CN102499924B - Application of porphyrin modified by diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or ethylene diamine tetraacetic acid - Google Patents

Abstract

The invention discloses an application of porphyrin modified by diethylene triamine pentaacetic acid or ethylene diamine tetraacetic acid or ethylene diamine tetraacetic acid, which has a structure shown below. Experiments show that the porphyrin modified by the diethylene triamine pentaacetic acid or the ethylene diamine tetraacetic acid or the ethylene diamine tetraacetic acid has good therapeutic effects during photodynamic therapy of a prostatic hyperplasia model of a rat.

Description

The purposes of diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin

Technical field

The present invention relates to the purposes of diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin.

Background technology

Continuous development along with the national economy level, China has entered the aging society stage, (benign prostate hyperplasia BPH) also more and more becomes the aged male of the influence common factor [1] of quality of life and as the commonly encountered diseases-benign prostatic hyperplasia of elderly men.Benign prostatic hyperplasia also claims prostate hyperplasia, is the commonly encountered diseases of middle-aging male.According to domestic statistics, 4O year the prevalence of male prostatic hyperplasia be that sickness rate increases along with the increase at age after 43%, 50 years old, 10 years old prevalence of every increase of age increases 1O%, reaches later in 75 years old [2] more than 90%.The pathogenic factor of hyperplasia of prostate is still not really clear.Most scholars think may be relevant with the dysequilibrium of gonadal hormone in the body.BPH causes prostatic increase mainly by a matter and body of gland composition hypertrophy, and cause bladder outlet obstruction (BOO) in two kinds of different modes, a kind of is to block because of the firm static that lump compressing that hypertrophy forms causes, another kind blocks [3] by comprising that matter and capsula prostatica are shunk the dynamic property that causes between neck of bladder, prostate smooth muscle tissue.Prostatic hyperplasia can cause dysuria, pain, bradyuria, initiation uremia etc.Have a strong impact on the quality of life of middle-aging male.Prostate hyperplasia is on pathologic angle, and cytosis is a hypertrophy, and cell increases to loose.It is cytosis that the hyperplasia of prostate pathology confirm, rather than the cell hypertrophy.At present the Therapeutic Method of BPH has: 1. Drug therapy; 2. operative treatment; 3. Minimally Invasive Surgery treatment.The uncertain therapeutic efficacy of Drug therapy is cut, and the cycle, long onset was slow, and more drug side effect and easily recurrence are arranged, and operative treatment exists that wound is big, complication is many, post-operative recovery waits defective slowly.Thereby the interventional therapy of Wicresoft has become the first-selection of clinical treatment BPH.Photodynamic therapy (PDT) is based on rayed can be transformed into active substance with inert substance.Present photodynamic therapy produces oxidation environment by the light activated material of the rayed of special wavelength (being photosensitizer).After light energy was absorbed by photosensitizer molecule, excited molecule transmitted an electronics to contiguous oxygen molecule, produced oxygen-derived free radicals or energy and was delivered to oxygen molecule from activated photosensitizer molecule, produced the singlet oxygen of excited state.The oxygen class material (ROS) that these reactions produce exists the phase short, but oxidability is strong, the reaction of energy inducing cytotoxic, apoptosis and destruction.The exploitation of novel photosensitive agent is current international research emphasis, and each medical research institute has developed novel photosensitive agent separately tin (II) etiopurpurin-dichloride, mTHPC, ALS2PC, ALA, photofrinII and motexafinlutetium etc.Photodynamics is mainly used in the treatment tumor, dermatosis, diseases such as optical fundus macula lutea at present.The advantage of photodynamic therapy be toxicity little, produce effects fast, targeting is strong, when killing and wounding proliferative cell, do not jeopardize normal structure. simultaneously, PDT is easy and simple to handle, the damage side effect is little, can carry out repeatedly, patient old to some, the overall health of patients difference also can treat, therapeutic effect to some non-neoplastic disease such as nevus flammeus, psoriasis, senile optical fundus maculopathy and atherosclerosis etc. is also satisfactory. owing to have above-mentioned advantage, the range of application of PDT just is being generalized in the more benign disease and is going.PDT treatment BPH rarely had report both at home and abroad.Our early-stage Study is found and has been synthesized a series of photosensitizer with good physicochemical property.Studies show that the almost dark toxicity of these a series of photosensitizer is very low, but the reaction of good singletstate productive rate energy inducing cytotoxic, apoptosis and destruction are arranged under the laser excitation of specific wavelength.We are based on this result, and imagination is used for these a series of novel photosensitizer the photodynamic therapy of BPH.Early-stage Study finds that the photodynamic therapy of compd A 1 can significantly kill and wound outgrowth prostata tissue.Thereby be expected to develop method and the photosensitizer of a kind of novel treatment BPH.

List of references:

1. that man of virtue and ability group, Sun Guang.China's urological diseases diagnosis and treatment guide (2009 editions).Beijing: People's Health Publisher, 2009:113-115.

2. Wang Ren is suitable, Xie Hengsheng, Mo Kejian etc.The present situation and the progress of selective ' beta '3 adrenergic energy receptor alpha 1 antagonist for treating benign prostatic hyperplasia.China's magazine of urology surgery, 2002,8:508-510.

3. Ge Jingping, Gong Juan, Ma Hongqing, etc. the clinical observation [J] of naftopidil treatment benign prostatic hyperplasia companion overactive bladder. Chinese andrology magazine, 2008,14 (10): 927-930.

Summary of the invention

The objective of the invention is to overcome the deficiencies in the prior art, the purposes of diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin is provided.

Technical scheme of the present invention is summarized as follows:

Diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin are in the application of preparation treatment benign prostatic hyperplasia medicine, and described diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin have following structure:

Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;

R1=-X-Y；

R2=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

R3=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

R4=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

N=2,3,4,5 or 6;

Described medicine is the optical dynamic therapy medicine.

Experimental results show that: diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin have shown excellent curative in photodynamic therapy rat prostate model of hyperplasia.

Description of drawings

Fig. 1 observes for the rat prostate tectology.

Wherein: A. rats in normal control group prostate acinus; B. model group rat prostate acinus; C. simple laser irradiation group rat prostate acinus; D. simple photosensitizer (A1) group rat prostate acinus; E.PDT-A1 low dosage (0.5mg/kgweight) treatment group; Dosage among the F.PDT-A1 (1mg/kgweight) treatment group; G.PDT-A1 high dose (2mg/kgweight) treatment group normal control group.

Fig. 2 is rat knot rectal tissue morphological observation.

Wherein: A. normal control group knot rectum; B. the model group rat is tied rectum; C. simple laser irradiation group rat knot rectum; D. only simple photosensitizer (A1) group rat knot rectum; E.PDT-A1 low dosage (0.5mg/kgweight) treatment group; Dosage among the F.PDT-A1 (1mg/kgweight) treatment group; G.PDT-A1 high dose (2mg/kgweight) treatment group normal control group.

The specific embodiment

The preparation method of diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin is referring to Chinese patent application CN201010184331.7.

Embodiment 1

Diethylene-triamine pentaacetic acid modified porphyrin chemical compound is to the therapeutical effect of rat prostate model of hyperplasia:

Diethylene-triamine pentaacetic acid modified porphyrin chemical compound (A1):, structural formula is:

Wherein M is H

R1=-X-Y R2=R3=R4=-H

Experimentation:

1. the foundation of BPH rat models and grouping: test and preceding 1 week place experimental situation to raise 35 SD male rats, 20～25 ℃ of room temperatures.Be divided at random that normal control group, model group, simple laser irradiation group, simple photosensitizer (A1) (2mg/Kg) are organized, totally 7 groups of PDT-A1 treatment groups (0.5mg/Kg, 1mg/Kg, 2mg/Kg treatment group), 5 every group.After adaptability fed for 1 week, each organizes rat with 10% chloral hydrate 300mg/kg intraperitoneal injection of anesthesia, undergo surgery under the sterile working, except that the normal control group free but do not excise the testis, all the other 3 groups are all excised skin suture behind the bilateral testes, local 75% alcohol disinfecting is treated conventional raising the in the clear-headed naturally rearmounted cage of animal.After recovering for 1 week naturally, the excision testis is respectively organized every of rat and is given the molten testosterone propionate 0.1mL of olive oil (containing testosterone propionate 0.5mg), every day 1 subcutaneous injection, matched group gives 0.9% sodium chloride injection 0.1mL, every day 1 subcutaneous injection, 4 groups of equal continuous subcutaneous injection 30d.

2.PDT therapeutic scheme: after 3 weeks of modeling, carry out the PDT treatment, simple laser irradiation group is not given photosensitizer (A1), and the laser irradiation energy density is 135J/cm ², spot diameter is 1.5cm; Simple photosensitizer (A1) group press 2mg/kg body weight dosage and inject photosensitizer A1 in the body of gland of prostatitis, irradiation not after the administration; PDT-A1 treatment group is pressed photosensitizer dosage 0.5mg/kg, 1mg/kg, 2mg/kg body weight and is injected in the body of prostate, is 135J/cm with energy density behind the 15min ²Laser illumination body of prostate 15mi n treatment after move to the darkroom, lucifuge is raised when drawing materials.

3. prostate weight in wet base and exponential mensuration: photodynamic therapy is after one week, put to death and respectively organize rat, carefully cut open and get two flank prostate, claim the rat prostate weight in wet base with electronic balance, and calculating prostate index (PI=prostate weight in wet base (mg)/rat body weight (g)), (seeing Table 1)

4. prostata tissue morphological observation: each is organized rat and wins prostate, is fixed in 4% formaldehyde, one sodium dihydrogen phosphate/sodium hydroxide solution by group, and through dehydration, paraffin embedding, section after the HE dyeing, is observed .(with ordinary optical microscope and seen Fig. 1)

5. rectum and bladder body morphological observation: each is organized rat and wins bladder and rectum, is fixed in 4% formaldehyde, one sodium dihydrogen phosphate/sodium hydroxide solution by group, and through dehydration, paraffin embedding, section after the HE dyeing, is observed .(with ordinary optical microscope and seen Fig. 2)

The result: 1. each experimental group is to the influence of rat prostate index (PI)

Photodynamic therapy to the prostate weight in wet base of prostatic hyperplasia rat due to the androlin and the exponential result of influence of prostate shown in table l. each group rat prostate index is carried out variance analysis, and statistical result shows: model group rat prostate weight in wet base and prostate index are all apparently higher than the normal control group; Simple light is compared no difference of science of statistics with simple photosensitizer group with the animal model group according to group; All the other each treatment groups all significantly suppress the hypertrophy of rat prostate, and significant difference is arranged, and certain metering dependency is arranged.

Table 1.A1-PDT is to the influence of experimental rat prostate weight in wet base and prostate index (PI)

Compare * P＜0.05 with model group

2. Fig. 1-A. rats in normal control group prostate acinus; The rats in normal control group prostatic epithelium is the monolayer column, and the lumen of gland rule is smooth; Intracavity has a spot of acidic secretion thing; Glandular epithelium karyon circle is positioned at basilar part;

Fig. 1-B. model group rat prostate acinus; Cell is arranged closely, and nuclear is positioned at basilar part, and the lumen of gland epithelium obviously is the nodositas hypertrophy, and the expansion of sawtooth sample is obvious, and it is outstanding to intracavity that the part body of gland is mamillary; Lumen of gland is intensive, and corpora amylacea increases in the lumen of gland. and a matter has hyperemia, calcification, a little hypertrophy of connective tissue;

C. simple laser irradiation group rat prostate acinus; D. simple photosensitizer (A1) group rat prostate acinus; E.PDT-A1 low dosage (0.5mg/kgweight) treatment group; Dosage among the F.PDT-A1 (1mg/kgweight) treatment group; G.PDT-A1 high dose (2mg/kgweight) treatment group normal control group.

Rat prostate tissue after the PDT treatment is seen Fig. 1-E. Fig. 1-F. Fig. 1-G., and the prostata tissue major part is coagulation necrosis, proliferation of fibrous tissue, and the prostate body of gland destroys, and part has inflammatory cell infiltration.

3. the contiguous knot of tissue rectum of prostate, each group knot rectal tissue is no abnormal, sees Fig. 2, among Fig. 2: A. normal control group knot rectum; B. the model group rat is tied rectum; C. simple laser irradiation group rat knot rectum; D. only simple photosensitizer (A1) group rat knot rectum; E.PDT-A1 low dosage (0.5mg/kgweight) treatment group; Dosage among the F.PDT-A1 (1mg/kgweight) treatment group; G.PDT-A1 high dose (2mg/kgweight) treatment group normal control group.

4. prostate is contiguous organizes bladder, and it is no abnormal that each organizes bladder body.

Conclusion: A1-PDT has better therapeutic effect to the rat prostate model of hyperplasia, and to prostate surrounding tissue knot rectum, bladder does not have influence.Illustrate that PDT is a kind of pattern of treatment prostatic hyperplasia of effective and safe.

Table 2-1 is the influence of diethylene-triamine pentaacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 2-2 is the influence of diethylene-triamine pentaacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 2-3 is the influence of diethylene-triamine pentaacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 3-1. is the influence of ethylenediaminetetraacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 3-2 is the influence of ethylenediaminetetraacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 3-3 is the influence of ethylenediaminetetraacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 4-1 is the influence of amine triacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 4-2 is the influence of amine triacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Table 4-3 is the influence of amine triacetic acid modified porphyrin-PDT to experimental rat prostate weight in wet base and prostate index (PI)

Claims (1)

1. diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin are in the application of preparation treatment benign prostatic hyperplasia medicine, and described diethylene-triamine pentaacetic acid or ethylenediaminetetraacetic acid or amine triacetic acid modified porphyrin have following structure:

Wherein M is H, Fe, Mn, Cu, Zn, Co, Pt or Mg;

R1=-X-Y；

R2=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

R3=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

R4=-X-Y ,-X-H ,-H ,-OCH ₃,-CH ₃Or-COOH;

N=2,3,4,5 or 6;

Described medicine is the optical dynamic therapy medicine.

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