【摘要】：腫瘤治療是當(dāng)今醫(yī)學(xué)界所面臨的重大難題之一,其主要原因是在治療過(guò)程中產(chǎn)生的巨大的毒副作用以及多藥耐藥性等。具有選擇性好、創(chuàng)傷小、無(wú)耐藥性等優(yōu)勢(shì)的光動(dòng)力治療是解決上述問(wèn)題的潛在選擇之一,另外,中藥的多位點(diǎn)、多階段的抗腫瘤機(jī)制使其在腫瘤治療中具有高效低毒的特性而賦予其廣闊的應(yīng)用前景。然而,這些治療方法存在著不同程度的問(wèn)題從而限制了其臨床的普遍應(yīng)用和發(fā)展。例如,光動(dòng)力治療的核心元素光敏劑存在水溶性差、無(wú)靶向性的問(wèn)題,在中藥姜黃素化療中,姜黃素存在生理?xiàng)l件易降解、生物利用度低的問(wèn)題。因此,如何通過(guò)合理的設(shè)計(jì),發(fā)揮納米技術(shù)在藥物遞送方面的優(yōu)勢(shì),構(gòu)建理想的納米載體和劑型,發(fā)展具有高效負(fù)載、腫瘤特異性富集和可控釋放的納米藥物是解決這些問(wèn)題的關(guān)鍵。受自然界中金屬蛋白的啟發(fā),基于短肽與Zn2+的配位作用、疏水作用等弱相互作用實(shí)現(xiàn)納米尺度的組裝,制備出具備良好應(yīng)用前景的靜脈注射制劑,用于抗腫瘤治療,其具體研究成果包括:(1)以Fmoc-His或Z-His-Phe與Zn2+為組裝基元,基于羧基、咪唑基與Zn2+的配位作用以及疏水作用、π-π堆疊等弱相互作用實(shí)現(xiàn)納米顆粒的可控自組裝,納米粒子尺寸均一,進(jìn)一步利用Zn2+與光敏劑Ce6的配位作用,通過(guò)共組裝實(shí)現(xiàn)高的負(fù)載率,NPs-Ce6在類(lèi)細(xì)胞溶酶體的微環(huán)境中具有pH和氧化還原雙重刺激響應(yīng)性,迅速解組裝,實(shí)現(xiàn)細(xì)胞內(nèi)的藥物釋放,在體內(nèi)外水平都比無(wú)載體光敏劑分子表現(xiàn)出增強(qiáng)的腫瘤靶向性和抗腫瘤效果。(2)以Zn2+與Fmoc-His和姜黃素的共配位作用為驅(qū)動(dòng)力,進(jìn)一步通過(guò)疏水作用、π-π堆疊等弱相互作用實(shí)現(xiàn)了新型的共組裝體設(shè)計(jì)的突破,共組裝體粒徑分布均一且可以通過(guò)改變?nèi)軇┑姆N類(lèi)實(shí)現(xiàn)尺寸的調(diào)控。通過(guò)一系列光譜表征了其共配位的分子結(jié)構(gòu),主要以1:1:1形式存在,共組裝納米顆粒實(shí)現(xiàn)了高的負(fù)載率且保證了姜黃素在生理?xiàng)l件下的穩(wěn)定性,與對(duì)照組姜黃素單體相比,在細(xì)胞水平及體內(nèi)水平上都表現(xiàn)出增強(qiáng)的腫瘤靶向性和抗腫瘤效果。因此,短肽和Zn2+調(diào)控藥物共組裝設(shè)計(jì)的納米顆粒在藥物有效遞送、提高生物利用度和降低毒副作用等方面都具有顯著的效果,有效地解決了光敏劑和中藥姜黃素等藥物在抗腫瘤光動(dòng)力治療和化療中的問(wèn)題。
[Abstract]:Cancer therapy is one of the most difficult problems in the medical field nowadays. The main reasons are the huge side effects and multidrug resistance in the course of treatment. Photodynamic therapy with advantages of good selectivity, little trauma and no resistance to drug resistance is one of the potential options to solve the above problems. In addition, there are many sites in traditional Chinese medicine. Multi-stage anti-tumor mechanism makes it have the characteristics of high efficiency and low toxicity in tumor therapy and gives it a broad application prospect. However, these treatments have varying degrees of problems, thus limiting their clinical application and development. For example, Guang Min, the core element of photodynamic therapy, has poor water solubility and no targeting. In curcumin chemotherapy, curcumin is easy to degrade under physiological conditions and low bioavailability. Therefore, how to make use of the advantages of nanotechnology in drug delivery through rational design, construct ideal nano-carrier and dosage form, and develop high-efficient loading, Tumor specific enrichment and controlled release of nanopharmaceuticals are key to solve these problems. Inspired by the metalloprotein in nature, based on the weak interaction of short peptide and Zn2, the nanoscale assembly was realized, and the intravenous injection preparation with good application prospect was prepared for antitumor therapy. The specific research results include: (1) based on the coordination and hydrophobic interaction of carboxyl, imidazolyl and Zn2, 蟺-蟺 stacking, the controllable self-assembly of nanoparticles is achieved by using Fmoc-His or Z-His-Phe and Zn2 as assembly units, and the size of nanoparticles is uniform. Further more, by using the coordination of Zn2 and Guang Min Ce6, the high loading rate was achieved by co-assembly. NPs-Ce6 had the double stimulative response of pH and redox in the microenvironment of lysosomal like cells, and was rapidly unassembled to realize the release of drugs in cells. In vitro and in vivo, both of them showed enhanced tumor targeting and antitumor effect compared with vector free Guang Min molecules. (2) the cocoordination of Zn2 with Fmoc-His and curcumin was the driving force. Through hydrophobic interaction, 蟺-蟺 stacking and other weak interactions, a breakthrough in the design of a new type of co-assembly is achieved. The particle size distribution of the co-assembly is uniform and the size of the co-assembly can be adjusted by changing the type of solvent. The molecular structure of the co-coordination was characterized by a series of spectra, mainly in the form of 1:1:1. The co-assembled nanoparticles achieved high loading rate and guaranteed the stability of curcumin under physiological conditions, compared with curcumin monomer in control group. Enhanced tumor targeting and anti-tumor effects were demonstrated at both cellular and in vivo levels. Therefore, the nanocrystalline nanoparticles designed by Zn2 and short peptides have remarkable effects in drug delivery, bioavailability and toxicity reduction. It has effectively solved the problems of Guang Min and curcumin in anti-tumor photodynamic therapy and chemotherapy.
【學(xué)位授予單位】：中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院過(guò)程工程研究所)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R730.5

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