生物降解聚酯作为抗癌药物和基因载体的研究
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摘要
癌症严重威胁着人类的健康,作为目前癌症主要治疗手段之一的化疗由于效果有限、毒副作用大、病人承受的痛苦多,治疗效果往往难以令人满意。基因治疗作为新兴的医学治疗手段被认为是21世纪改善人类健康的一个重要途径,众多的研究证明人类多种疾病都与基因的结构或功能改变密切相关。而成功的实行化疗和基因治疗很大程度上取决于发展一种适合的输运载体,使其不仅能够特异性地和有效地输送药物和基因到靶细胞,同时具有较低的毒副作用。运用纳米微球作为药物和基因载体不仅能够提高药物的溶解度和稳定性,增加其药理学治疗效果,还能够增强基因的转染效率。我们基于脂肪酶(CALB)催化反应机理设计、合成了一系列可降解的聚酯高分子材料,并结合纳米制备技术构建了几种不同的药物和基因纳米输运系统,改善了药物和基因的治疗水平。本论文的研究内容包括以下三个方面：
(1)证明了一种新的疏水性聚合物纳米微球可通过静脉给药途径有效地输送抗癌药喜树碱(Camptothecin, CPT)。该研究包括：利用CALB为催化剂,通过酶催化反应合成了不同ω-十五环内酯(PDL)成分比的聚(ω-十五环内酯-丁二酸二乙酯-丁二醇)(PPBS)共聚物,并采用该种可降解聚合物为载体,通过单层乳液-溶剂挥发技术成功制备了粒径100-300纳米且单分散性好的CPT纳米微球。该方法制备的CPT/PPBS纳米微球具有较高的载药量(12-22%)和包封率(～96%),表面Zeta电位约为-10 mV,且空白纳米微球对细胞基本无毒性。通过对CPT的包裹,有效提高了CPT在生理条件下的稳定性。体外释放试验表明PPBS纳米微球可实现对CPT长达40天的缓慢控制释放。更重要的是,与游离药物相比,CPT纳米微球具有增强细胞摄取,提高体外细胞毒性,增加药物在小鼠体内的循环时间以及增强体内抗肿瘤性等优点。这些结果表明PPBS纳米微球控释系统有望成为一种长效的化疗药物输运系统。
(2)构建了一种以poly(PDL-co-DO)为载体,包载柔红霉素和siRNA的纳米微球控释系统。首先,小鼠体内植入试验证实该聚合物具有较好的生物相容性；其次,成功制备了平均粒径在200纳米左右的poly(PDL-co-DO)纳米微球,其降解速度可根据PDL:DO比例来调控,其中poly(PDL-co-42%DO)纳米微球在70天内平均每天分子量大约下降0.84%；更进一步,采用poly(PDL-co-DO)为载体制备的DNR纳米微球的载药量较高,且释放速率可控；为进一步研究该聚合物作为核酸的传递载体,采用poly(PDL-co-42%DO)为载体,与双层乳液-溶剂挥发技术相结合,通过优化制备工艺(加入亚精氨为siRNA分子缔合物),制备了包封率较高的siRNA纳米微球,体外细胞基因沉默试验表明其具有增强siRNA基因沉默的功能。该实验为下一步开发基因载体材料提供了理论指导。
(3)针对基因载体的特点,通过引入氨基取代单体,采用酶催化聚合反应合成了一系列的可降解氨基聚酯材料,研究了其作为基因载体的转染效率,并探讨了聚合物结构与基因转染效率的关系。具体来说,成功地将C4-C12的二酯以及不同氨基取代基的二乙醇胺(如：甲基、乙基、n-丁基、t-丁基、苯基)引入到聚酯分子链中。通过酸性条件下叔氨可质子化这一特点,使得该类阳离子聚合物可通过静电力缔合带负电的DNA分子形成聚合物/DNA纳米复合体。采用Luciferase和GFP报告基因为模型的体外细胞基因转染试验证明,PMSC、PESC以及PDL-PMSC聚合物的基因转染效率比Lipofectamine 2000更高,而且细胞毒性非常小。研究表明聚合物/DNA复合体粒径越小(＜100 nm),细胞摄取越多；而酸性条件下表面Zeta电位值越高,“质子海绵效应”越强,细胞摄取后能够帮助DNA逃离内涵体,从而形成的基因转染效率也越高。更进一步的小鼠体内基因转染试验证明PDL-PMSC和PMSC较PEI来说,具有更高效的基因转染效率。新型可降解氨基聚酯材料的这些特点使其有望发展成为新一代的安全有效的非病毒基因载体。
Current chemotherapy is far from satisfactory:drug treatments often have limited effectiveness and patients suffer from serious side effects. Gene therapy represents a novel form of medical treatment that is expected to have major impact on human health in 21st century since a large number of human diseases are caused by genetic disorders. The success of chemotherapy or gene therapy is largely dependent on the development of a vehicle or vector that can selectively and efficiently deliver drug and gene to target cells with minimal toxicity. The use of nano-sized particles in cancer therapy and gene delivery is particularly exciting, as these materials can increase drug solubility and stability, as well as improve pharmacological effect and gene transfection efficiency. Herein, we reported that a series of biodegradable aliphatic polyester with diverse structures were designed and synthesized via enzymatic copolymerization using Candida antarctica lipase B (CALB) as the catalyst. Combing nano-fabrication technology, we developed several biodegradable polymeric drug and gene delivery systems, which would significantly improve the cancer treatment and gene transfection. There are three parts in this dissertation, including:
PartⅠ, we show that degradable particles of a hydrophobic polymer can effectively deliver camptochecin to tumors after i.v. administration. Free-standing nanoparticles with diameters of 100-300 nm were successfully fabricated from highly hydrophobic, biodegradable poly(ω-pentadecalactone-co-butylene-co-succinate) (PPBS) copolyesters. PPBS copolymers with various compositions were synthesized via copolymerization of o-pentadecalactone (PDL), diethyl succinate (DES), and 1,4-butanediol (BD) using CALB as the catalyst. Camptothecin (CPT,12-22%) was loaded into PPBS nanoparticles with high encapsulation efficiency (up to 96%) using a modified oil-in-water single emulsion technique. The CPT-loaded nanoparticles had a zeta potential of about-10 mV. PPBS particles were non toxic in cell culture. Upon encapsulation, the active lactone form of CPT was remarkably stabilized and no lactone-to-carboxylate structural conversion was observed for CPT-loaded PPBS nanoparticles incubated in both phosphate-buffered saline (PBS, pH=7.4) and DMEM media for at least 24 hr. In PBS at 37℃, CPT-loaded PPBS nanoparticles showed a low burst CPT release (20-30%) within the first 24 hrs followed by a sustained, essentially complete, release of the remaining drug over the subsequent 40 days. Compared to free CPT, CPT-loaded PPBS nanoparticles showed a significant enhancement of cellular uptake, higher cytotoxicity against Lewis lung carcinoma and 9L cell lines in vitro, a longer circulation time, and substantially better antitumor efficacy in vivo. These results demonstrate the potential of PPBS nanoparticles as long-term stable and effective drug delivery systems in cancer therapy.
PartⅡ, we have developed a polymeric nanoparticles system for both Daunorubicin and siRNA delivery by using poly(PDL-co-DO). First, mice test experiments showed that random poly(PDL-co-DO) copolymers had good biocompatibility. No significant abnormal tissue growth was observed polymer films were implanted in mice for up to four weeks. Second, free-standing nanoparticles with 200 nm size in average were successfully prepared from poly(PDL-co-DO). The degradation rate of the nanoparticles was studied over a 70-day period in phosphate buffered saline (PBS) solution at 37℃. On average, the molecular weight (Mn) of the particles decreased by approximately 0.84% per day. Furthermore, daunorubicin was encapsulated into poly(PDL-co-DO) nanoparticles with high loading. DNR released from the loaded nanoparticles exhibited a biphasic trend consisting of an initial burst followed by a gradual sustained release. Finally, high encapsulation efficiency siRNA/poly(PDL-co-42%DO) nanoparticles were successfully prepared at optimize condition (spermindine, as a counterion, was added to condense siRNA). In vitro gene knockdown experiments indicated that siRNA/poly(PDL-co-42%DO) nanoparticles gave a significant enhanced luciferase gene silence. With the further development, poly(PDL-co-DO) nanoparticles could be potentially used as hydrophilic drug and gene delivery vehicles.
PartⅢ, a series of biodegradable poly(amine-co-esters) were synthesized in one step via enzymatic copolymerization of lactone, diesters and amino-substituted diols. More specifically, C4-C12 diesters (i.e., from succinate to dodecanedioate) and diethanolamine comonomers with either an alkyl (methyl, ethyl, n-butyl,t-butyl) or an aryl (phenyl) substituent on nitrogen were successfully incorporated into the poly(amine-co-ester) chains. Upon protonation at slightly acidic conditions, these poly(amine-co-esters) readily turned to cationic polyelectrolytes, which are capable of condensing with polyanionic DNA to form polyplex nanoparticles. In vitro cell transfection screening revealed that three of the copolymers, poly (ω-pentadecalactone-N-methyldiethyleneamine sebacate) (PDL-PMSC), poly(N-methyldiethyleneamine sebacate) (PMSC) and poly(N-ethyldi-ethyleneamine sebacate) (PESC), possessed comparable or even higher transfection efficiency in delivering pLucDNA compared to that of Lipofectamine 2000. Studies on the physical properties and morphology of PESC/pLucDNA, PMSC/pLucDNA and PDL-PMSC/pLucDNA nanoparticles showed that both polyplexes had desirable particle sizes (< 100 nm) for cellular uptake and are capable of functioning as proton sponges to facilitate endosomal escape after cellular uptake. These polyplex nanoparticles exhibited extremely low cytotoxicity. Furthermore, gene transfection experiments performed using mouse tumor models showed that PDL-PMSC and PMSC are substantially more effective gene carrier than PEI in delivering pLucDNA to the tumor cells in vivo. All these properties make the poly(amine-co-esters) to be promising non-viral vectors for safe and efficient DNA delivery in gene therapy.
(1)证明了一种新的疏水性聚合物纳米微球可通过静脉给药途径有效地输送抗癌药喜树碱(Camptothecin, CPT)。该研究包括：利用CALB为催化剂,通过酶催化反应合成了不同ω-十五环内酯(PDL)成分比的聚(ω-十五环内酯-丁二酸二乙酯-丁二醇)(PPBS)共聚物,并采用该种可降解聚合物为载体,通过单层乳液-溶剂挥发技术成功制备了粒径100-300纳米且单分散性好的CPT纳米微球。该方法制备的CPT/PPBS纳米微球具有较高的载药量(12-22%)和包封率(～96%),表面Zeta电位约为-10 mV,且空白纳米微球对细胞基本无毒性。通过对CPT的包裹,有效提高了CPT在生理条件下的稳定性。体外释放试验表明PPBS纳米微球可实现对CPT长达40天的缓慢控制释放。更重要的是,与游离药物相比,CPT纳米微球具有增强细胞摄取,提高体外细胞毒性,增加药物在小鼠体内的循环时间以及增强体内抗肿瘤性等优点。这些结果表明PPBS纳米微球控释系统有望成为一种长效的化疗药物输运系统。
(2)构建了一种以poly(PDL-co-DO)为载体,包载柔红霉素和siRNA的纳米微球控释系统。首先,小鼠体内植入试验证实该聚合物具有较好的生物相容性；其次,成功制备了平均粒径在200纳米左右的poly(PDL-co-DO)纳米微球,其降解速度可根据PDL:DO比例来调控,其中poly(PDL-co-42%DO)纳米微球在70天内平均每天分子量大约下降0.84%；更进一步,采用poly(PDL-co-DO)为载体制备的DNR纳米微球的载药量较高,且释放速率可控；为进一步研究该聚合物作为核酸的传递载体,采用poly(PDL-co-42%DO)为载体,与双层乳液-溶剂挥发技术相结合,通过优化制备工艺(加入亚精氨为siRNA分子缔合物),制备了包封率较高的siRNA纳米微球,体外细胞基因沉默试验表明其具有增强siRNA基因沉默的功能。该实验为下一步开发基因载体材料提供了理论指导。
(3)针对基因载体的特点,通过引入氨基取代单体,采用酶催化聚合反应合成了一系列的可降解氨基聚酯材料,研究了其作为基因载体的转染效率,并探讨了聚合物结构与基因转染效率的关系。具体来说,成功地将C4-C12的二酯以及不同氨基取代基的二乙醇胺(如：甲基、乙基、n-丁基、t-丁基、苯基)引入到聚酯分子链中。通过酸性条件下叔氨可质子化这一特点,使得该类阳离子聚合物可通过静电力缔合带负电的DNA分子形成聚合物/DNA纳米复合体。采用Luciferase和GFP报告基因为模型的体外细胞基因转染试验证明,PMSC、PESC以及PDL-PMSC聚合物的基因转染效率比Lipofectamine 2000更高,而且细胞毒性非常小。研究表明聚合物/DNA复合体粒径越小(＜100 nm),细胞摄取越多；而酸性条件下表面Zeta电位值越高,“质子海绵效应”越强,细胞摄取后能够帮助DNA逃离内涵体,从而形成的基因转染效率也越高。更进一步的小鼠体内基因转染试验证明PDL-PMSC和PMSC较PEI来说,具有更高效的基因转染效率。新型可降解氨基聚酯材料的这些特点使其有望发展成为新一代的安全有效的非病毒基因载体。
Current chemotherapy is far from satisfactory:drug treatments often have limited effectiveness and patients suffer from serious side effects. Gene therapy represents a novel form of medical treatment that is expected to have major impact on human health in 21st century since a large number of human diseases are caused by genetic disorders. The success of chemotherapy or gene therapy is largely dependent on the development of a vehicle or vector that can selectively and efficiently deliver drug and gene to target cells with minimal toxicity. The use of nano-sized particles in cancer therapy and gene delivery is particularly exciting, as these materials can increase drug solubility and stability, as well as improve pharmacological effect and gene transfection efficiency. Herein, we reported that a series of biodegradable aliphatic polyester with diverse structures were designed and synthesized via enzymatic copolymerization using Candida antarctica lipase B (CALB) as the catalyst. Combing nano-fabrication technology, we developed several biodegradable polymeric drug and gene delivery systems, which would significantly improve the cancer treatment and gene transfection. There are three parts in this dissertation, including:
PartⅠ, we show that degradable particles of a hydrophobic polymer can effectively deliver camptochecin to tumors after i.v. administration. Free-standing nanoparticles with diameters of 100-300 nm were successfully fabricated from highly hydrophobic, biodegradable poly(ω-pentadecalactone-co-butylene-co-succinate) (PPBS) copolyesters. PPBS copolymers with various compositions were synthesized via copolymerization of o-pentadecalactone (PDL), diethyl succinate (DES), and 1,4-butanediol (BD) using CALB as the catalyst. Camptothecin (CPT,12-22%) was loaded into PPBS nanoparticles with high encapsulation efficiency (up to 96%) using a modified oil-in-water single emulsion technique. The CPT-loaded nanoparticles had a zeta potential of about-10 mV. PPBS particles were non toxic in cell culture. Upon encapsulation, the active lactone form of CPT was remarkably stabilized and no lactone-to-carboxylate structural conversion was observed for CPT-loaded PPBS nanoparticles incubated in both phosphate-buffered saline (PBS, pH=7.4) and DMEM media for at least 24 hr. In PBS at 37℃, CPT-loaded PPBS nanoparticles showed a low burst CPT release (20-30%) within the first 24 hrs followed by a sustained, essentially complete, release of the remaining drug over the subsequent 40 days. Compared to free CPT, CPT-loaded PPBS nanoparticles showed a significant enhancement of cellular uptake, higher cytotoxicity against Lewis lung carcinoma and 9L cell lines in vitro, a longer circulation time, and substantially better antitumor efficacy in vivo. These results demonstrate the potential of PPBS nanoparticles as long-term stable and effective drug delivery systems in cancer therapy.
PartⅡ, we have developed a polymeric nanoparticles system for both Daunorubicin and siRNA delivery by using poly(PDL-co-DO). First, mice test experiments showed that random poly(PDL-co-DO) copolymers had good biocompatibility. No significant abnormal tissue growth was observed polymer films were implanted in mice for up to four weeks. Second, free-standing nanoparticles with 200 nm size in average were successfully prepared from poly(PDL-co-DO). The degradation rate of the nanoparticles was studied over a 70-day period in phosphate buffered saline (PBS) solution at 37℃. On average, the molecular weight (Mn) of the particles decreased by approximately 0.84% per day. Furthermore, daunorubicin was encapsulated into poly(PDL-co-DO) nanoparticles with high loading. DNR released from the loaded nanoparticles exhibited a biphasic trend consisting of an initial burst followed by a gradual sustained release. Finally, high encapsulation efficiency siRNA/poly(PDL-co-42%DO) nanoparticles were successfully prepared at optimize condition (spermindine, as a counterion, was added to condense siRNA). In vitro gene knockdown experiments indicated that siRNA/poly(PDL-co-42%DO) nanoparticles gave a significant enhanced luciferase gene silence. With the further development, poly(PDL-co-DO) nanoparticles could be potentially used as hydrophilic drug and gene delivery vehicles.
PartⅢ, a series of biodegradable poly(amine-co-esters) were synthesized in one step via enzymatic copolymerization of lactone, diesters and amino-substituted diols. More specifically, C4-C12 diesters (i.e., from succinate to dodecanedioate) and diethanolamine comonomers with either an alkyl (methyl, ethyl, n-butyl,t-butyl) or an aryl (phenyl) substituent on nitrogen were successfully incorporated into the poly(amine-co-ester) chains. Upon protonation at slightly acidic conditions, these poly(amine-co-esters) readily turned to cationic polyelectrolytes, which are capable of condensing with polyanionic DNA to form polyplex nanoparticles. In vitro cell transfection screening revealed that three of the copolymers, poly (ω-pentadecalactone-N-methyldiethyleneamine sebacate) (PDL-PMSC), poly(N-methyldiethyleneamine sebacate) (PMSC) and poly(N-ethyldi-ethyleneamine sebacate) (PESC), possessed comparable or even higher transfection efficiency in delivering pLucDNA compared to that of Lipofectamine 2000. Studies on the physical properties and morphology of PESC/pLucDNA, PMSC/pLucDNA and PDL-PMSC/pLucDNA nanoparticles showed that both polyplexes had desirable particle sizes (< 100 nm) for cellular uptake and are capable of functioning as proton sponges to facilitate endosomal escape after cellular uptake. These polyplex nanoparticles exhibited extremely low cytotoxicity. Furthermore, gene transfection experiments performed using mouse tumor models showed that PDL-PMSC and PMSC are substantially more effective gene carrier than PEI in delivering pLucDNA to the tumor cells in vivo. All these properties make the poly(amine-co-esters) to be promising non-viral vectors for safe and efficient DNA delivery in gene therapy.
引文
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