KR101577264B1 - Preparation method of hydrophobic photodynamic chemicals solubilized hydrophilic positively-charged polymers and drug delivery systems using the same - Google Patents

Abstract

The present invention relates to a method for preparing a hydrophilic positive charge polymer complex in which a hydrophobic photodynamic drug is encapsulated and a drug delivery system using the polymer complex. More particularly, the present invention relates to a branched polyethyleneimine (bPEI) or a reducible bPEI To a polymer complex in which a hydrophobic photodynamic drug pheophorbide (PheoA) is encapsulated in a hydrophilic positively charged polymer, and a method for producing the same. The present invention also provides a composition for a photoreactive anticancer comprising a polymer complex in which a hydrophobic branching type positively charged polymer is encapsulated with a pheophorbide (PheoA). The present invention also provides a drug delivery composition comprising a polymer complex in which a hydrophobic photodynamic drug is encapsulated in a hydrophilic branching type positive charge polymer.

Description

The present invention relates to a method for producing a hydrophilic positively charged polymer complex in which a hydrophobic photodynamic drug is encapsulated and a drug delivery system using the polymer complex,

The present invention relates to a method for producing a hydrophilic positively charged polymer in which a hydrophobic photodynamic drug is encapsulated, and a drug delivery system using the polymer.

Because hydrophobic photodynamic or photo-responsive chemical drugs are not well soluble in water, solubilization with hydrophilic polymers or nanostructures is needed. Solubilization of hydrophobic photodynamic chemical agents in aqueous phase is mainly achieved by (1) chemically bonding a hydrophobic chemical to a hydrophilic polymer, or (2) hydrophobicity in the hydrophobic region of a nanoparticle made using an amphiphilic material It is obtained by enclosing the chemical substance in a physical way. (3) solubilize the hydrophobic chemical through non-porous bonding with the hydrophilic polymer, and (4) physically encapsulate the nanoparticle with the cavity.

In the application of gene transfer, gene expression efficiency can be improved by using a photodynamic chemical agent or a light-responsive chemical structure. Examples reported in the literature include a method of irradiating a gene to a cell cultured in a cell culture medium containing a hydrophobic photodynamic chemical drug within 4 hours after the gene carrier is treated to allow the gene carrier to enter the cell more efficiently, So that it can escape from the same organelle. Also, when nanoparticles encapsulating photodynamic chemical drugs by physical or chemical methods are used as gene carriers, they are irradiated within 4 hours to escape from endosomes, thereby enhancing the effect of the encapsulated gene drug.

The present inventors have also found that a hydrophobic branched photopolymerizable polymer having solubilized a hydrophobic photodynamic chemical pheophorbide a is prepared and a hydrophobic chemical agent capable of exhibiting an anticancer effect of a drug solubilized in the polymer itself It can be used as a carrier and it can form a complex with negatively charged gene or protein because it has a positive charge and it can be co-delivered with different physicochemical or biological properties by using one drug delivery system Thus completing the present invention.

Korean Registered Patent No. 10-1136555 (Published Feb. 20, 2011)

It is an object of the present invention to provide a polymer composite in which a hydrophobic photodynamic drug is encapsulated in a hydrophilic branching type positive charge polymer.

Another object of the present invention is to provide a method for preparing a photoreceptor, which comprises the steps of dissolving a hydrophobic photodynamic drug and a hydrophilic branching type positive charge polymer in a solvent and stirring; And a step of dialyzing and filtering the agitated mixture.

It is still another object of the present invention to provide a composition for photoreactive anticancer comprising a polymer complex in which a hydrophobic branching type positive charge polymer is encapsulated with a pheophorbide (PheoA).

Another object of the present invention is to provide a drug delivery composition comprising a polymer complex in which a hydrophobic photodynamic drug is encapsulated in a hydrophilic branching type positive charge polymer.

The hydrophilic branching type positively charged polymer obtained by solving the hydrophobic photodynamic chemical substance prepared in the present invention can be obtained by a method of enclosing a drug in the inner space of a dendrimer (Medina SH, El-Sayed MEH, Chem Rev 109 (2009), 3141-3157) . ≪ / RTI > For example, the internal secondary amine or tertiary amine of polypropyleneimine dendrimer is hydrophobic under basic conditions, and hydrophobic chemical can be enclosed in this hydrophobic space.

As described above, the present invention relates to a secondary amine (hereinafter referred to as " secondary amine ") present in the internal space of a branched polyethyleneimine and a reducing branched polyethyleneimine having a disulfide bond as a stimulus- ) And tertiary amines may have a hydrophobic environment at pH above their pKa (mainly secondary amine is pH 7 and tertiary amine is pH 5-6), and in this hydrophobic environment, a hydrophobic photodynamic chemical, A pheophorbide a can be enclosed. That is, a hydrophilic positively charged macromolecule can be prepared by solubilizing the hydrophobic photodynamic chemical pheophorbide a by a physical method.

The hydrophilic positively charged polymer solubilized with the hydrophobic photodynamic chemical drug pheophorbide a can be used as a hydrophobic chemical carrier which can exhibit the anticancer effect of the solubilized drug itself and has a negative charge, The band can be complexed with genes or proteins to co-deliver drugs of different physico-chemical or biological properties using a single drug delivery system.

Particularly, after the reducing branched polyethylenimine and its gene or protein complex, in which the pheophorbide a is solubilized, enter the cell, the disulfide bond present in the reducing branched polyethyleneimine has a high concentration in the cytoplasm or nucleus (Pheophorbide a) which is solubilized in the polymer because it can be cleaved by the glutathione present in the drug, and the drug, including the gene and the protein, can be released rapidly, and a better drug effect can be obtained .

In the present invention, a nanocomposite formed of a branched polyethylenimine and a gene in which pheophorbide a is solubilized is introduced into cells through endocytosis, and the hydrogen ion buffering ability of the polyethyleneimine is utilized After a sufficient time (about 12 hours) to allow the nanocomposite to escape from the endosome, the light is irradiated and the promoter of the gene using the reactive oxygen species (ROS) produced by the photodynamic chemical drug And thus higher gene expression efficiency can be obtained.

In order to achieve the above object, the present invention provides a polymer complex in which a hydrophobic photodynamic drug is encapsulated in a hydrophilic branching type positive charge polymer. Preferably, the hydrophobic photodynamic drug is contained in an amount of 0.5 to 50% by weight based on the total weight of the polymer composite.

Also, the present invention provides a method for preparing a photopolymerizable composition comprising: dissolving a hydrophobic photodynamic drug and a hydrophilic branched positive charge polymer in a solvent and stirring; And a step of dialyzing and filtering the stirred mixture.

Preferably, the hydrophobic photodynamic drug is selected from the group consisting of pheophorbide a (PheoA), phthalocyanine, Porphyrin, Chlorin e6, Indocyanine green, Foscan ) Or hypericin, and the hydrophilic branched positive charge polymer is branched polyethyleneimine (bPEI) or reducible bPEI, but is not limited thereto.

The present invention also provides a composition for a photoreactive anticancer comprising a polymer complex in which a hydrophobic branching type positively charged polymer is encapsulated with a pheophorbide (PheoA). Preferably, the hydrophilic branched positive charge polymer is branched polyethyleneimine (bPEI) or reducible bPEI, but is not limited thereto. Preferably, the cancer is but is not limited to breast cancer (MCF7 cells) or cervical cancer (HeLa cells).

The present invention also provides a drug delivery composition comprising the polymer complex in which a hydrophobic photodynamic drug is encapsulated in the hydrophilic branching type positive charge polymer.

Preferably, the hydrophobic photodynamic drug is selected from the group consisting of pheophorbide a (PheoA), phthalocyanine, Porphyrin, Chlorin e6, Indocyanine green, Foscan ) Or hypericin, and the hydrophilic branched positive charge polymer is branched polyethyleneimine (bPEI) or reducible bPEI, but is not limited thereto.

In particular, the composition is characterized in that it carries a negatively charged molecular material, which may be DNA, RNA, protein, peptide or biologically active drug, but is not limited thereto.

The anticancer composition or composition for drug delivery according to the present invention may contain a pharmaceutically effective amount of a drug alone or may include one or more pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutically effective amount as used herein refers to an amount sufficient for a drug to be administered to an animal or a human to exhibit a desired physiological or pharmacological activity. However, the pharmaceutically effective amount may be appropriately changed depending on the age, body weight, health condition, sex, administration route and treatment period of the subject to be administered.

The term "pharmaceutically acceptable" as used herein means physiologically acceptable and does not generally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to a human. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

The anticancer composition or drug delivery composition according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or muscular, and the dose of the drug may vary depending on the route of administration, the age, sex, The severity of the disease, and the like. In addition, the polymer composition for drug delivery of the present invention may be administered in combination with a known compound capable of enhancing the desired effect of the drug.

The " drug " used in the present invention is a substance capable of inducing a desired biological or pharmacological effect by promoting or inhibiting a physiological function in the body of an animal or human, and is a chemical or biological substance (1) prevent undesired biological effects such as infection prevention and have a preventive effect on the organism, (2) alleviate the condition caused by the disease, for example, the pain or infection resulting from the disease And (3) mitigate, reduce or completely eliminate disease from organic matter.

The hydrophilic positively charged polymer solubilized with the hydrophobic photodynamic chemical drug pheophorbide a of the present invention can be used as a hydrophobic chemical drug delivery material capable of exhibiting the anticancer effect of the solubilized drug itself, Therefore, it is possible to co-deliver drugs of different physico-chemical or biological characteristics by using a single drug delivery system by forming a complex with a negatively charged gene or protein. Particularly, after the reducing branched polyethylenimine and its gene or protein complex, in which the pheophorbide a is solubilized, enter the cell, the disulfide bond present in the reducing branched polyethyleneimine has a high concentration in the cytoplasm or nucleus (Pheophorbide a) which is solubilized in the polymer because it can be cleaved by the glutathione present in the drug, and the drug, including the gene and the protein, can be released rapidly, and a better drug effect can be obtained .

1 is HeLa (A), MCF7 (B ) , and the toxicity of cancer MCF7 / ADR-RES (C) RPC-bPEI for cell _{0 .8 kDa} -PheoA _6% and a peoh Four carbide (pheophorbide a) (dark- toxicity and light-toxicity (exposure for 36 h, n = 6).
FIG. 2 shows the result of MCF7 cells infused with RPC-bPEI _{0 .8 kDa} -PheoA _{6 %} and pheophorbide a for 4 hours in a cell culture medium containing serum (the concentration of treated PheoA was 0.5 μg / mL ).
Figure 3 shows the particle size and zeta potential of the polymer / gene complex.
Figure 4 shows the results of transfection of the polymer / gene complex (weight ratio 5) to MCF7 cells for 24 hours with or without light irradiation. The complex was irradiated with light 12 hours after treatment of the cells.
FIG. 5 shows measurement results of reactive oxygen species (MCF7 cells) produced by PheoA and RPC-bPEI _{0 .8 kDa} -PheoA _{6 %} with or without light irradiation.
Figure 6 shows the results of NFKB activation produced by RPC-bPEI _{0 .8 kDa} -PheoA _{6 %} with or without light irradiation (MCF7 cells).
Figure 7 shows the particle size and zeta potential of a polymer / protein complex.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

< Example  1> Perofabide  a ( pheophorbide  a; PheoA )end Solubilized Branches Poly Ethyleneimine or reducing Branches  Production of polyethylene imine

Pheophorbide a (PheoA) was synthesized using branched polyethyleneimine (bPEI) of various molecular weights or its reducible bPEI (Kang HC et al., Biomaterials 32 (2011) 1193-1203) . The prepared polymer and PheoA are dissolved in dimethyl sulfoxide (DMSO) and stirred for 24 hours. The polymer-PheoA solution is put into the dialysis membrane, the dimethyl sulfoxide is removed from the aqueous phase by dialysis, and the PheoA precipitated or not solubilized in the aqueous phase is removed by filtration. The filtered polymer-PheoA aqueous solution is lyophilized to obtain a branched polyethylenimine (bPEI-PheoA) and a reducing branched polyethyleneimine (RPC-bPEI-PheA) in which PheoA is solubilized.

The PheoA content in the polymer in which the prepared PheoA drug is solubilized is determined by dissolving the polymer in dimethylsulfoxide and using the concentration-absorbance standard curve of the drug obtained at about 410 nm. The PheoA content in the reducing polymer is obtained by treating PheoA with 20 mM of dithiothreitol (DTT) at 37 ° C for 10 minutes. The obtained PheoA is dissolved in dimethyl sulfoxide and evaluated using the concentration-absorbance standard curve of the drug.

When the molecular weight is by using a 0.8kDa, 1.2kDa, 1.8kDa of branched polyethyleneimine _{(bPEI 0 .8 kDa, bPEI 1.2kDa} , bPEI 1 .8 kDa) sikyeoteul solubilizing PheoA, showed high PheoA content than the target amount. For example, when the target content be 10wt%, the actual _{bPEI 0 .8 kDa -PheoA, bPEI 1.2kDa} -PheoA, bPEI 1 .8 46wt% content of PheoA solubilized in -PheoA _kDa, respectively, 39wt%, 24wt% . In the process of dissolving lyophilized bPEI-PheoA in the aqueous phase again, some of the freeze-dried bPEI-PheoA did not dissolve and PheoA precipitated. However, if the solubilizing PheoA using a 25kDa bPEI _{25kDa, 25kDa} bPEI was able to solubilize the PheoA slightly higher than the target content to the content PheoA -PheoA, lyophilized bPEI -PheoA _25kDa have also been re-dissolve in the water phase. In addition, when linear polyethyleneimine of 25 kDa was used, PheoA was not solubilized. That is, branched polyethylenimine having a high molecular weight is suitable for stable solubilization of PheoA.

bPEI _{0 .8} reducing _kDa branched polyethyleneimine made using; when using the (RPC-bPEI _{0 .8 kDa} 15 kDa molecular weight of the polymer used ~ 40 kDa), the ability to target similar to the content of solubilizing the actual content PheoA And the lyophilized RPC-bPEI-PheoA was also dissolved in the water phase.

< Example  2> Perofabide  a ( pheophorbide  a; PheoA )end Solubilized Branches  Polyethyleneimine or reducing Branches  Polyethyleneimine Intracellular  Inflow capacity and Light responsiveness  Anticancer effect

The photoreactive anticancer effect of pheophorbide a (PheoA) contained in the branched polymer was evaluated by MTT, a well - known cytotoxicity assay. 5,000 cells per well of a 96-well plate were cultured for one day, and cells were treated with various concentrations of PheoA-containing polymer (bPEI _{25 kDa} -PheoA or RPC-bPEI _{0 .8 kDa} -PheoA) or PheoA drug . After 12 hours, the cells were changed to fresh cell culture medium. Cells were cultured for 24 hours at 677 nm, and MTT solution was added to evaluate cytotoxicity. In order to evaluate the presence of light-toxicity, a dark-toxicity experiment is performed as a control.

The degree of cellular uptake of chemical drugs is analyzed by flow cytometry using the PheoA drug's own fluorescence. 500,000 cells per well of a 6-well plate were added and cultured for 24 hours. After the cells were treated with PheoA or PheoA-solubilized polymer for 4 hours, the cells were detached, and PheoA .

To evaluate the light-toxicity of 6 wt% PheoA-solubilized reducing branched polyethyleneimine (RPC-bPEI _{0 .8 kDa} -PheoA _6% ; molecular weight about 20 kDa) As a result, the anticancer effect was greater than that of PheoA alone (FIG. 1 and Table 1). That is, the optical response of anti-cancer effect of the reducing branched polyethyleneimine the PheoA is solubilized in the case of MCF7 cells compared to anti-cancer effects of PheoA (concentration of 50% cell death) IC ₅₀ is about 2 times, MCF7 / ADR-RES cells , About 5 to 6 times, and about 3 times for HeLa cells. However, cytotoxicity of _25kDa bPEI -PheoA do not differ by the presence or absence of irradiation light, bPEI _25kDa optical response of the anti-cancer effect -PheoA was not observed.

PheoA and RPC-bPEI _{0 .8 kDa} -PheoA when the handle _6% in MCF7 cells, in the case of the reducing branched polyethyleneimine PheoA solubilization than the case treated with PheoA alone has about 6 times higher intracellular influx ability (Fig. 2). This explains that the _{RPC-bPEI 0 .8 kDa -PheoA 6} % of the intracellular influx ability, in spite of falling than PheoA and shows better optical response of anti-cancer effect.

HeLa, MCF7 and MCF7 / ADR-RES _.8 one RPC-bPEI ₀ treatment in cells _kDa -PheoA _6% and peoh Four carbide for a cancer toxicity (dark-toxicity) and phototoxicity (light-toxicity) of (pheophorbide a) IC ₅₀ (exposure for 36 hours, n = 6) IC ₅₀ (μg / mL) PheoA _{RPC-bPEI 0 .8 kDa -PheoA 6} % Cancer toxicity
(dark-toxicity) Phototoxicity
(light-toxicity) Cancer toxicity
(dark-toxicity) Phototoxicity
(light-toxicity) HeLa 3.0 0.42 2.6 0.14 MCF7 6.5 0.8 6.3 0.4 MCF7 / ADR-RES 5.1 1.4 7.1 0.25

< Example  3> Perofabide  a ( pheophorbide  a; PheoA )end Solubilized Branches  Polyethyleneimine or reducing Branches  Production of gene complexes of polyethyleneimine, gene expression effect and mechanism

The branched polyethylenimine (bPEI-PheoA, RPC-bPEI-PheoA) with solubilized PheoA forms a negatively charged gene and nanosized nanocomposite because it is positively charged. That is, a negative charge solution containing a positive charge polymer solution and a gene is prepared, and then the two solutions are mixed to form a nanocomposite. 100,000 cells per well of a 12-well plate are incubated for 24 hours and then replaced with serum-free cell culture medium one hour before the preparation of the prepared nanosynthesis complex. Nano-gene complex is transfected into cells, and after 4 hours, serum-free cell culture medium is replaced with serum-containing cell culture medium and cells are cultured for 8 hours. After irradiation with light of 677 nm, the cells were cultured for 12 hours, and gene expression efficiency was evaluated.

_{RPC-bPEI 0 .8 kDa / pDNA} , RPC-bPEI 0 .8 kDa -PheoA 2% / pDNA, RPC-bPEI 0 .8 kDa -PheoA 6% / pDNA complexes prepared in different weight ratio (WR), like Figure 3, some The particle size of about 100 nm was observed at a weight ratio of 5 and the zeta potential was increased as the amount of positively charged polymer increased. When the transfection of the complex in MCF7 cells, as shown in Figure 4, the weight ratio of _{5 RPC-bPEI 0 .8 kDa /} pDNA, RPC-bPEI 0 .8 kDa -PheoA 2% / pDNA, RPC-bPEI 0 .8 kDa The gene expression efficiency of the PheoA _6% / pDNA complex was 1.6 times, 5.5 times, and 13.8 times higher than that without light, respectively.

To elucidate the mechanism of gene expression enhancement of PheoA - solubilized polymer, we evaluated the production of reactive oxygen species and NFκB activation ability. PheoA produces active oxygen species during light irradiation. PheoA-solubilized polymer (RPC-bPEI _{0 .8 kDa} -PheoA _{6 %} ) also binds to reactive oxygen species to produce reactive oxygen species. Was evaluated using a reagent (DCFDAH ₂ ). 100,000 MCF7 cells are placed in a 35-mm dish and incubated for 24 hours. Cells are treated with PheoA or RPC-bPEI _0.8 kDa -PheoA _6% for PheoA concentration of 0.5 ug / mL. After 4 hours, the cell culture medium is changed with phosphate buffer, and then the light is irradiated at 677 nm and DCFDAH ₂ is added, followed by further incubation for 30 minutes. After washing the cells several times with phosphate buffer, intracellular fluorescence induced by active oxygen species is measured using a confocal microscope.

In order to evaluate whether the active oxygen species activates NFκB, NFκB-Luc gene, in which luciferase can be expressed when NFκB is present, was used. 200,000 MCF7 cells are plated on a 12 well plate for 24 hours and then transfected with the bPEI _{25 kDa} / pNFκB-Luc complex. For 24 hours, further treated after the culture, PheoA or _{RPC-bPEI 0 .8 kDa -PheoA 6} %. After 4 hours, the light is irradiated at 677 nm, and after further incubation for 2 hours, the expression level of luciferase is measured.

As shown in FIG. 5, the degree of production of reactive oxygen species was evaluated using fluorescence intensity. When the control light of MCF7 cells was irradiated with light, the intensity of relative fluorescence was not changed, but when the light was irradiated to PheoA-treated cells, the fluorescence intensity was increased by about 2.1 times. Further, the fluorescence intensity was increased by about 1.8 times when the cells treated with _{RPC-bPEI 0 .8 kDa -PheoA 6} % also was a squat light. For PheoA and _{RPC-bPEI 0 .8 kDa -PheoA 6} %, shows that by the irradiation of light that the active oxygen species generated.

FIG. 6 shows the expression level of NFkappaB according to whether light was irradiated or not. In the case of control cells, the presence or absence of light irradiation did not induce the difference in NFkappaB expression. However, RPC-bPEI _0.8 kDa -PheoA _6% When light is irradiated on the treated cells, the expression level of NFkB increases by about 6.6 times. That is, when the cells are treated with RPC-bPEI 0.8 _kDa -PheoA _6% , active oxygen species are produced in the cells, and this reactive oxygen species again increases the expression amount of NFκB. Increased NFkB may act on a specific promoter of the gene transferred into the cell to reactivate the promoter that has lost activation, resulting in increased protein expression of the transferred gene.

< Example  4> Perofabide  a ( pheophorbide  a; PheoA )end Solubilized Branches  Polyethyleneimine or reducing Branches  Preparation of protein complex of polyethyleneimine

The branched polyethylenimine (bPEI-PheoA, RPC-bPEI-PheoA) with solubilized PheoA forms a negatively charged protein and nanoscale nanocomposite because it is positively charged. That is, a negative charge solution including a positive charge polymer solution and a protein is prepared, and then the two solutions are mixed to form a nanocomposite.

The _{RPC-bPEI 0 .8 kDa -PheoA 6} % / BSA conjugate in a variety of weight ratio (WR) was prepared using the _{RPC-bPEI 0 .8 kDa -PheoA 6} % and bovine serum albumin (BSA). As shown in FIG. 7, the particle size of the nanocomposite was about 370 nm in weight ratio 1, 200 nm in weight ratio, and 10 nm in weight ratio 5, and their zeta potentials were about 5 to 10 mV.

Claims (15)

A polymer complex in which a hydrophobic photodynamic drug is physically encapsulated in a hydrophilic branching type positive charge polymer, which is branched polyethyleneimine (bPEI) or a reducing bPEI (reducible bPEI). The method of claim 1, wherein the hydrophobic photodynamic drug is selected from the group consisting of pheophorbide a (PheoA), phthalocyanine, Porphyrin, Chlorin e6, Indocyanine green, (Foscan), and hypericin (Hypericin). delete The polymer composite according to claim 1, wherein the hydrophobic photodynamic drug is contained in an amount of 0.5 to 50% by weight based on the total weight of the polymer composite. A hydrophobic photodynamic drug and a hydrophilic branching type positive charge polymer having branched polyethyleneimine (bPEI) or reducing bPEI (bpEI) dissolved in a solvent; And
And a step of dialyzing and filtering the agitated mixture, wherein the hydrophobic photodynamic drug is physically encapsulated in the hydrophilic branching type positively charged macromolecule. 6. The method of claim 5, wherein the hydrophobic photodynamic drug is selected from the group consisting of pheophorbide a (PheoA), phthalocyanine, Porphyrin, Chlorin e6, Indocyanine green, (Foscan) and hypericin (Hypericin). &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; delete For light-responsive anticancer chemically containing a polymer complex in which a physiologically encapsulated pheophorbide (PheoA) is attached to a hydrophilic branching type positive charge polymer, which is a branched polyethyleneimine (bPEI) or a reducible bPEI Composition. delete [Claim 9] The composition according to claim 8, wherein the cancer is breast cancer or cervical cancer. A composition for drug delivery comprising a polymer complex in which a hydrophobic photodynamic drug is physically encapsulated in a hydrophilic branching type positive charge polymer having branched polyethyleneimine (bPEI) or reducing bPEI (reducible bPEI). 12. The method of claim 11, wherein the hydrophobic photodynamic drug is selected from the group consisting of pheophorbide a (PheoA), phthalocyanine, Porphyrin, Chlorin e6, Indocyanine green, Wherein the drug is one selected from the group consisting of Foscan and Hypericin. delete 12. The composition for drug delivery according to claim 11, wherein the composition delivers a negative chargeable molecular substance. 15. The drug delivery composition according to claim 14, wherein the negative chargeable molecular material is DNA, RNA, protein, peptide or biologically active drug.

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