本文選題：紫杉醇 + 不飽和脂肪酸前藥　； 參考：《沈陽藥科大學(xué)》2016年博士論文

【摘要】：惡性腫瘤嚴(yán)重威脅著人類的健康�；熓侵委煇盒阅[瘤的一個(gè)重要手段,然而,普通制劑的化療方案存在化療效率低下和毒副作用嚴(yán)重等問題。隨著納米技術(shù)在藥物傳遞領(lǐng)域的廣泛應(yīng)用,這些問題有所改善。但是,目前應(yīng)用于臨床的納米制劑還存在諸多不足,包括:載藥量低(通常低于10%)、穩(wěn)定性差、載體材料相關(guān)的毒副作用和儲(chǔ)存過程中藥物的結(jié)晶和泄漏等問題。因此,設(shè)計(jì)和構(gòu)建新型的高效納米藥物傳遞系統(tǒng)仍然是亟待解決的難題。此外,前藥策略也被廣泛用于抗癌藥物的傳遞。其中,紫杉醇-不飽和脂肪酸前藥的研究取得了很大的進(jìn)展。例如,紫杉醇-二十二碳六烯酸前藥(PTX-DHA)已經(jīng)進(jìn)入了臨床Ⅲ期研究。然而,最新的臨床結(jié)果顯示,與一線化療藥物相比,PTX-DHA前藥的療效并沒有顯著優(yōu)勢(shì)。在PTX-DHA前藥結(jié)構(gòu)中,紫杉醇和二十二碳六烯酸是通過酯鍵直接相連的,這可能會(huì)導(dǎo)致紫杉醇很難從強(qiáng)疏水的脂溶性前藥上斷裂下來,影響其抗腫瘤效果。與正常細(xì)胞相比,腫瘤細(xì)胞內(nèi)的高氧化還原微環(huán)境已經(jīng)被廣泛用來設(shè)計(jì)氧化還原敏感的藥物傳遞系統(tǒng)。針對(duì)PTX-DHA的臨床效果不佳和傳統(tǒng)納米制劑的不足,本課題分別以單硫醚鍵、間隔雙硫醚鍵和二硫鍵作為氧化還原敏感的化學(xué)連接臂設(shè)計(jì)了一系列紫杉醇-油酸前藥,并構(gòu)建了氧化還原敏感的紫杉醇-油酸小分子前藥自組裝納米藥物傳遞系統(tǒng)。在此基礎(chǔ)上,比較了這些不同的氧化還原敏感的化學(xué)連接臂對(duì)前藥納米粒的體外釋放、細(xì)胞毒性、藥動(dòng)學(xué)行為、體內(nèi)分布以及抗腫瘤效果的影響。首先,以單硫醚鍵、間隔雙硫醚鍵和二硫鍵作為氧化還原敏感的化學(xué)連接臂設(shè)計(jì)了三個(gè)氧化還原敏感的紫杉醇-油酸前藥(PTX-S-OA、PTX-2S-OA和PTX-S-S-OA),并以酯鍵直接相連的非敏感紫杉醇-油酸前藥(PTX-OA)作為對(duì)照。四個(gè)前藥化合物均能在乙醇-水混合溶劑體系中自組裝形成前藥納米粒(PTX-OA納米粒、PTX-S-OA納米粒、PTX-2S-OA納米粒和PTX-S-S-OA納米粒),前藥納米粒的粒徑均在100nm左右。然而,由于這些前藥納米粒表面的疏水性很強(qiáng),它們?cè)邴}溶液中的膠體穩(wěn)定性較差,會(huì)因"鹽析"作用而使得納米結(jié)構(gòu)被破壞,并析出沉淀。為了應(yīng)對(duì)這一問題并延長(zhǎng)前藥納米粒在血液中的循環(huán)時(shí)間,在前藥納米粒制備過程中加入15%的維生素E聚乙二醇2000琥珀酸酯(TPGS2k)作為PEG修飾劑,制備了PEG化的小分子前藥自組裝納米粒(PTX-OA/TPGS2k 納米粒、PTX-S-OA/TPGS2k 納米粒、PTX-2S-OA/TPGS2k 納米粒和 PTX-S-S-OA/TPGS2k納米粒)。這些PEG修飾的前藥納米粒具有粒徑均勻(100nm左右)、載藥量高(50%)和穩(wěn)定性好等優(yōu)點(diǎn)。以含過氧化氫(H2O2)或二硫蘇糖醇(DTT)的磷酸鹽緩沖液(PBS,pH7.4)-乙醇混合溶液(70/30,v/v)為釋放介質(zhì),考察了PEG化的小分子前藥自組裝納米粒在氧化條件或還原條件下釋放紫杉醇的情況。PTX-OA前藥具有很高的穩(wěn)定性,無論在含氧化還原劑的釋放介質(zhì)還是在空白釋放介質(zhì)中,PTX-OA/TPGS2k納米粒幾乎不釋放紫杉醇。相比之下,PTX-S-S-OA具有非常好的還原敏感特性,在含有10mMDTT的釋放介質(zhì)中,PTX-S-S-OA/TPGS2納米粒在2 h內(nèi)釋放了超過90%的紫杉醇。PTX-S-OA和PTX-2S-OA都具有氧化還原雙敏感特性,且PTX-S-OA較PTX-2S-OA具有更高的氧化還原雙敏感響應(yīng)能力。在含有H2O2或DTT的釋放介質(zhì)中,PTX-S-OA/TPGS2k納米粒均比PTX-2S-OA/TPGS2k納米粒能更快地釋放紫杉醇。體外釋放結(jié)果表明酯鍵相連的PTX-OA前藥的釋藥速度非常慢,釋藥過于緩慢可能是導(dǎo)致臨床中PTX-DHA前藥藥效不佳的原因。本課題設(shè)計(jì)的兩個(gè)氧化還原雙敏感的前藥(PTX-S-OA和PTX-2S-OA)和一個(gè)還原敏感的前藥(PTX-S-S-OA)能在氧化還原環(huán)境中選擇性快速釋放紫杉醇,有望實(shí)現(xiàn)在腫瘤細(xì)胞內(nèi)氧化還原微環(huán)境中特異性快速釋藥,提高紫杉醇的抗腫瘤效果并降低對(duì)正常組織的毒副作用。采用MTT法考察了 PEG修飾的小分子前藥自組裝納米粒對(duì)人鱗狀上皮細(xì)胞癌細(xì)胞(KB-3-1),人大細(xì)胞肺癌細(xì)胞(H460)和人卵巢癌細(xì)胞(OVCAR-8)的細(xì)胞毒性。由于前藥存在釋放母藥的過程,因此,前藥自組裝納米粒的體外細(xì)胞毒性均比Taxol低一些。不同前藥自組裝納米粒的細(xì)胞毒性大小順序?yàn)镻TX-S-S-OA/TPGS2k納米粒PTX-S-OA/TPGS2k納米粒PTX-2S-OA/TPGS2k納米粒PTX-OA/TPGS2k納米粒。值得注意的是,在設(shè)定的藥物濃度范圍內(nèi),PTX-OA/TPGS2k納米粒沒有表現(xiàn)出明顯的細(xì)胞毒性。細(xì)胞毒性結(jié)果表明,前藥納米粒的細(xì)胞毒性大小與紫杉醇從前藥中的釋放難易程度相關(guān),化學(xué)連接臂對(duì)腫瘤細(xì)胞內(nèi)氧化還原環(huán)境的敏感性越高,紫杉醇就越容易從前藥中被釋放出來,其細(xì)胞毒性就越大。此外,我們還研究了KB-3-1細(xì)胞對(duì)香豆素-6標(biāo)記的PEG化小分子前藥自組裝納米粒的細(xì)胞攝取情況。香豆素-6溶液劑和香豆素-6標(biāo)記的小分子前藥自組裝納米粒的細(xì)胞攝取都具有時(shí)間依賴性。與香豆素-6溶液劑相比,香豆素-6標(biāo)記的小分子前藥自組裝納米粒在0.5 h和2 h均具有更高的細(xì)胞攝取。以Sprague-Dawley(SD)大鼠為模型動(dòng)物,比較了Taxol、未修飾的小分子前藥自組裝納米粒和PEG修飾的小分子前藥自組裝納米粒的體內(nèi)藥動(dòng)學(xué)行為。與未修飾的前藥納米粒和Taxol相比,PEG修飾的前藥納米粒均能顯著延長(zhǎng)藥物在血液中的循環(huán)時(shí)間。由于化學(xué)連接臂的氧化還原敏感性不同,PEG化的各前藥納米粒的藥動(dòng)學(xué)也存在一定差異。其中,由于PTX-OA前藥酯鍵的高度穩(wěn)定性,PTX-OA/TPGS2k納米粒的AUC0-24h值(前藥與母藥加和)最大。不同PEG化的前藥納米粒的AUC0-24h值(前藥與母藥加和)的大小順序?yàn)?PTX-OA/TPGS2k納米粒PTX-2S-OA/TPGS2k納米粒PTX-S-S-OA/TPGS2k納米粒PTX-S-OA/TPGS2k納米粒。此外,我們以人鱗狀上皮細(xì)胞癌(KB-3-1)荷瘤裸鼠為研究對(duì)象,考察了DiR標(biāo)記的PEG化小分子前藥自組裝納米粒的組織分布情況。DiR溶液劑的熒光主要分布在肺部,在腫瘤組織中的熒光十分微弱。與DiR溶液劑相比,DiR標(biāo)記的PEG化小分子前藥自組裝納米粒在腫瘤組織的熒光強(qiáng)度顯著增加。體內(nèi)分布結(jié)果表明,前藥納米粒能顯著增加藥物在腫瘤部位的積蓄,減少藥物在非腫瘤部位的分布。以人鱗狀上皮細(xì)胞癌(KB-3-1)荷瘤裸鼠為動(dòng)物模型,考察了 Taxol和PEG修飾的小分子前藥自組裝納米粒的體內(nèi)抗腫瘤效果。PBS和PTX-OA/TPGS2k納米粒不能有效抑制腫瘤細(xì)胞的生長(zhǎng),荷瘤裸鼠的腫瘤體積生長(zhǎng)迅速。相比之下,PTX-2S-OA/TPGS2k納米粒和Taxol能在一定程度上延緩腫瘤的生長(zhǎng),但二者之間的抗腫瘤效果并沒有統(tǒng)計(jì)學(xué)差異。更重要的是,PTX-S-OA/TPGS2k納米粒和PTX-S-S-OA/TPGS2k納米粒組展現(xiàn)出很強(qiáng)的抑制腫瘤細(xì)胞生長(zhǎng)的能力。給藥結(jié)束后,PTX-S-OA/TPGS2k納米粒給藥組中荷瘤裸鼠的腫瘤體積幾乎沒有增長(zhǎng)。更令人驚喜的是,在PTX-S-S-OA/TPGS2k納米粒組中荷瘤裸鼠的腫瘤幾乎消失不見了。體內(nèi)抗腫瘤效果與體外釋放結(jié)果和細(xì)胞毒性結(jié)果相一致,表明化學(xué)連接臂對(duì)腫瘤細(xì)胞內(nèi)氧化還原條件的敏感性越高,越容易實(shí)現(xiàn)紫杉醇在腫瘤細(xì)胞內(nèi)的特異性快速釋放,相應(yīng)的前藥納米粒的抗腫瘤效果就越好。此外,在整個(gè)給藥過程中,對(duì)照組和給藥組的荷瘤裸鼠的體重都沒有減輕,也沒有發(fā)現(xiàn)明顯的肝腎毒性。體內(nèi)藥效結(jié)果表明PTX-S-OA/TPGS2k納米粒和PTX-S-S-OA/TPGS2k納米粒在具有明顯的抗腫瘤效果的同時(shí),沒有對(duì)機(jī)體造成顯著的非特異性毒性,是安全有效的抗癌藥物傳遞系統(tǒng)。
[Abstract]:Malignant tumor is a serious threat to human health. Chemotherapy is an important means for the treatment of malignant tumors. However, there are some problems in the chemotherapy regimen of general preparation, such as low efficiency of chemotherapy and serious side effects. With the extensive application of nanotechnology in the field of drug delivery, these problems have improved. However, it is currently used in clinical nanoscale. There are many deficiencies in the preparation, including low drug loading (usually less than 10%), poor stability, toxic and side effects associated with carrier materials, and the crystallization and leakage of drugs during storage. Therefore, the design and construction of a new efficient nanoscale delivery system is still a difficult problem to be solved. In addition, the prodrug strategy is also widely used for anticancer. Drug delivery. Among them, paclitaxel - unsaturated fatty acid predrugs have made great progress. For example, paclitaxel - twenty-two - carbon six - acid prodrug (PTX-DHA) has entered clinical stage III studies. However, the latest clinical results show that the efficacy of PTX-DHA prodrugs is not significantly superior to first-line chemotherapeutic drugs. Before PTX-DHA In drug structure, taxol and twenty-two carbon six enoic acids are connected directly through ester bonds, which may cause Taxol to be difficult to break down from strong hydrophobic, fat soluble prodrugs and affect its antitumor effect. Compared with normal cells, high redox microenvironment in tumor cells has been widely used to design redox sensitive drugs. In view of the poor clinical effect of PTX-DHA and the shortage of traditional nanoscale preparation, we designed a series of taxol - oleic acid precursor with monosulfide bond, septal disulfide bond and two sulfur bond as redox sensitive chemical arm, and constructed the self assembly of paclitaxel oleic acid small molecular prodrug with redox sensitivity. On this basis, the effects of these different redox sensitive chemical connections on the release, cytotoxicity, pharmacokinetics, in vivo distribution and antitumor effects of these different redox sensitive chemical connections are compared. First, the mono ether bond, the septal disulfide bond and the two sulfur bond are used as the oxidation-sensitive chemical connections. Three redox sensitive paclitaxel oleic acid prodrugs (PTX-S-OA, PTX-2S-OA and PTX-S-S-OA) were designed and the non sensitive paclitaxel oleic acid prodrug (PTX-OA) was directly linked by ester bonds as a control. The four prodrug compounds could be self assembled to form precursor nanoparticles (PTX-OA nanoparticles, PTX-S-OA nanoparticles, PT) in a mixed solvent system of ethanol water. X-2S-OA nanoparticles and PTX-S-S-OA nanoparticles), the particle size of the precursor nanoparticles is around 100nm. However, because of the strong hydrophobicity of these nanoparticles, the colloids in the salt solution are less stable, and the nanostructures will be destroyed and precipitated because of the "salting out" effect. In the blood circulation time, 15% vitamin E polyethylene glycol 2000 succinate (TPGS2k) was added to the preparation of prodrug nanoparticles as PEG modifier, and the PEG small prodrug self assembled nanoparticles (PTX-OA/TPGS2k nanoparticles, PTX-S-OA/TPGS2k nanoparticles, PTX-2S-OA/TPGS2k nanoparticles and PTX-S-S-OA/TPGS2k nanoparticles) were prepared. The PEG modified prodrug nanoparticles have the advantages of homogeneous particle size (about 100nm), high drug loading (50%) and good stability. The release medium containing the phosphate buffer solution (PBS, pH7.4) ethanol mixture (70/30, v/v) containing hydrogen peroxide (H2O2) or two sulfur sugol (DTT) is used as the release medium, and the PEG small prodrug self assembled nanoparticles in the oxidation strip are investigated. The release of taxol in parts or reduction conditions.PTX-OA prodrug has high stability, PTX-OA/TPGS2k nanoparticles almost do not release taxol in the release medium containing redox agents or in the blank release medium. By contrast, PTX-S-S-OA has a very good and original sensitivity, P in the release medium containing 10mMDTT. TX-S-S-OA/TPGS2 nanoparticles release more than 90% of paclitaxel.PTX-S-OA and PTX-2S-OA in 2 h, both of which have redox dual sensitivity, and PTX-S-OA has a higher redox dual sensitive response ability than PTX-2S-OA. In the release medium containing H2O2 or DTT, PTX-S-OA/TPGS2k nanoparticles can be faster than PTX-2S-OA/TPGS2k nanoparticles. Release of paclitaxel. In vitro release results show that the release rate of the PTX-OA prodrug linked by the ester bond is very slow and the release is too slow may be the cause of the poor efficacy of the clinical PTX-DHA prodrug. Two redox two redox prodrugs (PTX-S-OA and PTX-2S-OA) and a reductive prodrug (PTX-S-S-OA) can be oxidized by this subject. The selective rapid release of taxol in the reduction environment is expected to achieve specific and rapid drug release in the redox microenvironment of tumor cells, improve the antitumor effect of taxol and reduce the toxic and side effects on normal tissues. The MTT method was used to investigate the PEG modified small prodrug self assembled nanoparticles on human squamous cell carcinoma cells (KB- 3-1) cytotoxicity of human lung cancer cells (H460) and human ovarian cancer cells (OVCAR-8). The cytotoxicity of prodrug self assembled nanoparticles in vitro is lower than that of Taxol because of the presence of precursor drugs. The order of cytotoxicity of different prodrug self assembled nanoparticles is PTX-S-S-OA/TPGS2k nanorp PTX-S-OA/TPGS2k Na It is worth noting that PTX-OA/TPGS2k nanoparticles do not exhibit obvious cytotoxicity in the range of drug concentration, and the cytotoxicity results of PTX-OA/TPGS2k nanoparticles show that the cytotoxicity of prodrug nanoparticles is related to the release of paclitaxel in the prodrugs, and the chemical link arm pair The higher the sensitivity of the redox environment in the tumor cells, the more easily the paclitaxel is released in the prodrug, the more cytotoxic it is. In addition, we also studied the cell uptake of the KB-3-1 cells labeled by the coumarin -6 PEG small molecule prodrug self assembled nanoparticles. The small molecules marked by coumarin -6 solution and coumarin -6 The cell uptake of the prodrug self assembled nanoparticles was time dependent. Compared with the coumarin -6 solution, the small molecular prodrug self assembled nanoparticles marked by coumarin -6 had higher cell uptake at 0.5 h and 2 h. Sprague-Dawley (SD) rats were used as model animals to compare Taxol, unmodified small molecular prodrug self assembled nanoparticles and P The pharmacokinetics of EG modified small molecular prodrug self assembled nanoparticles in vivo. Compared with unmodified prodrug nanoparticles and Taxol, PEG modified prodrug nanoparticles can significantly prolong the cycle time of the drug in the blood. The pharmacokinetics of PEG precursor nanoparticles are also certain because of the different redox sensitivity of the chemical arm. Differences. Among them, the AUC0-24h value of PTX-OA/TPGS2k nanoparticles is the largest because of the high stability of the ester bond of the PTX-OA precursor. The AUC0-24h value of the different PEG precursor nanoparticles (prodrugs and mother drugs) is the PTX-OA/TPGS2k nanoparticles PTX-2S-OA/ TPGS2k nanoparticles PTX-S-S-OA/TPGS2k nanoparticles PTX-S-OA/TPGS2k. Nanoparticles. In addition, we studied human squamous cell carcinoma (KB-3-1) tumor bearing nude mice. The tissue distribution of DiR labeled PEG small molecular prodrug self assembled nanoparticles was investigated. The fluorescence of.DiR solution was mainly distributed in the lungs, and the fluorescence in the tumor tissues was very weak. Compared with the DiR solution, the PEG fraction of the DiR marker The fluorescence intensity of the self assembled nanoparticles in the tumor tissues increased significantly. The distribution in vivo showed that the prodrug nanoparticles could significantly increase the accumulation of drugs at the tumor site and reduce the distribution of drugs in the non tumor sites. Human squamous cell carcinoma (KB-3-1) nude mice were used as animal models, and the small molecules modified by Taxol and PEG were investigated. The anti-tumor effects of.PBS and PTX-OA/TPGS2k nanoparticles in the prodrug self assembled nanoparticles do not effectively inhibit the growth of tumor cells, and tumor bearing nude mice grow rapidly. In contrast, PTX-2S-OA/TPGS2k nanoparticles and Taxol can delay the growth of the tumor to a certain extent, but the anti tumor effect between the two is not statistically significant. More importantly, PTX-S-OA/TPGS2k nanoparticles and PTX-S-S-OA/TPGS2k nanoparticles showed a strong ability to inhibit the growth of tumor cells. After the end of the drug, the tumor volume of the tumor bearing nude mice in the PTX-S-OA/TPGS2k nanoparticles group was almost no increase. And, surprisingly, the tumor bearing nude mice in the PTX-S-S-OA/TPGS2k nanoparticles group The tumor is almost disappeared. The antitumor effect in vivo is in accordance with the results of in vitro release and cytotoxicity, which indicates that the more sensitive the chemical connection arm is to the redox conditions in the tumor cells, the more easily the specific rapid release of taxol in the tumor cells, the better the antitumor effect of the corresponding prodrug nanoparticles. In addition, the body weight of the tumor bearing nude mice in the control group and the administration group was not reduced and no obvious liver and kidney toxicity was found in the control group and the administration group. The results showed that the PTX-S-OA/TPGS2k nanoparticles and PTX-S-S-OA/TPGS2k nanoparticles had no significant non specific toxicity to the body while having obvious antitumor effects. It is a safe and effective anti-cancer drug delivery system.
【學(xué)位授予單位】：沈陽藥科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R943

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10 ;[J];;年期

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