of formula VIII; in vertical hatching porphysomes of the derivative of formula IX.

[0138] Figure 10 shows the percentage of cell viability, S. aureus (A) and P. aeuriginosa (B): in black: porphysomes from Lovell, JF et al. (called "Pyrolipid") in HEPES buffer; in gray: porphysomes of the derivative of formula VI, in white: porphysomes of the derivative of formula VII; in diagonal hatching: porphysomes of the derivative of formula VIII, in diamond hatching: porphysomes of the derivative of formula IX. % Bacteria survival = % bacterial survival; Control = 0 μM; Only light = 0 μM + light; Dark (1 or 10 μM) = 1 or 10 μM + no light. [Chem 20] EXAMPLES

[0139] Six cyclic tetrapyrrole derivatives according to the invention were prepared and then used to form porphysomes. Their formulae VI to XI are reproduced below:

[0140] [Chem 6]

[0141] [Chem 8]

[0142]

[0143] 5 [Chem 10]

[0144]

[0145] [Chem 11]

[0146] 5

[0147] Reagents and materials for the synthesis of derivatives of formula VI to X The reagents and materials used for the syntheses of derivatives of formula VI to XI were obtained from the following suppliers: pheophorbide-a (Pheo-a, >95%, mixture of diastereoisomers, Mw = 592.69 g / mol) and pyropheophorbide-a (Pyro-a, >95%, Mw = 534.g / mol): Livchem Logistics GmbH (Frankfurt, Germany); ({1-[(carboxymethyl)sulfanyl]-1-methylethyl}sulfanyl) acetic acid (> 99%, Mw = 224.23 g / mol); 9-Fluorenylmethyl carbazate (96%; Mw = 254.28 g / mol), tert-butyl (2-aminoethyl)carbamate (> 99%, Mw = 160.22 g / mol) and HCldioxane (4M in dioxane): abcr Gmbh (Karlsruhe, Germany);

[0148] Amberlite® IRA-400 in its chloride form, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCI, > 98%, Mw = 191.70 g / mol); 1- [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, > 97%, Mw = 380.23 g / mol); 4-

[0149] (Dimethylamino)pyridine (DMAP, > 99%, Mw = 122.17 g / mol); Dowex® 50WX8-100 ion exchange resin in its hydrogenated form; N,N-diisopropylethylamine (DIPEA, 99%, Mw = 129.24 g / mol); HEPES (99.5%, Mw = 238.31 g / mol); sodium chloride (NaCl, 99%, Mw = 58.44 g / mol); anhydrous chloroform (>99%, stabilized with amylene); anhydrous dimethylformamide (DMF); sodium sulfate (Na2SO4, 99%, Mw = 142.04 g / mol) and triethylamine (Mw = 101.19 g / mol) - Sigma Aldrich (St. Louis, MO, USA); phospholipids and 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (16:0 Lyso-PC, 99%, 495.63 g / mol): Avant! Polar Lipids (Alabaster, AL, USA).

[0150] Dialysis tubing Spectra / Por® 6, MWCO 1 kDa: SERVA (Heidelberg, Germany);

[0151] Silica (60M, 0.04-0.063 mm) \Macherey-Nagel Gmbh and co (Düren, Germany).

[0152] All reagents were used without prior purification.

[0153] EXAMPLE 1: Synthesis of the derivative of formula VI

[0154] Synthesis of intermediate compound A:

[0155] 100 mg (0.200 mmol) of 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine), 113 mg (0.500 mmol) of ({1-[(carboxymethyl)sulfanyl]-1-methylethyl}sulfanyl) acetic acid, 116 mg (0.600 mmol) of EDC-HCl and 123 mg (0.600 mmol) of DMAP were dissolved in 5 mL of anhydrous chloroform.

[0156] 5 g of glass beads were added and the mixture was sonicated for 12 h at 25 ° C under argon atmosphere. The mixture was then filtered and the filtrate was incubated for 12 h with DOWEX® resin. The mixture was then filtered and the filtrate was concentrated by evaporation in vacuo. The dry residue was suspended in 2 mL of water and purified by dialysis with a cut-off threshold of 1 kDa. The purified suspension was finally lyophilized to obtain 117 mg of compound A of formula (XXI) which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0157] 1 H NMR (300 MHz, CDCl3) - chemical shifts (ppm): 4.36 (s, 2H), 4.24- 4.15 (m, 2H), 4.09 (s, 1 H), 4.03-3.98 (m, 2H), 3.80 (bs, 2H), 3.56 - 3.39 (m, 4H), 3.34 (s, 9H), 2.33 (t, J = 7.2 Hz, 2H), 1.63 (bs, 6H), 1.27 (bs, 26H), 0.90 (t, 6.9 Hz, 3H);

[0158] 13C NMR (75 MHz, CDCl3) - chemical shifts (ppm): 182.70, 173.87, 170.42, 61.44, 54.36, 34.15, 33.11, 31.90, 30.30, 29.70, 29.42, 29.33, 24.92, 22.65, 14.0;

[0159] Electrospray mass spectrometry (ESI / MS): theoretical for C31H59NO10PS2 [M- H]": 700.3 atomic mass units (amu), measured for C3iH59NOwPS2[MH]": 700.3 amu.

[0160] [Chem 21]

[0161] Synthesis of intermediate compound B:

[0162] 50 mg (0.090 mmol) of pyropheophorbide-a, 47 mg (0.185 mmol) of 9-Fluorenylmethyl carbazate and 70 mg (0.185 mmol) of HATU were dissolved in 5 mL of anhydrous chloroform. 33 μL (0.18 mmol) of DI PEA was added and the mixture was kept under stirring and argon atmosphere for 4 h. The solvent and excess DI PEA were then removed by evaporation in vacuo.

[0163] The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography [CHCl3:MeOH:(98:2)] to provide 50 mg of compound B of formula (XXII) which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0164] 1 H NMR (300 MHz, CDC-3) - chemical shifts (pm): 9.25-9.17(d, 1 H), 8.45- 8.39(s, 1 H), 7.95-7.74 (q, 1 H), 7.7-.7.64 (d, 2H), 7.51-7.45 (d, 2H), 7.35-7.28 (t, 2H), 7.26- 7.19 (t, 2H), 6.2-5.98 (m, 2H), 5.16-4.85 (q, 2H), 4.47-4.29 (m, 2H), 4.27-4.19 (d, 2H), 4.16- 4.07 (d, 1 H), 3.59-3.45 (m, 2H), 3.38-3.07 (m, 6H), 2.02-1.96 (s, 1H), 1.79-1.73 (s, 1H),

[0165] I .72-1.63 (d, 2H), 1.61-1.5 (t, 3H);

[0166] 13C NMR (75 MHz, CDC-3) - chemical shifts (pm): 213.46, 146.77, 144.99, 143.67, 141.56, 141.34, 137.78, 136.19, 131.55, 130.35, 129.14, 127.78, 127.66, 127.07, 124.95, 122.47, 120.35, 120.02, 119.84, 106.04, 105.36, 104.00, 97.15, 92.94, 67.87, 67.32, 51.48, 49.93, 47.97, 47.17, 46.81, 30.25, 29.76, 22.99, 19.38, 17.32, 11.99,

[0167] II .82, 1 1.15;

[0168] Electrospray mass spectrometry (ESI MS): theoretical for C48H47N6O4 [M +H] + : 771.3 amu, measured for C48H47NeO4[M +H] + : 771.4 uma. Final formulation of the derivative of formula VI: 20 mg (0.025 mmol) of compound B was dissolved in 2 mL of anhydrous DMF and 1 mL of DIPEA. The mixture was stirred under an argon atmosphere for 5 hours at room temperature, protected from light, until the Fmoc group was completely deprotected.

[0169] 15 mg (0.020 mmol) of compound A and 16 mg (0.040 mmol) HATU were mixed in 2 mL of anhydrous DMF, kept stirring under argon atmosphere for 5 h at room temperature, before being mixed with compound B.

[0170] The mixture thus obtained was stirred under an argon atmosphere for 18 hours at room temperature and away from light.

[0171] The DMF was then removed by evaporation under vacuum. The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography with gradient elution [from CHCl3:MeOH: (95:5) to CHCl3:MeOH:H2O (68:30:2)], to obtain 15 mg of the derivative of formula VI which was characterized by proton and carbon-13 NMR and mass spectrometry, the results being summarized below:

[0172] 1H RMN (400 MHz, DMSO-d6) - déplacements chimiques (ppm) : 10.08-9.82 (t, 1 H); 9.71-9.65 (s, 1 H); 9.44-9.38 (s, 1 H); 8.92-8.86 (s, 1 H); 8.25-8.13 (q, 1 H); 7.76-7.62 (m, 1 H); 6.43-6.31 (d, 1 H); 6.25-6.15 (d, 1 H); 5.27-5.05 (m, 2H); 4.64-4.55 (m, 1 H); 4.38-4.29 (d, 1 H); 4.28-4.2 (m, 1 H); 4.16-4.10 (m, 1 H); 4.08-4.02 (m, 2H); 3.83-3.76 (t, 2H); 3.71-3.65 (d, 2H); 3.62-3.58 (m, 3H); 3.53-3.48 (m, 2H); 3.45-3.44 (s, 1 H); 3.44-3.41 (s, 2H); 3.38-3.35 (m, 1 H); 3.21-3.18 (s, 2H); 3.15-3.07 (m, 9H); 2.3-2.19 (m, 3H); 1 .88-1 .76 (d, 3H); 1.65-1.58 (t, 3H); 1.57-1.53 (m, 4H); 1.23-1.19 (s, 9H); 1.08-1.03 (m, 6H);

[0173] 13 C RMN (75 MHz, DMSO-d6) - déplacements chimiques (ppm) : 204.82, 191.09, 130.43, 129.07, 127.20, 122.89, 114.25, 96.53, 65.48, 62.27, 53.14, 51.10, 40.37, 40.10, 39.82, 39.54, 39.27, 38.99, 38.71 , 33.25, 32.21 , 31.16, 30.33, 30.12, 29.77, 28.87, 28.63, 28.32, 24.26, 22.85, 22.02, 17.38, 13.82, 11.92, 11.61 , 10.84;

[0174] Mass spectrometry (MALDI): theoretical for C64H95N7O 11 PS2 [M+H]+: 1232.61 amu, measured for C64H95N7O 11 PS2[M+H]+: 1232.66 uma.

[0175] EXAMPLE 2: Synthesis of the derivative of formula VII

[0176] Synthesis of intermediate compound C:

[0177] 50 mg (0.084 mmol) of pheophorbide-a, 43 mg (0.168 mmol) of 9-Fluorenylmethyl carbazate and 64 mg (0.168 mmol) of HATU were dissolved in 5 ml of anhydrous chloroform.

[0178] 30 μL (0.168 mmol) of DIPEA was added and the mixture was kept stirring under argon atmosphere for 4 h. The solvent and excess DIPEA were then removed by evaporation under vacuum. The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography [CHCl3:MeOH:(98:2)] to provide 62 mg of compound C of formula (XXIV) which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0179] 1H RMN (300 MHz, CDCl3) - déplacements chimiques (ppm) :9.09-9.03 (s, 1 H), 9.03-8.94 (s, 1 H), 8.33-8.23 (s, 1 H), 8.01-7.82 (s, 1 H), 7.72-7.60 (q, 1 H), 7.60-7.52 (d, 2H), 7.43-7.33 (d, 2H), 7.25-7.17 (t, 2H), 7.16-7.08 (t,2H), 6.15-5.9 (m, 3H), 5.2-5.12 (s, 1 H), 4.29-4.21 (d, 2H), 4.17-4.09 (d, 2H), 4.01-3.92 (m, 2H), 3.9-3.78 (m, 1 H), 3.67-3.61 (s,2H), 3.41-3.35 (m, 1 H), 3.31-3.25 (s, 2H), 3.13-3.07 (s, 2H), 3.13-3.07 (s, 2H), 3.00-2.94 (s, 2H), 2.75-2.50 (s, 9H), 1.64-1.56 (d, 2H), 1.53-1.43 (t, 3H);

[0180] 13 C RMN (75 MHz, CDCl3) - déplacements chimiques (ppm) :189.62, 172.42, 172.17, 169.79, 161.07, 156.39, 155.57, 150.84, 149.53, 145.07, 143.61 , 143.40, 141.97, 141.24, 141.05, 137.72, 136.45, 136.10, 135.95, 131.82, 128.88, 128.66, 127.70, 127.56, 127.02, 126.94, 124.93, 122.55, 119.94, 119.75, 104.96, 104.18, 97.30, 93.06, 67.78,

[0181] 67.26, 64.78, 52.85, 51.02, 50.17, 47.08, 46.74, 38.58, 31.03, 30.23, 29.72, 22.97, 22.68,

[0182] 19.27, 17.31, 11.90, 11.84, 11.07;

[0183] Electrospray mass spectrometry (ESI / MS): theoretical for C50H49N6O6 [M+H] + : 829.36 amu, measured for C50H49N6O6 [M+H] + : 829.5 uma. final of the derivative of formula VII:

[0184] 20 mg (0.024 mmol) of compound C were dissolved in 2 mL of anhydrous DMF and 1 mL of DIPEA. The mixture was stirred under argon for 5 h at room temperature, protected from light, until the Fmoc group was completely deprotected. 15 mg (0.020 mmol) of compound A and 16 mg (0.040 mmol) of HATII were mixed in 2 mL of anhydrous DMF, stirred under argon for 5 h at room temperature, before being mixed with the deprotected compound C.

[0185] The mixture thus obtained was stirred under an argon atmosphere for 18 hours at room temperature and away from light.

[0186] The DMF was then removed by evaporation under vacuum. The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography with gradient elution [from CHCl3:MeOH: (95:5) to CHCl3:MeOH:H2O (68:30:2)], to obtain 12 mg of the derivative of formula VII which was characterized by proton and carbon-13 NMR and mass spectrometry, the results being summarized below:

[0187] 1 H NMR (400 MHz, DMSO-d6) - chemical shifts (ppm): 8.52-8.44 (d, 1 H); 8.34-8.27 (d, 1 H); 7.34-7.26 (q, 1 H); 6.48-6.14 (m, 1 H); 5.77-5.71 (s, 1 H); 4.14-3.9 (m, 1 H); 3.86-3.8 (s, 1 H); 3.8-3.71 (m, 1 H); 3.68-3.62 (s, 1 H); 3.51-3.48 (s, 1 H); 3.47-3.4 (d, 3H); 3.37-3.26 (bs, 9H); 3.27-3.19 (s, 3H); 3.16-3.06 (m, 4H); 2.57-2.52 (s, 4H); 2.27-2.15 (m, 1 H); 1.69-1.58 (m, 1 H); 1.58-1.47 (m, 2H); 1.37-1.30 (d, 1 H); 1.3-1.19 (m, 9H); 1.17-1.09 (m, 5H); 0.88-0.75 (m, 3H);

[0188] 13C NMR (75 MHz, DMSO-d6) - chemical shifts (ppm): 158.32, 155.08, 148.49, 147.08, 127.68, 119.41, 94.02, 73.01, 65.46, 54.93, 53.12, 40.38, 40.10, 39.82, 39.54, 39.27, 38.99, 38.71, 31.24, 30.25, 30.20, 28.91, 26.54, 24.46, 24.27, 22.35, 22.03, 19.94, 17.34, 14.11 , 13.84, 11.94, 10.85, 9.58;

[0189] Mass spectrometry (MALDI): theoretical for C66H97N7O13PS2 [M+H]+: 1290.62 amu, measured for C66H97N7O13PS2 [M+H]+: 1290.64 amu.

[0190] EXAMPLE 3: Synthesis of the derivative of formula VIII

[0191] Synthesis of intermediate compound D:

[0192] 400 mg (0.056 mmol) of sphingomyelin (Egg SM) was dissolved in 20 mL of 0.5 M hydrogen chloride in methanol. The mixture was kept stirring under argon atmosphere for 5 days at 55°C.

[0193] The solvent was then removed by evaporation under vacuum, and the dry residue was redissolved in a minimum volume of chloroform-methanol (9:1) to be purified by silica column chromatography [CHCl3: MeOH: H2O (65:25:4)]. 117.8 mg of lysosphingomyelin were thus obtained. 73.9 mg (0.33 mmol) of thioacetal, 126.5 mg (0.660 mmol) of EDC and 75.9 mg (0.660 mmol) of N-hydroxysuccinimide (NHS) were dissolved in 3 mL of anhydrous DMF and stirred under argon atmosphere for 1 hour at room temperature.

[0194] 50 mg (0.11 mmol) of lysosphingomyelin and 101.2 mg (0.880 mmol) of DIPEA suspended in 2 mL of anhydrous DMF were added to the mixture.

[0195] The mixture was stirred for 48 hours at room temperature. The solvent was then evaporated under vacuum and the dry residue suspended in 5 mL of water with sonication, then dialyzed for 3 days against water, with water replacement 3 times per day, with a 1 kDa cut-off membrane, to obtain 43 mg of compound D of formula (XXV).

[0196] Final synthesis of the derivative of formula VIII

[0197] 31 mg (0.040 mmol) of compound B and 98 mg (0.80 mmol) of DMAP were dissolved in

[0198] 3 mL of anhydrous DMF and mixed for 8 hours at room temperature under an argon atmosphere until complete deprotection of the Fmoc group.

[0199] 24 mg (0.036 mmol) of compound D and 30.4 mg (0.080 mmol) of HATU were dissolved in 2.0 mL of DMF. The mixture was kept stirring under argon atmosphere for 1 h, then added to the previous mixture. The whole was kept stirring at room temperature under argon atmosphere protected from light for 24 h.

[0200] The solvent was then removed under vacuum. The dry residue was redissolved in 10 mL of chloroform and incubated with DOWEX® resin to remove the base, before removing the resin by filtration. The excess chloroform was evaporated under vacuum and the dry residue was resuspended in a minimal volume of chloroform.

[0201] The solvent was then removed by evaporation under vacuum. The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography (CHCl3: MeOH: H2O (65:25:4)). The collected fraction was dried by evaporation under vacuum followed by 24 hours of lyophilization to obtain 17 mg of derivative of formula VIII which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0202] 1 H NMR (400 MHz, DMSO-d6) - chemical shifts (ppm): 9.18 (s, 1 H), 9.16 (s, 1 H), 8.41 (s, 1 H), 7.86-7.76 (dd, 1 H), 7.18 (br m, 8H, f), 6.16-6.01 (dd, 2H), 5.21-4.88 (dd, 2H), 4.37-4.34 (m, 1 H), 4.23-4.19 (m, 1 H+2H, f), 4.00 (m, 1 H), 3.53-3.46 (q, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 3.00 (s, 3H), 2.54-1.93 (m, 2H+2H), 1.68-1.65 (d, 3H), 1.54 (t, 3H);

[0203] 13C NMR (101 MHz, DMSO-d6) - chemical shifts (ppm): 196.57, 171.99, 144.54, 133.64, 129.43, 77.41, 76.99, 76.56, 54.43, 32.36, 31.84, 30.32, 29.56, 29.26, 22.81, 22.60, 17.18, 14.03, 11.83, 11.50, 10.89;

[0204] Mass spectrometry (MALDI): theoretical for [M]+: 1200.62 amu, measured for [M]+: 1200.61 amu.

[0205] EXAMPLE 4: Synthesis of the derivative of formula IX

[0206] Synthesis of intermediate compound E

[0207] 50 mg (0.090 mmol) of pyropheophorbide-a, 30 mg (0.186 mmol) of tert-butyl hydrazinecarboxylate and 70 mg (0.186 mmol) of HATU were dissolved in 5 mL of anhydrous chloroform. 80 μL (0.465 mmol) of DIPEA were added and the mixture was stirred under argon atmosphere for 4 h. The solvent and excess DIPEA were then removed by evaporation under vacuum. The dry residue was suspended in 10 mL of dichloromethane and washed with 3 times 30 mL of water.

[0208] The organic phase was dried with sodium sulfate and incubated with DOWEX® resin for 1 h. Then the mixture was filtered and the filtrate was concentrated by evaporation in vacuo to obtain 61.7 mg of a compound E1 of formula (XXVI).

[0209] [Chem 26]

[0210]

[0211] 50 mg (0.080 mmol) of compound E1 was suspended in 2 ml of HCl-dioxane (2 M) and stirred at room temperature for 4 h. 48 mL of ice-cold diethyl ether was added and the suspension was cooled to -20 °C for 4 h.

[0212] The precipitate formed was washed with 3 times 20 mL of ice-cold diethyl ether, to provide 50.8 mg of compound E of formula (XXVII) which was characterized by mass spectrometry, the results being summarized below:

[0213] Electrospray mass spectrometry (ESI / MS): theoretical for C53H41N6O2 [M+H] + : 577.3 amu, measured for C53H41N6O2 [M+H]+ : 577.3 uma. final of the derivative of formula IX

[0214] 30 mg (0.047 mmol) of compound E, 27 mg (0.038 mmol) of compound A and 22 mg (0.058 mmol) of HATU were dissolved in 2.5 mL of DMF and 54.0 μL (0.312 mmol) of DIPEA. The mixture was kept stirring under argon atmosphere for 12 h at 40 °C.

[0215] The DMF was then removed by evaporation under vacuum. The dry residue was suspended in a minimum volume of chloroform and purified by silica column chromatography with gradient elution [from CHCl3:MeOH: (90:10) to CHCl3:MeOH:H2O (65:25:4)], to obtain 17.7 mg of derivative of formula IX which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0216] 1H RMN (400 MHz, DMSO-d6) - déplacements chimiques (ppm) :9.64 (s, 1 H), 9.38 (s, 1 H), 8.87 (s, 1 H),8.58 - 8.05 (m, 1 H, NH), 8.17 (dd, 1 H, J=11 .7-17.8 Hz), 6.36 (d, J = 17.9 Hz, 1 H), 6.19 (d, J = 11.6 Hz, 1 H), 5.32- 5.10 (m, 2H), 5.01- 5.09 (m, 1 H), 4.57 (m, 1 H), 4.23 - 4.17 (m, 2H), 4.14 - 4.00 (m, 3H), 3.80 (m, 2H),3.65 (q, 2H,J=8.0 Hz), 3.58 (s, 3H),3.50 (m, 2H), 3.42 (s, 3H), 3.39 - 3.36 (m, 4H),3.22 (m, 2H),3.17 (s, 3H), 3.13 (m, 4H), 3.10 (s, 9H), 2.70 - 2.57(m, 2H),2.14 (t, 2H,J=7.4Hz), 1.79 (d, 3H, J=7.2 Hz), 1.60 (t, 3H, J=7.4Hz),1 .44 (s, 3H), 1.42 (s, 3H),1.27 - 0.92 (m, 26H), 0.78 (t, 7.0 Hz, 3H,J=7.0 Hz), - 1.99 (s, 1 H) ;

[0217] 13C NMR (101 MHz, DMSO-d6) - chemical shifts (ppm): 195.33, 172.62, 170.02, 169.57, 169.57, 148.02, 141.35, 140.64, 137.08, 131.56, 128.80, 118.15, 117.68, 105.86, 104.07, 96.54, 94.55, 79.15, 71.86, 71.78, 70.42, 67.96, 64.07, 62.25, 58.33, 56.69, 53.13, 53.09, 43.41 , 34.30, 33.31 , 32.55, 32.37, 31.24, 30.01 , 29.16, 29.04, 28.99, 28.95, 28.84, 28.65, 28.40, 24.32, 22.91 , 22.04, 17.42, 17.21 , 13.89, 13.84, 11.95, 10.42;

[0218] Mass spectrometry (MALDI): theoretical for C66H99N7O11S2 [M+H]+: 1260.65 amu, measured for C66H99N7O11PS2 [M+H]+: 1260.67 amu.

[0219] EXAMPLE 5: Synthesis of the derivative of formula X

[0220] Synthesis of intermediate compound F

[0221] 50 mg (0.084 mmol) of pheophorbide-a, 30 mg (0.186 mmol) of tert-butyl (2-aminoethyl)carbamate and 70 mg (0.186 mmol) of HATU were dissolved in 5 mL of anhydrous chloroform. 80 μL (0.465 mmol) of DIPEA were added and the mixture was stirred under argon atmosphere for 4 h. The solvent and excess DIPEA were then removed by evaporation under vacuum. The dry residue was suspended in 10 mL of dichloromethane and washed with 3 times 30 mL of water.

[0222] The organic phase was dried with sodium sulfate and incubated with DOWEX® resin for 1 h. Then the mixture was filtered and the filtrate was concentrated by evaporation in vacuo to obtain 60 mg of a compound F1 of formula (XXVIII).

[0223] [Chem 28]

[0224]

[0225] 50 mg (0.080 mmol) of compound F1 was suspended in 2 mL of HCl-dioxane (2M) and stirred at room temperature for 4 h. 48 mL of ice-cold diethyl ether was added and the suspension was cooled to -20°C for 4 h.

[0226] The precipitate formed was washed with 3 times 20 mL of ice-cold diethyl ether, to provide 51 mg of compound F of formula (XXIX) which was characterized by mass spectrometry, the results being summarized below:

[0227] Electrospray mass spectrometry (ESI / MS): theoretical for C33H37N6O2 [M+H] + : 635.3 amu, measured for C33H37N6O2 [M+H] + : 635.4 uma.

[0228] [Chem 29]

[0229] 3

[0230] Final synthesis of the derivative of formula X 30 mg (0.045 mmol) of compound E, 26 mg (0.037 mmol) of compound A and 30 mg (0.079 mmol) of HATU were dissolved in 2.5 mL of DMF and 50.0 μL (0.296 mmol) of DIPEA. The mixture was stirred under argon atmosphere for 12 h at 40 °C. The DMF was then removed by evaporation in vacuo. The dry residue was suspended in a minimal volume of chloroform and purified by silica column chromatography with gradient elution [from CHCl3:MeOH:NEts(9:1:0.1) to CHCl3:MeOH:H2O:NEts(65:25:4:0.1)], to obtain 13 mg of derivative of formula X which was characterized by proton and carbon 13 NMR and mass spectrometry, the results being summarized below:

[0231] 1H RMN (400 MHz, DMSO-d6) - déplacements chimiques (ppm) :9.76 (s, 1 H), 9.44 (s, 1 H), 8.91 (s, 1 H), 8.47 (m, 1 H, NH),8.18 (dd, 1 H, J=11 .7-17.8 Hz),), 6.43 (s, 1 H),6.35 (d, J = 17.9 Hz, 1 H), 6.29 (d, J = 11.6 Hz, 1 H), 5.03 (m, 1 H), 4.57 (m, 1 H), 4.26 - 3.95 (m, 5H),3.82 (s, 2H),3.79 - 3.68 (m, 4H),3.58 (s, 3H),3.51 - 3.45(m, 2H),3.43 (s, 3H),3.40 - 3.33 (m, 4H), 3.21 (s, 3H), 3.18 (m, 2H), 3.14 (m, 2H), 3.09 (s, 9H),2.72 (m, 2H),2.28 (m, 2H),2.15 (t, 2H, J=7.4Hz), 1.77 (d, 3H, J=7.2 Hz), 1.63 (t, 3H, J=7.5Hz ),1 .42 (s, 3H), 1.39 (s, 3H),1 .20 - 1 .01 (m, 26H),0.80 (t, 7.0 Hz, 3H, J=7.0 Hz),-1 .79 (s, 1 H) ;

[0232] 13C NMR (101 MHz, DMSO-d6) - chemical shifts (ppm): 189.73, 173.76, 173.05, 172.21, 170.13, 169.76, 169.02, 150.82, 149.47, 149.31, 145.63, 140.03, 136.77, 136.32, 134.99, 132.72, 129.39, 128.94, 128.33, 123.63, 120.05, 105.83, 97.41, 94.44, 70.93, 65.86, 64.73, 63.17, 62.52, 59.01, 58.06, 56.81, 53.59, 53.15, 52.10, 51.63, 49.88,

[0233] 45.89, 45.86, 44.05, 41.94, 41.72, 39.16, 38.56, 34.61, 33.70, 32.98, 31.74, 31.68, 30.53,

[0234] 30.48, 29.48, 29.37, 29.24, 29.14, 29.07, 28.90, 28.81 , 24.73, 23.31 , 22.53, 22.48, 21.60,

[0235] 19.02, 17.83, 14.34, 12.71, 12.42, 12.15, 11.42, 11.27;

[0236] Mass spectrometry (MALDI): theoretical for C68H101N7O13PS2 [M+H]+: 1318.66 amu, measured for C68H101N7O13PS2 [M+H]+: 1318.68 amu.

[0237] EXAMPLE 6: Preparation of porphysomes by self-assembly of derivatives of formulas VI to XI

[0238] Porphysomes of the derivatives of formulae VI to XI were prepared by the lipid thin film hydration method, followed by vesicle extrusion. For this, each of the derivatives of formulae VI to XI was dissolved with an equimolar percentage of cholesterol (47.5 mol%) in the presence of 5 mol% of DSPE-PEG2000 (of formula XVIII - Reference: Avanti Polar Lipids 880120C) in approximately 2 mL of a chloroform:methanol mixture (9:1 v / v).

[0239] The addition of DSPE-PEG2000 prevents the aggregation of porphysomes and improves their stability in biological media.

[0240] The organic solvents were then removed by vacuum evaporation at 45°C for 3 h and the resulting film was rehydrated with 1 mL of HEPES buffer, to obtain a final derivative concentration of 1 mM. Then, the suspension was subjected to 9 freeze-thaw cycles and the assemblies were extruded including 15 passes through an 800 nm pore size polycarbonate membrane, followed by another extrusion including 15 passes through a 200 nm pore size polycarbonate membrane, at a temperature of 60°C.

[0241] Porphysomes of the derivative of formula VI were also prepared with the method described previously but with 95 mol% of derivative of formula VI and 5 mol% of DSPE-PEG2000.

[0242] The hydrodynamic diameter of the resulting assemblies was measured by dynamic light scattering (DLS) (Nano ZS90, Malvern) and the results are summarized in Table 1 below. All DLS measurements were performed at 25°C.

[0243] [Table 1]

[0244] EXAMPLE 7: Optical properties of derivatives and their porphysomes

[0245] Figure 1 graph A (respectively B) shows the absorption (respectively fluorescence) spectrum of the assemblies of derivatives of formula VI:Cholesterol:DSPE-PEG2000 (47.5:47.5:5 mol %) (solid curve) and after dissociation (dotted curve) caused by the addition of TRITON X100 (final percentage: 1% v / v).

[0246] Figure 2 (respectively D) graph G shows the absorption (respectively fluorescence) spectrum of the assemblies of derivative of formula VII:Cholesterol:DSPE-PEG2000 (47.5:47.5:5 mol %) before (black curve) and after dissociation (dotted curve) caused by the addition of TRITON X100 (final percentage v / v 1%).

[0247] These graphs clearly show the fluorescence quenching associated with the formation of assemblies, compared to the derivatives of formulas VI and VII taken alone. This demonstrates the potential of porphysomes as photothermal agents.

[0248] EXAMPLE 8: Photothermal properties The porphysomes obtained from the derivative of formula VI (respectively VII) and cholesterol at an equimolar percentage and in the presence of 5 mol% of DSPE-PEG2000 were diluted in a HEPES buffer (10 mM, pH 7.4, NaCl 150 mM) to have a final concentration of derivative of 200 μM.

[0249] 1 mL of each suspension thus prepared was placed in a quartz cuvette and illuminated with a laser diode (λ max =670 nm) placed at a distance of 4 cm and at a power of 400 mW (to obtain a surface power density of the order of 800 mW / cm 2 ).

[0250] Temperature was recorded every 30 seconds for 3 laser diode on-off cycles performed for each porphysome type.

[0251] The results are reproduced in graph A in Figure 3.

[0252] Temperature increases of between 14-18°C and well-reproducible cycles are observed. This graph confirms the potential of the assemblies to be used as photothermal agents that induce a moderate temperature increase.

[0253] Furthermore, the comparison of the absorbance spectra of each type of assembly (graph B figure 3: porphysome of the derivative of formula VI; graph C figure 4: porphysome of the derivative of formula VII) before illumination (solid curve) and after illumination (dotted curve) allows to observe a significant decrease in absorbance after illumination. Without wishing to be bound by any theory, this observation could be explained by a photo-bleaching induced by generation of singlet oxygen and / or free radicals, which would cause the release of porphyrin molecules from the assembly.

[0254] EXAMPLE 9: Efficacy against Gram+ and Gram- bacteria

[0255] Bacterial strains used for the studies include Gram (+) S. aureus CIP4.83 and Gram (-) P. aeruginosa PAO1.

[0256] Bacteria were grown in lysogeny broth (LB) (Peptone 10 gL-1, NaCl 10 g / L and 5 g / L yeast extract).

[0257] The bacterial strains were stored at -80°C.

[0258] For the preparation of planktonic cultures, individual colonies were picked and inoculated into 10 mL of LB broth medium overnight at 37°C at 160 rpm on an orbital shaker. The optical density (OD) of the bacterial suspension was determined by measuring the absorbance at 600 nm (OD600).

[0259] A first pre-culture with absorbance OD600 = 5.0 was obtained. A new culture was started at OD600 = 0.05 by diluting 100 μL of the culture at OD600 = 5 in 10 mL of LB broth. The culture was incubated until an OD600 = 0.2 was recorded. A 100 μL aliquot was taken from the OD600 = 0.2 solution and centrifuged for 10 min at 6000 rpm. The supernatant was removed and the pellet resuspended in autoclaved PBS (4 mL for S. aureus and 3 mL for P. aeruginosa) to stop bacterial division.

[0260] Phototoxicity was assessed by incubating 200 μL of bacterial suspension (10 5bacteria per mL) with suspensions of LPC-TK-HYD-Pyro, LPC-TK-HYD-Pheo, LPC-TK-EDA-Pyro and LPC-TK-EDA-Pheo liposomes (respectively derivatives VI, VII, IX and X) formulated in the presence of an equimolar concentration of cholesterol and 5 mol% of DSPE-PEG2000, concentrations 0.1 μM, 1 μM, 2.5 μM and 10 μM for P. Aeruginosa and concentrations 0.01 μM, 0.05 μM, 0.1 μM and 1 μM for S. Aureus) for 10 min. After incubation, the suspensions were illuminated for 10 min with an X-ray diode laser max = 670 nm and an output power of 400 mW (surface power 800 mW.cm' 2 ). After illumination, the suspension was serially diluted in PBS (10' 1 M to 10' 4 M) and 100 μ dLe of each dilution were plated on LB Petri dishes (LB + 15% agar).

[0261] The number of colony-forming units (CFU) for each dilution was counted after 24 h of incubation at 37°C. CFU for each experiment were normalized to the untreated control and plotted as concentration versus % cell viability. Each assay was performed in triplicate. The results are reproduced in Figure 5 and Figure 6.

[0262] It is observed that cell viability is maintained in the presence of each of the porphysomes tested in the absence of light (case 10 μM + without light).

[0263] Each of the porphysomes tested on bacteria allows to reduce cell viability in case of illumination with an exceptional efficacy against Staphylococcus Aureus with IC 90 lower in all cases than 0.05 μM.

[0264] The same trend was obtained against Pseudomonas Aeruginosa bacteria with a two-fold increased efficacy depending on the compound compared to classical conjugates.

[0265] EXAMPLE 10: In vitro evaluation of phototoxicity on a PC3 cell line

[0266] PC3 prostate cancer cells were cultured in Roswell Park Memorial Institute 1640 (RPMI 1640) medium supplemented with 10% FBS and antibiotics (100 IU / mL penicillin - 100 pg / mL streptomycin) in a humidified incubator at 37°C under an atmosphere including 5% CO2. Cells were transferred to new culture flasks every three days at 70-80% confluence, after dissociation using trypsin.

[0267] PC3 cells were then seeded into 96-well plates with 200 μL of cell culture medium at a concentration of 5000 cells / well. The cells were incubated at 37°C for 24 hours to become adherent. The next day, cell treatment with 4 different solutions was performed: Pheophorbide-a or Pyropheophorbide-a, derivative of formula VII or derivative of formula VI in DMSO ((Methanesulfinyl)methane), and a porphysome suspension of derivative of formula VII:Cholesterol:DSPE-PEG2000 or derivative of formula VI:Cholesterol:DSPE-PEG2000 in HEPES.

[0268] Solutions were prepared with serial dilution in RPMI-1640 medium and cells were treated with 20 μL of each solution. The final volume in each well was 220 μL. The final porphyrin concentration range was 0.1–5 μM (Pheophorbide-a or Pyropheophorbide-a), 0.1–20 μM (formula VII derivative or formula VI derivative and corresponding porphysomes).

[0269] To allow for complete internalization of the tested molecules or porphysomes, the cells were incubated for an additional 24 hours. The third day included a medium change to remove non-internalized compounds. Some plates were kept in the incubator for dark toxicity assessment, while others were illuminated for 17 minutes, 34 minutes, or 51 minutes. The indicated period corresponds to a light dose of 2 J / cm 2 , 4 J / cm 2 , and 6 J / cm 2 , respectively.

[0270] The light treatment took place using an LED array with a λ max of 660 nm, and an irradiance of 2 mW / cm 2 After illumination, cells were incubated at 37°C under 5% CO2.

[0271] The next day, an MTT assay was performed. 20 μL of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide solution was added to each well, and the cells were incubated for an additional 2 hours to achieve crystallization. The medium was then removed, and the converted formazan was solubilized in 200 μL of DMSO. The plates with the latter were homogenized using a shaker. Finally, an optical density (OD) measurement at 570 nm via Plate Reade ELISA was performed.

[0272] The percentage of cell viability as a function of concentration was extrapolated for each compound or assembly. Experiments were triplicated.

[0273] The experiments allowed to determine the median inhibitory concentration (IC50) as a function of the light dose for each of the compounds tested.

[0274] It is observed that the IC50 values ​​of porphysomes decrease with increasing light dose (Figures 7 and 8). Without wishing to be bound by any theory, this may be due to the increased generation of EOR, for example singlet oxygen and / or free radicals.

[0275] Furthermore, an IC 50 of the order of 0.15 μM (respectively 0.42 μM) was measured for the derivative of formula VI in porphysome form (respectively for the derivative of formula VII in porphysome form) with a surface irradiation energy of 6 J / cm 2, much lower than that measured for the same derivative in free form in DMSO (2.42 μM, respectively 0.62 μM) and lower than that measured for pheophorbide-a (respectively pyropheophorbide-a) in DMSO, namely an IC 50 of the order of 0.9 μM (respectively 0.5 μM).

[0276] The porphysomes of the compounds of formula VII and VI according to the invention also have the advantage of exhibiting a much lower dark toxicity than that of pheophorbide-a and pyropheophorbide-a respectively, and can be selectively activated by irradiation at low surface energies with a limited photothermal effect.

[0277] It is also observed that the Pyr3LPC assemblies, which do not present a photosensitive fragment analogous to the LP fragment, have an IC50 at least 10 times higher than that of the porphysomes of the derivatives of formulas VI and VII under the same irradiation conditions.

[0278] EXAMPLE 11: Comparison of the photodynamic effect of compounds VI, VII, VIII and IX with the compounds of Lovell, JF et al.

[0279] Lovell, JF et al., 2011, Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nature Materials, 10(4), 324-332, and Bronstein, LG, et al., 2022, Phospholipid-porphyrin conjugates: deciphering the driving forces behind their supramolecular assemblies. Nanoscale, 14(19), 7387-7407, describe porphysomes, formed by tetrapyrrolic macrocycle-phospholipid conjugates in which conjugation is mediated by either an ester or an amide bond, respectively. Such porphysomes therefore lack a moiety comprising a functional group sensitive to reactive oxygen species.

[0280] Comparative in vitro tests were carried out with such porphysomes and the compounds which are the subject of the invention, in order to compare their photodynamic effects, according to the protocol of example 10.

[0281] Figure 9 represents the median inhibitory concentration (IC50, μM) on a PC3 cell line as a function of the surface light energy received, for: the porphysomes of Lovell, JF et al. (called “Pyrolipid”) in HEPES buffer; the porphysomes of the derivative of formula VI of the invention, the porphysomes of the derivative of formula VII, the porphysomes of the derivative of formula VIII and the porphysomes of the derivative of formula IX.

[0282] IC 50 values ​​of 0.79 μM, 0.34 μM and 0.15 μM were measured for the formula VI derivative in the form of porphysomes with surface irradiation energies of 2, 4 and 6 J / cm2 respectively, much lower than those measured for the porphysomes of Lovell, JF et al., of 13.62 μM, 11.52 and 7.77 μM.

[0283] This clearly shows an improvement in the IC50 of the derivative of formula VI in the form of porphysomes of 17, 34 and 52 times at surface irradiation energies of 2, 4 and 6 J / cm2 respectively compared to the porphysomes of Lovell, JF et al. at the same surface energies. The same trend was also observed for the compounds of formulae VII, IX and X.

[0284] Thus, a 50-fold improvement in photodynamic properties was measured for the compounds of the invention compared to the porphysomes of Lovell, JF et al.

[0285] EXAMPLE 12: Comparison of the efficacy against Gram+ and Gram bacteria of compounds VI, VII, VIII and IX with the compounds of Lovell, JF et al.

[0286] The tests were carried out as mentioned in Example 9.

[0287] Figure 10 shows the percentage of cell viability, S. aureus and P. aeuriginosa for porphysomes of the Pyrolipid derivative (Lovell, JF et al.), porphysomes of the derivative of formula VI, porphysomes of the derivative of formula VII, porphysomes of the derivative of formula VIII, and porphysomes of the derivative of formula IX.

[0288] In general, the porphysomes of the invention tested on bacteria make it possible to reduce cell viability in the event of illumination with IC90 100 times and 2 times more effective on Staphylococcus aureus and Pseudomonas aeuriginosa compared with the porphysomes of Lovell, JF et al.

[0289] More specifically, the IC90 values ​​of porphysomes formulated with compounds exhibiting the ROS-sensitive group (i.e. Thioketal) of formulas VI, VII IX and X are two orders of magnitude lower against Staphylococcus aureus and two times lower against Pseudomonas aeruginosa compared to porphysomes of the Pyrolipid molecule.

Claims

CLAIMS 1. Self-assembling cyclic tetrapyrrole derivative of formula (I): (I), in which R1 is selected from a hydroxyl group, a glycerol group, an ethanolamine group, a serine group and a choline group, and characterized in that: - R2 is chosen from a fatty acid and a fragment sensitive to reactive oxygen species of formula (II) or (III): - R3 is chosen from an aliphatic chain and a hydrogen atom; and - R5 is chosen from a hydrogen atom, an aliphatic chain, and a fragment sensitive to reactive oxygen species of formula (IV): (IV); LP designating a fragment comprising a functional group sensitive to reactive oxygen species and R4 designating a group of atoms comprising at least one tetrapyrrolic macrocycle, at least one of R2 and R5 comprising an LP fragment sensitive to reactive oxygen species, or one of the salts or conjugate acids or bases of this derivative.

2. Cyclic tetrapyrrole derivative according to claim 1 wherein R4 is selected from porphyrin and its derivatives, phthalocyanine and its derivatives, and chlorine and its derivatives.

3. A cyclic tetrapyrrole derivative according to any preceding claim, wherein the at least one LP moiety sensitive to reactive oxygen species comprises a functional group selected from a thioether group, a thioacetal group, a dithioacetal group, a disulfide group, a diselenide group and an enol ether group.

4. A cyclic tetrapyrrole derivative according to any preceding claim, wherein the at least one LP moiety sensitive to reactive oxygen species is linked to the R4 group by a peptide bond.

5. Cyclic tetrapyrrole derivative according to any one of the preceding claims, wherein R2 is a fatty acid chosen from natural fatty acids, and / or R3 and / or R5 is (are each) an aliphatic chain which is that of a natural fatty acid.

6. A cyclic tetrapyrrole derivative according to any preceding claim wherein R2 is a fatty acid and R3 is a hydrogen atom.

7. Cyclic tetrapyrrole derivative according to any one of claims 1 to 5 in which R3 is an aliphatic chain of formula (V) is a hydrogen atom.

8. Cyclic tetrapyrrole derivative according to any one of claims 1 to 7, chosen from: (VI), (VII), 9. Cyclic tetrapyrrole derivative according to any one of claims 1 to 8 for use as a medicament.

10. Cyclic tetrapyrrole derivative according to any one of claims 1 to 8 for use in the treatment of cancer or in the treatment of bacterial infections.

11. Porphysome formed by the self-assembly of at least two cyclic tetrapyrrole derivatives, or their salts, conjugate acids or bases, according to any one of claims 1 to 8.

12. Porphysome according to claim 11 wherein the cyclic tetrapyrrole derivatives, or their salts, conjugate acids or bases, are all identical.

13. Porphysome according to claim 11 or claim 12 comprising an equimolar percentage of cholesterol and cyclic tetrapyrrole derivative.

14. Porphysome according to claim 13 further comprising the compound of formula (XVIII):

15. Porphysome according to any one of claims 11 to 14 for use as a medicament.

16. Porphysome according to any one of claims 11 to 14 for its use in the treatment of cancer or in the treatment of bacterial infections.

17. A pharmaceutical composition comprising a cyclic tetrapyrrole derivative according to any one of claims 1 to 8 or a porphysome according to any one of claims 11 to 14 in a pharmaceutically acceptable medium.

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