【摘要】：納米載藥系統(tǒng)因其獨(dú)特的結(jié)構(gòu)特點(diǎn)和理化性質(zhì)在腫瘤治療方面得到廣泛的研究與應(yīng)用。為了實(shí)現(xiàn)高效而低毒的化療效果,許多高校、科研院所及醫(yī)藥企業(yè)在此方面開展了大量的研發(fā)工作。隨著納米技術(shù)和載體材料的迅猛發(fā)展,各種各樣的納米載藥系統(tǒng)不斷涌現(xiàn)。為了著實(shí)提高化療藥物的抗腫瘤效果,合理設(shè)計(jì)與構(gòu)建納米載體系統(tǒng)至關(guān)重要。為此,本論文基于機(jī)體和腫瘤生理性質(zhì),系統(tǒng)考察了粒徑對(duì)聚合物膠束藥物遞送效率的影響,在此基礎(chǔ)上設(shè)計(jì)并構(gòu)建了一種腫瘤微酸環(huán)境響應(yīng)性藥物載體系統(tǒng)。本論文的主要研究內(nèi)容如下：1、粒徑對(duì)聚合物膠束體內(nèi)外性能的影響研究。通過對(duì)聚合物投料比的控制,合成出一系列不同分子量的MPEG-PLA共聚物,制備了30、45、60、118和230 nm等不同粒徑的聚合物膠束,系統(tǒng)考察了粒徑對(duì)膠束體內(nèi)外性能的影響。實(shí)驗(yàn)結(jié)果表明,粒徑對(duì)60 nm及以下小粒徑膠束體內(nèi)外性能的影響不明顯。這些小粒徑膠束具有較強(qiáng)的腫瘤組織滲透能力,腫瘤部位蓄積量大,但體內(nèi)循環(huán)時(shí)間短。大粒徑膠束(230 nm)的穩(wěn)定性稍差,藥物釋放速率稍快,細(xì)胞內(nèi)化能力稍弱,體內(nèi)循環(huán)時(shí)間短及腫瘤內(nèi)穿透能力弱。相比之下,粒徑118 nm的膠束具有較長的體內(nèi)循環(huán)時(shí)間,但瘤內(nèi)穿透能力不及小粒徑膠束。粒徑對(duì)膠束的體外細(xì)胞毒性的影響不明顯。體內(nèi)藥效學(xué)結(jié)果表明,小粒徑膠束能顯著提高藥物的抑瘤效果。2、構(gòu)建了一種針對(duì)腫瘤微酸環(huán)境響應(yīng)的粒徑/電位可變藥物遞送系統(tǒng),載體材料為含有聚(β-氨基酯)(PAE)鏈段的兩親性嵌段共聚物MPEG-PLA-PAE。采用該聚合物制備了粒徑為100-200 nm的膠束,證明了具有較長的體內(nèi)循環(huán)時(shí)間。在腫瘤部位的低pH環(huán)境下,由于PAE鏈段發(fā)生質(zhì)子化作用,膠束的核殼結(jié)構(gòu)發(fā)生重構(gòu),致使膠束的粒徑減小和表面電荷增加,從而增強(qiáng)了其在腫瘤組織中的穿透能力并促進(jìn)了腫瘤細(xì)胞的攝取。因此,該智能載體系統(tǒng)具有體內(nèi)循環(huán)時(shí)間長、腫瘤內(nèi)穿透能力強(qiáng)、腫瘤細(xì)胞攝取量高和腫瘤內(nèi)蓄積量大等優(yōu)勢(shì),能顯著提高藥物的抗腫瘤效果。采用姜黃素和多西他賽兩種模型藥物,以人乳腺癌MCF-7細(xì)胞和人口腔表皮樣癌KB細(xì)胞分別建立兩種體內(nèi)外藥效學(xué)評(píng)價(jià)模型,對(duì)該載體系統(tǒng)的體內(nèi)外性能進(jìn)行評(píng)價(jià)。
[Abstract]:Nano-drug delivery system has been widely studied and applied in tumor therapy because of its unique structure and physical and chemical properties. In order to achieve the effect of high efficiency and low toxicity, many universities, scientific research institutes and pharmaceutical enterprises have carried out a lot of research and development in this field. With the rapid development of nanotechnology and carrier materials, a variety of nano-drug delivery systems are emerging. In order to improve the anti-tumor effect of chemotherapeutic drugs, it is very important to design and construct nano-carrier system. Therefore, based on the physiological properties of human body and tumor, the effect of particle size on delivery efficiency of polymer micelles was systematically investigated, and a novel drug carrier system for tumor microacid environment was designed and constructed. The main contents of this thesis are as follows: 1. The effect of particle size on the properties of polymer micelles in vivo and in vitro. A series of MPEG-PLA copolymers with different molecular weights were synthesized by controlling the feed ratio of polymers. Polymer micelles with different particle sizes, such as 30O45,60118 and 230 nm, were prepared. The effects of particle size on the properties of micelles in vivo and in vitro were systematically investigated. The experimental results show that the effect of particle size on the in vivo and in vitro properties of micelles with small particle size under 60 nm is not obvious. These small micelles have strong osmotic ability of tumor tissue, large accumulation of tumor site, but short circulation time in vivo. The stability of large particle micelles (230 nm) was slightly poor, the drug release rate was faster, the ability of cell internalization was weak, the internal circulation time was short and the penetration ability of tumor was weak. In contrast, the micelles with a diameter of 118 nm had a longer circulating time in vivo, but the intratumoral penetration ability was not as good as that of the small diameter micelles. The effect of particle size on the cytotoxicity of micelles in vitro was not obvious. The results of pharmacodynamics in vivo showed that the small particle size micelles could significantly improve the inhibitory effect of the drug. A novel particle size / potential variable drug delivery system was constructed for the response of tumor microacid environment. The carrier material is amphiphilic block copolymer MPEG-PLA-PAE. containing poly (尾 -aminoester) (PAE) segment. The micelles with a particle size of 100 to 200 nm were prepared by using the polymer. It was proved that the micelles had a long circulating time in vivo. In the low pH environment of the tumor site, the core-shell structure of the micelles was reconstructed due to the protonation of the PAE segment, which resulted in the decrease of the particle size and the increase of the surface charge of the micelles. It enhances its penetrating ability in tumor tissue and promotes the uptake of tumor cells. Therefore, the intelligent carrier system has the advantages of long internal circulation time, strong penetrating ability, high uptake of tumor cells and large amount of tumor accumulation, which can significantly improve the anti-tumor effect of the drug. By using curcumin and docetaxel, two in vitro and in vivo pharmacodynamics evaluation models of human breast cancer MCF-7 cells and human oral epidermoid carcinoma KB cells were established to evaluate the in vitro and in vivo performance of the vector system.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R943

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