Method for obtaining photosensitive nanopolymers to encapsulate hydrophilic and hydrophobic molecules

Abstract

The present invention relates to a method for synthesising a photosensitive polyethylene glycol (PEG) and methyl ether-poly(d,l-lactide) (PDLLA) polymer by tosylating its organic group. The photosensitive PEG-PDLLA polymer is functionalised by opening the Lactide monomer ring by polymerising and covalently bonding with the alcohol terminal group of PEG via an esterification with the tosylated organic group. The nanopolymer obtained using the disclosed method is suitable for controlled release processes of hydrophobic and hydrophilic active ingredients with specific delivery based on photodynamic therapy. The PEG-PDLLA-based nanopolymer obtained is able to encapsulate hydrophobic and hydrophilic active ingredients, configuring a nanocarrier with amphiphilic filler with high potential for photodynamic therapy. The method in turn involves nanoprecipitation by removing the organic solvent with optimal photo response properties to UV light.

Description

[0001] METHOD FOR OBTAINING PHOTOSENSITIVE NANOPOLYMERS FOR ENCAPSULATION OF HYDROPHILIC OR HYDROPHOBIC MOLECULES

[0002] FIELD OF INVENTION

[0003] The present invention is related to the technical field of materials for the encapsulation of active ingredients, especially with new polymeric materials suitable for regulating and dosing the release of molecules in specific applications.

[0004] BACKGROUND OF THE INVENTION

[0005] Nanoencapsulation is a rapidly expanding technology for transporting active pharmaceutical ingredients (APIs) [1]. In some cases, it is necessary to release APIs in an accelerated manner to increase their therapeutic effect, compared to their diffusion counterpart

[0015] . Thus, so-called nanocarriers protect APIs from degradation, improve their bioavailability and stability, and release them in a controlled manner

[0020] .

[0006] Among these nanocarriers are polymerosomes, which are defined as vesicular particles made from amphiphilic polymers. Polymerosomes have high potential as a platform for transporting both hydrophobic molecules (in the corona) and hydrophilic molecules (in the core).

[0007] Polymerosomes are presented as useful candidates in nanomedicine, due to their subcellular size and their ability to carry diagnostic and therapeutic molecules.

[0008] Polymeric nanocarriers are chemically modified to contain photosensitive molecules that can undergo structural or conformational changes

[0018] . Therefore, photo-isomerization and photo-disruption by exposure to ultraviolet (UV) light can trigger the spatiotemporal release of active ingredients through an external stimulus

[0021] .

[0009] In this context, in the field of obtaining polymeric nanocarriers, the self-assembly of polymersomes can be carried out in a wide variety of ways, one of which is the so-called solvent-swap method. This method consists of dissolving a copolymer in a "good" solvent followed by the slow addition of a "lean" solvent. The increasing amount of "lean" solvent in the mixture leads to the formation of a hydrophobic membrane as a result of the copolymer's reorganization.

[0010] The outcome of such a solvent change methodology depends largely on the respective properties of the organic solvent and its interaction with the basic components of the polymer.

[0011] In general, so-called "good" solvents promote material-solvent interactions, where polymers can dissolve at a molecular level. Conversely, non-solvents or so-called "poor" solvents encourage polymer-polymer (hydrophobic) interactions, where polymer chains fold around each other and knot together.

[0012] The solvation and desolvation of polymers, and how they influence polymer aggregation, play a significant role in driving the self-assembly process toward the formation of bilayer membranes or micellar structures. Furthermore, solvents affect how polymers pack into self-assembled structures, which, in turn, influences how they undergo subsequent shape-change processes.

[0013] Although polymeric nanocarriers based on PLGA, PEG, PEG-PDLLA exhibit high biocompatibility, biodegradability, and reproducibility, characterizing them as optimal nanoencapsulation systems for biomedical applications

[0019] , there are few disclosures in the state of the art that develop the self-assembly and shape transformation of various copolymers.

[0014] Polyethylene glycol (PEG) is a biocompatible polymer widely used in nanocarrier formulation strategies

[0022] . The attachment of polyethylene glycol (PEG) to a protein-based drug generates a derivative generically called a pegylated compound. Prior art includes a prior art involving poly(ethylene glycol)-β-poly(D,L-lactide) (PEG-PDLLA). This prior art reveals the self-assembly of PEG-PDLLA polymers into polymerosomes and subsequent morphological control. In this process, the particles are dialyzed either against water to produce spherical particles, against salt to induce tubular formation, or the particles are first extruded and then dialyzed to form spherical polymerosomes or tubes.Upon exposure to hypertonic conditions, these spherical structures can undergo a shape transformation process, induced by osmosis, into prolates or oblates, depending on the chemical composition of the copolymer used during initial assembly. Another author developed non-spherical polymerosomes using a dialysis procedure in which block copolymers were dissolved in an organic solvent, after which water was added to induce polymer assembly. Subsequently, the organic solvent was removed via dialysis. This previous work demonstrated this condition for both non-degradable block copolymers, such as poly(ethylene glycol)-poly(styrene), and biodegradable block copolymers.In this way, tubular polymersomes (nanotubes) and bowl-shaped vesicles known as stomatocytes were generated, comprising poly(ethylene glycol)-poly(D,L-lactide) (PEG-β-PDLLA) block copolymers [2]. Finally, the influence of formulation factors, such as salt concentration, on the assembly of PEG-β-PDLLA copolymers containing 10 wt% carboxylic acid or amine-modified derivatives was evaluated. Using optimized conditions, tubular and spherical polymersomes were generated using copolymer mixtures.

[0015] Photosensitive therapy

[0016] Photodynamic therapy (PDT) combines light, photosensitizer, and oxygen for cancer treatment [3]. The combination of the three components generates reactive singlet oxygen (iO₂). 2), which induces cytotoxic reactions that produce cell death, either by apoptosis or necrosis[4]. 2-Nitrobenzyl alcohol, (NA) is a photosensitive molecule commonly used for photo-disruption processes in the presence of UV light

[0023] ,

[0017] Unlike conventional treatments such as chemotherapy or radiotherapy, photosensitive therapy has significantly reduced side effects and improved selectivity towards cancer cells [5]-[8]. Methylene blue (MB) and curcumin are widely used as photosensitizers in photodynamic therapy applications [9],

[0010] . However, they are readily reduced by reductases in biological environments, which hinders their downstream applications.

[0018] The encapsulation of photosensitizers has allowed their transport and the protection of their photodynamic activity [1]. In this context, methylene blue

[0012] and curcumin

[0013] have been encapsulated as a model of hydrophilic and hydrophobic charge, respectively and individually.

[0019] Among the encapsulation technologies known in the state of the art, nanomicelles and liposomes have been developed for the encapsulation of hydrophobic and hydrophilic cargo, respectively

[0014] ,

[0015] , which allows, protecting their activity, improving their availability, and having a greater cell interaction

[0016] ,

[0017] ,

[0020] Nanopolymerosomes possess the ability to transport cargo with both solubility tendencies, increasing their therapeutic efficiency [5],

[0018] ,

[0021] Under these conditions, the present invention solves the problem related to spatiotemporally controlled PA release processes by synthesizing a photosensitive polymer based on PEG-PDLLA. The PEG-PDLLA photosensitive polymer obtained by the method disclosed below is easily adjustable in terms of morphology and composition to adapt to future applications, for example, in the delivery of therapeutic drugs.

[0022] BRIEF DESCRIPTION OF THE INVENTION

[0023] In a first object, the present invention relates to a method for synthesizing a photosensitive polymer poly(ethylene glycol) PEG Y and methyl ether-poly(d,l-lactide) PDLLA. The method comprises the following steps: activation of a photoresponsive molecule by tosylation of its organic group;

[0024] - Functionalize poly(ethylene glycol) PEG and methyl ether-poly(d,l-lactide) PDLLA by opening the Lactide monomer ring through polymerization and covalent bonding with the terminal alcohol group of PEG via esterification with the tosylated organic group; precipitate the resulting PEG-PDLLA polymer in diethyl ether; remove the solvent from the PEG-PDLLA polymer by filtration or centrifugation; dry the product under vacuum; obtain the amphiphilic PEG-PDLLA polymer

[0025] The resulting nanopolymer is suitable for controlled release processes of hydrophobic and hydrophilic active ingredients with specific delivery from photodynamic therapy.

[0026] In one embodiment of the method, the photoresponsive molecule is a nitrobenzyl alcohol. Activation of the molecule is achieved through tosylation of its alcohol group. In another embodiment of the method, the target molecule is a 2-nitrobenzyl alcohol.

[0027] In a second object, the present invention discloses the PEG-PDLLA-based nanopolymer. The resulting nanopolymerosome exhibits the capacity to encapsulate hydrophobic and hydrophilic active ingredients, forming an amphiphilic charge nanocarrier with high potential for photodynamic therapy.

[0028] In the preferred embodiment, the capsules obtained from the nanopolymerosome obtained by the method disclosed have a particle diameter between 100 and 200 nm.

[0029] The objects described above, as well as any additional objects that may apply, will be set out in detail and with the necessary sufficiency in the descriptive chapter that is disclosed below, which will constitute the basis of the claim chapter.

[0030] BRIEF DESCRIPTION OF THE FIGURES

[0031] FIG. 1: Schematic of the synthesis of the photosensitive polymer PEG-PDLLA from the activation of the alcohol group of PEG.

[0032] FIG. 2: A. Photographs of one method for activating the tosyl group of methylated PEG. B. Photographs of one method for carrying out the precipitation, filtration, and drying steps of the byproduct.

[0033] FIG. 3: A. Photographs of one method for carrying out the steps of centrifugation, solvent removal, purification, lyophilization and obtaining a solid powder.

[0034] FIG. 4: A. FT-IR spectra. B. UV-vis spectrum of the photosensitive polymer and PEG-Methylated as a control.

[0035] FIG. 5: Schematic figure of the distribution, chemical (A) and morphological (B) structure. Particle diameter size by dynamic light scattering (C), and zeta potential by electrophoretic light scattering (C).

[0036] FIG. 6: TEM micrograph of the obtained nanocapsules (A) Images obtained at 0.5 pm (B). Magnified capsule with an average diameter of 200 nm. (C) Images of capsules showing sizes between 100 and 200 nm, (D) Image of the formed nanocapsules with a measurement signal of 100 nm. FIG 7: FT-IR spectra of the synthesis of PEG-PDLLA and its precursors PEG-Methyl Ether and Lactide Monomer.

[0037] FIG 8: Characterization of PEG-PDLLA-based nanopolymersomes. Transmission electron microscopy images (A and B). Particle diameter size by dynamic light scattering (C), and zeta potential by electrophoretic light scattering (D). Black and yellow bars at 500 and 100 nm, respectively.

[0038] FIG 9: Concentration profile of curcumin and co-encapsulated methylene blue after extraction from nanopolymerases and dilution in ethanol (A), with maximum absorption peaks at 425 and 655 nm, respectively. Absorbance-concentration curve of curcumin and methylene blue dispersed in ethanol (B and C, respectively).

[0039] FIG 10: Illustrative scheme of the assembly of nanopolymersomes for the encapsulation of active ingredients (photosensitizers) with hydrophilic and hydrophobic tendencies.

[0040] DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention arises as a response to the need to provide photosensitive materials with the capacity to encapsulate molecules of a hydrophobic or hydrophilic nature, suitable for application in controlled release procedures of active pharmaceutical ingredients (APIs).

[0042] The description of the embodiment of the present invention is not intended to limit its scope, but rather to serve as a particular example thereof. It is expected that a person skilled in the art will understand that equivalent embodiments do not depart from the spirit and scope of the present invention in its broadest sense.

[0043] The present invention relates to a method for obtaining nanopolymerosomes based on the amphiphilic polymer PEG-PDLLA.

[0044] The photosensitive polymeric nanomicelle obtained by the disclosed method exhibits great potential for the spatiotemporally controlled release of active pharmaceutical ingredients (APIs), increasing their therapeutic effect for biomedical applications, given their capacity to encapsulate and transport active ingredients (photosensitizers) with hydrophilic and hydrophobic tendencies. Furthermore, obtaining the capsules involves nanoprecipitation by removal of the organic solvent, resulting in optimal photoresponsive properties to UV light. Synthesis of the photosensitive polymer PEG-PDLLA

[0045] The synthesis of the photosensitive polymer involves the activation of a photoresponsive molecule, preferably nitrobenzyls, by tosylation of its organic group.

[0046] In the preferred embodiment, the target molecule for activation is 2-nitrobenzyl alcohol, by tosylation of its alcohol group.

[0047] The synthesis of the photosensitive polymer comprises two stages. The first stage involves the tosylation of PEG and its functionalization with the photosensitive molecule.

[0048] In the preferred embodiment, the synthesis of the photosensitive polymer PEG-PDLLA comprises the activation of the alcohol group of PEG, by means of tosylation and functionalization with the alcohol of the photosensitive molecule to be activated, as can be seen in accordance with the scheme illustrating FIG. 1.

[0049] The photosensitive polymer PEG-PDLLA is deprotonated, optionally in the presence of an oxidized anion, preferably potassium bicarbonate, in dimethylformamide, preferably between 40° and 70°C. Subsequently, under the same conditions, the methylated PEG is covalently anchored.

[0050] In one embodiment, the synthesis of the photosensitive polymer PEG-PDLLA is carried out using 1 to 5 mg of methylated PEG and 2 to 6 mg of tosyl, preferably 4-toluenesulfonyl. The mixture is dissolved in dichloromethane in a cold bath. 1 to 5 mL of triethylamine is added dropwise to the resulting solution. The solution is stirred for 3 hours in the cold bath, followed by approximately 48 hours of stirring at room temperature.

[0051] In the previous example, a color change is evident, demonstrating the correct tosylation of the methylated PEG, as shown in FIG. 2A. Subsequently, the tosylated PEG is purified. Impurities are precipitated in cold diethyl ether and removed by filtration, and the product is then dried under vacuum, as shown in FIG. 2B.

[0052] Optionally, the reaction can be stopped in cold diethyl ether, divided into two centrifuge tubes to precipitate the solid at 4500 rpm for 15 min, and removing the solvent.

[0053] The photosensitive polymer is purified by dialysis in water for approximately 24 hours at 300 rpm, finally obtaining a solid yellow powder upon lyophilization, as shown in FIG. 3. Results and analysis

[0054] The photosensitive polymer PEG-PDLLA is evaluated by Fourier transform infrared (FT-IR) and UV-Vis spectroscopy (FIG. 14 AB, respectively). The 2-nitrobenzyl alcohol is characterized by the peak at 3500 cm⁻¹ 1 (-OH), and around 1450 cm' 1 the benzyl group. PEG-methylated is characterized by the 3500 cm' curve 1 of the terminal alcohol, already 2800 cm' 1by the -CH2-CH2- groups. The PEG-PDLLA obtained has the characteristic benzyl peak, from -CH2-CH2, and there is no presence of the terminal alcohol (3500 cm' 1 ) of NA (FIG. 4A).

[0055] Similarly, the presence of the absorbance peak at 350 nm, corresponding to the functionalized NA, is noteworthy, as the absorbance curve of PEG-methylated does not have this peak and it obscures the other characteristic peak at 275 nm of NA (FIG. 4B). Compared to product 1 from the first report, it is highlighted that the alcohol groups are no longer present in the PEG-PDLLA, demonstrating the high efficiency of the synthesis method.

[0056] Formation of photosensitive polymeric nanomicelles

[0057] The resulting photosensitive polymer is suitable for encapsulating hydrophobic and hydrophilic molecules via nanoprecipitation by removal of the organic solvent. This polymer was efficiently used for the formation and self-assembly of PEG-PDLLA-based nanomicelles.

[0058] Initially, it was verified that PEG-PDLLA is soluble in water and insoluble in THF, so 0.25 mg / ml was dissolved in 1 ml of distilled water. Then, 1 ml of THF / Dioxane water (volume:volume ratio of 4:1) was dripped onto the solubilized polymer at a rate of 1 ml / h, while stirring at 50 rpm. This allowed small bubbles of the hydrophobic solvent to form, directing the hydrophobic heads (NA) of the PEG-PDLLA polymer towards the center, immersed in water (FIG. 5A).

[0059] Subsequently, this dispersion was transferred to a dialysis membrane and dialyzed against water for 24 hours at 300 rpm. This entrainment of the hydrophobic solvent allows the nanomicelles to self-assemble, becoming dispersed in the water (FIG. 5B), as exemplified in FIG. 10.

[0060] The nanocarrier self-assembles, with a hydrophobic core (NA), a hydrophilic surface (PEG), a particle size of 4.3 nm (FIG. 5C), and a surface charge of -37.3 mV (FIG. 5D), indicating that the nanomicelles are monodisperse. Figure 6 shows that the particle sizes are within the correct range (100-200 nm) described in Figure 5 for the particle size distribution. Nanopolymersome formation was achieved using the corrected methodology with low temperatures during tosylation. The samples also show excess PEG and / or tosyl particles from the reactions. Figure 16B shows the formation of a well-formed and defined hydrophilic layer.

[0061] The synthesis method for the photosensitive polymer PEG-PDLLA described herein involves the activation of the nitrobenzyl organic groups with tosyl, followed by etherification with the terminal alcohol of the methylated PEG. This PEG-PDLLA exhibits the characteristic absorbance peak of nitrobenzyl, with an amphiphilic tendency.

[0062] The synthesis of a new photosensitive polymer PEG-PDLLA has been achieved based on the biocompatible polymer PEG and the photosensitive molecule (2-nitrobenzyl alcohol in the preferred embodiment).

[0063] The organic solvent removal nanoprecipitation method was efficiently employed for the self-assembly of PEG-PDLLA-based nanomicelles. This method allowed the formation of small bubbles of the hydrophobic solvent, directing the hydrophobic heads of the PEG-PDLLA polymer toward the center, immersed in water.

[0064] The dialysis methodology washed away the hydrophobic solvent, allowing the completion of the structuring process of the nanomicelles dispersed in water.

[0065] The nanomicelles exhibited a spherical morphology, with a hydrophobic core (DN) and a hydrophilic surface (PEG). These nanomicelles possess the ability to encapsulate hydrophobic active ingredients for transport in a hydrophilic medium. Their size of 194.3 nm and surface charge of -37.3 mV indicated that they can interact efficiently within a cellular environment and are monodisperse.

[0066] When photosensitive polymeric nanomicelles are irradiated with UV light, they exhibit a decrease in their characteristic absorbance peaks (346 and 381 nm) corresponding to the photo-disruption of the photosensitive molecule. This dislodges the photosensitive molecule from the PEG, producing an imbalance in the micellar structure and its subsequent disruption. Therefore, they possess high potential for the release of active ingredients, with external spatiotemporal control for biomedical applications. The examples described below are presented to illustrate preferred aspects of the invention but do not constitute a limitation of its scope.

[0067] Encapsulation of curcumin and methylene blue

[0068] Poly(ethylene glycol) methyl ether-poly(d,l-lactide) (PEG-PDLLA), through the opening of the lactide monomer ring, polymerizes and covalently bonds to the terminal alcohol group of PEG via esterification. In this way, the hydrophilic segment is PEG, and the hydrophobic segment is PDLLA.

[0069] PEG-Methyl ether PEG-PDLLA Lactide monomer

[0070] Initially, the lactide monomer is purified before its subsequent reaction with PEG. Between 1 and 3 g of lactide monomer are solubilized in an excess of ethyl acetate, and then crystallized at a reduced temperature. The liquid is then removed, and the purified lactide monomer is obtained.

[0071] In the procedure, 300 to 400 mg of lactide monomer in poly(ethylene glycol) methyl ether and 0.1 to 0.2 mmol of Sn(Oct)₂tin octocyanate were reacted in dry toluene under argon reflux. The reaction was heated to 120 °C for 48 hours with slow stirring. A color change indicates proper polymerization and anchoring of the copolymer. Finally, the PEG-PDLLA is precipitated with cold diethyl ether, the solvents are removed, and the polymer is dried at room temperature.

[0072] Co-encapsulation of photosensitizers

[0073] 1.45 pM methylene blue and curcumin were solubilized in 1 mL of water and 1 mL of THF / dioxane with 0.25 mg / mL of PEG-PDLLA, respectively. Self-assembly and polymersome formation then proceeded via the nanoprecipitation method described in the previous section. Subsequently, the polymer was purified by dialysis, and the unencapsulated load was removed. The loaded polymersomes were disaggregated in an acidic solution to extract the encapsulated load, which was then precipitated by centrifugation and diluted in ethanol for subsequent quantification.

[0074] The nanopolymersome obtained by the method of the present invention encapsulated the photosensitizers curcumin and methylene blue, as hydrophobic and hydrophilic fillers, with a loading capacity of 30.7% and 2.3%, respectively. Figure 10 illustrates one embodiment of the nanopolymersome assembly for the encapsulation of active ingredients (photosensitizers) with hydrophilic and hydrophobic tendencies.

[0075] Figure 9 shows the successful extraction of the curcumin and methylene blue for encapsulation, with their corresponding absorbance peaks at 425 and 655 nm (Figure 9A). These were co-solubilized in ethanol to determine the encapsulated concentration using their respective solubility curves (Figure 9B-C, equations 1 and 2). This allowed for the determination of their loading capacity (LC) and encapsulation efficiency (LE), as shown in Table 1.

[0076] Concentration Load capacity Load efficiency (uM) (LC) (%) (LE) (%)

[0077] Curcumin 0.006323 30.7 41.6

[0078] Methylene blue 0.004529 2.3 13.2

[0079] Table 1. Encapsulated concentration, loading capacity (LC) and encapsulation efficiency (LE) of methylene blue and curcumin in PEG-PDLLA nanopolymersomes.

[0080] The concentration of AM and encapsulated curcumin was determined using equations (1) and (2), as well as the determination of the loading capacity (LC) and encapsulation efficiency (LE), using equations (3) and (4).

[0081] C(pM) = (ABS-0.0267) / 51.1286; R 2 = 0.9996 (1)

[0082] C(pM) = (ABS-0.0504) / 183.18; R 2 = 0.9974 (2)

[0083] LC (%) = (mass of loaded polymersomes / mass of dye in polymersomes) x 100% (3)

[0084] LE (%) = (mass loaded with polymersomes / mass in supernatant) x 100% (4) Results

[0085] The precursors and the obtained PEG-PDLLA were evaluated by Fourier transform infrared (FT-IR) spectroscopy (FIG. 7).

[0086] PEG-methyl ether is characterized by the small 3500 cm' curve 1 of the terminal alcohol, already 2800 cm' 1 by the -CH2-CH2- groups. The Lactide monomer is mainly characterized by the 1755 cm' peak 1 due to the carbonyl groups on the ring. PEG-PDLLA is characterized by a peak extension of 1755 cm⁻¹ 1 due to ester formation and the more prominent bend of the terminal -OH at 3482 cm' 1 , with the characteristic peaks of PEG-methyl ether remaining.

[0087] The organic solvent removal nanoprecipitation method was efficiently employed for the formation and self-assembly of PEG-PDLLA-based nanopolymersomes. The absence of surfactant allows for their natural formation. Upon removal of the hydrophobic solvent by dialysis, the hydrophobic segments begin to agglomerate due to differences in water solubility. However, due to the block polymer characteristics of PEG-PDLLA, the nanocarrier self-assembles, forming a hydrophilic core, a hydrophobic phase, and a hydrophilic surface (FIG. 8A-B). This hydrophobic phase, with an approximate size of 13 nm, was observed after staining with 1% w / v phosphotungstic acid. Nanopolymersomes were obtained with an average particle size of 185.7 nm (FIG. 8C), and a surface charge of -37.7 mV (FIG. 8D), indicating that the nanopolymersomes are monodisperse.This diameter size allows for proper interaction with a cellular medium, either to adhere to the surface or to internalize, transporting photosensitizers (charges) with polar and non-polar tendencies.

[0088] When methylene blue dissolves in water, and curcumin in the organic solvent, it facilitates the encapsulation of the AM within the hydrophilic interior of the nanopolymersome, as well as the encapsulation of curcumin within its hydrophobic phase. Although the hydrophobic segment is smaller compared to the hydrophilic interior, it encapsulates hydrophobic cargoes more stably and efficiently.

[0089] Because the amphiphilic polymer PEG-PDLLA is more soluble in the hydrophobic solvent, it increases interaction with curcumin (the hydrophobic load) during polymersome self-assembly and encapsulation. Since the polymer's exterior is also hydrophilic, this reduces the AM's encapsulation capacity, causing it to orient itself outwards and thus be removed during dialysis. The AM has been encapsulated on nanoplatforms with a similar encapsulation capacity (2%) [6], just as nanopolymersomes have encapsulated hydrophobic and hydrophilic loads separately (29% and 2%, respectively)

[0018] , highlighting consistent encapsulation behavior. This demonstrates the high co-encapsulation efficiency of hydrophobic and hydrophilic photosensitizers, increasing the likelihood and potential of photodynamic therapy.

[0090] Furthermore, it postulates the nanosystem as a carrier with high potential for transporting ambiphilic cargoes, increasing its therapeutic effect for biomedical applications.

[0091] The synthesis process for PEG-PDLLA has been successfully standardized, starting with the purification of the lactide monomer through crystallization, followed by covalent functionalization with PEG-methyl ether. This copolymer was accurately characterized by FT-IR, exhibiting ambiphilic properties suitable for subsequent assembly as a nanopolymersome.

[0092] The nanoprecipitation method has allowed the correct formation of the monodisperse nanopolymersomes, in which the hydrophobic and hydrophilic phases were differentiated, with an average particle diameter size of 185.7 nm, with a surface charge of -37.7.

[0093] PEG-PDLLA-based nanopolymesosomes co-encapsulated the photosensitizers curcumin and AM as hydrophobic and hydrophilic cargo, exhibiting a cargo capacity of 30.7% and 2.3%, respectively. This suggests that the loaded nanosystems have high potential for photodynamic therapy and for transporting ambiphilic cargo.

[0094] It should be understood that the present invention is not limited to the modalities described and illustrated, since, as will be evident to a person versed in the technical subject, there are possible variations and modifications which, by preserving the spirit and scope of this invention, are understood to be within the scope of the attached claims.

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Claims

CLAIMS 1. A method for obtaining an amphiphilic photosensitive polymer for the encapsulation of hydrophobic and hydrophilic active ingredients, characterized in that it comprises the following steps: activation of a photoresponsive molecule by tosylation of its organic group; functionalizing poly(ethylene glycol) PEG and methyl ether-poly(d,l-lactide) PDLLA by means of opening the Lactide monomer ring, by polymerization and covalent bonding with the terminal alcohol group of PEG, through esterification with the tosylated organic group; precipitating the obtained PEG-PDLLA polymer in diethyl ether; removing the solvent by filtration or centrifugation of the PEG-PDLLA polymer; drying the product under vacuum; obtaining the amphiphilic PEG-PDLLA polymer.

2. Method for obtaining an amphiphilic photosensitive polymer of claim 1 characterized in that the photoresponsive molecule corresponds to nitrobenzyls, 3. Method for obtaining an amphiphilic photosensitive polymer of claims 1 and 2 characterized in that the activation of the molecule is carried out by tosylation of its alcohol group.

4. Method for obtaining an amphiphilic photosensitive polymer of claims 1 to 3 characterized in that the target molecule is 2-nitrobenzyl alcohol.

5. Method for obtaining an amphiphilic photosensitive polymer of claim 1 characterized in that the functionalization of PDLLA with the tosylated organic group in the presence of PEG is carried out between 1 and 5 mg of PEG-methylated and 2 to 6 mg of 4-toluenesulfonyl.

6. Method for obtaining an amphiphilic photosensitive polymer of claim 1 characterized in that the precipitation of the obtained PEG-PDLLA polymer in diethyl ether is carried out under the following operating conditions: dissolve the mixture in dichloromethane in a cold bath; add between 1 and 5 ml of triethylamine dropwise to the solution obtained; stir the resulting solution for 3 hours in the cold bath; stir at room temperature for approximately 48 hours.

7. Method for obtaining an amphiphilic photosensitive polymer of claim 1 characterized in that the PEG-PDLLA photosensitive polymer is deprotonated in the presence of potassium bicarbonate in dimethylformamide.

8. Capsules obtained from the nanopolymersome obtained by the method of claims 1 to 7 characterized in that they have a particle diameter between 100 and 200 nm.

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