摘要
乙二醇壳聚糖是一种壳聚糖衍生物,它能够在任何pH值的水溶液中溶解,具有壳聚糖的生物相容性、生物降解性、低免疫原性、生物活性等特点。本文选择乙二醇壳聚糖作为母体聚合物,通过引入不同的疏水基团,合成了一系列具有不同物理化学性质的两亲性乙二醇壳聚糖聚合物。这种两亲性聚合物能在水溶液中通过分子内及分子间的疏水作用力形成自聚集纳米粒。这种纳米粒具有核-壳结构,疏水性的内核和亲水性的外壳,疏水性的内核可以作为药物的储库,因此可以用作疏水性药物的载体。
本文采用二步反应将胆固醇接枝到乙二醇壳聚糖,首先将胆固醇进行羧基化,将胆固醇与琥珀酸酐反应生成胆固醇半琥珀酸酯(CHS),然后用1-乙基-3-(3-二甲基氨丙基)碳二亚胺盐酸盐(EDC)与N-羟基琥珀酰亚胺(NHS)作为偶联剂,将胆固醇半琥珀酸酯的羧基与乙二醇壳聚糖主链的氨基进行反应,得到胆固醇疏水改性乙二醇壳聚糖共聚物(CHGC)。利用红外光谱、核磁共振、元素分析法对其结构进行表征。通过控制胆固醇半琥珀酸酯与乙二醇壳聚糖的反应投料比例,合成三种不同取代度的聚合物。两亲性的乙二醇壳聚糖在水溶液中通过探头超声作用下自聚集形成单分散性的纳米粒,共聚物在水溶液中的最低临界聚集浓度(CAC)通过芘荧光探针法测定,随着共聚物中疏水取代基团含量的增多,CAC值降低。纳米粒的形态采用透射电子显微镜(TEM)来观察,粒径大小采用动态光散射法(DLS)测定。CHGC自聚集纳米粒的形态呈球形,粒径在228～353 nm。以吲哚美辛(indomethacin,IND)为模型药物,体外评价载药IND-CHGC纳米粒的性质。采用透析法制备载药IND-CHGC纳米粒,纳米粒的形态呈球形,且粒径比空白纳米粒更大。载药纳米粒体外释放行为表明,药物释放符合Weibull释放模型,呈两相释药。稳定性研究表明,冻干或低温有利于载药纳米粒的保存。
基于两亲性的CHGC自聚集纳米粒性质,选用阿霉素(doxorubicin,DOX)作为模型药物,制备载阿霉素CHGC纳米粒,使其成为一种“隐形”的长循环纳米粒,并可通过增强滞留和渗透(enhanced permeability and retention,EPR)效应提高靶向治疗肿瘤的目的。以CHGC1(取代度为6.7%)为载体材料,采用透析法制备载药纳米粒(DCN),随着阿霉素投药量的增加,纳米粒的载药量也增加,但包封率随之降低。载药纳米粒的形态呈球形,随着载药量的增大,纳米粒的粒径增大。应用差示扫描量热法(DSC)和荧光淬灭方法测定阿霉素在纳米粒中的分布状态,结果表明阿霉素包裹在纳米粒里面,并且以无定型或分子状态存在。载药纳米粒DCN的zeta电位大小与分散介质的pH值有一定关系,分散介质的pH值越低,zeta电位越大。研究载药纳米粒DCN在pH 5.5、6.5、7.4的PBS释放介质中的体外释放行为,结果表明,载药纳米粒随着载药量的增大药物释放速度减慢,在pH值越低的条件下,药物释放越快。在体外37℃的PBS(pH 7.4)条件下,阿霉素包裹在纳米粒中比较稳定,然而游离阿霉素不稳定容易发生降解。稳定性研究表明,载药纳米粒DCN应冻干保存。
建立了高效液相色谱(HPLC)测定阿霉素在血浆样品和组织样品中含量的方法。大鼠体内药动学研究结果显示,DCN-16(载药量为9.36%)可以显著延长阿霉素的体内循环时间。与阿霉素组比较,DCN-167以延长平均滞留时间(MRT)(P＜0.01)和降低体内消除率(CL)(P＜0.01),其药.时曲线下面积(AUC_(0-∞))为阿霉素组的5.61倍(P＜0.01)。DCN-16能够延长在荷S180瘤小鼠血浆中的时间,增加阿霉素在肿瘤内的分布,DCN-16在肿瘤组织中的AUC_(0-∞)是阿霉素组的2.56倍(P＜0.05),表明载药纳米粒具有长循环的特性和肿瘤靶向作用。DCN-16组在肝脏、脾脏中的AUC_(0-∞)均大于阿霉素组(P＜0.05),DCN-16组在心脏、肺脏、肾脏的AUC_(0-∞)均比阿霉素组小(P＜0.05),说明载药纳米粒能够降低心脏和肾脏的毒性,同时也说明纳米粒能够在体内长时间滞留。载药纳米粒DCN-16在肿瘤组织中的相对摄取率(R_e)和峰浓度比(C_e)分别为2.56±0.30和1.49±0.24,表明载药纳米粒DCN-16对S180肿瘤的趋向性大于阿霉素。
采用四甲基氮唑蓝比色(MTT)法考察了空白CHGC1纳米粒与载药纳米粒DCN-16对MCF-7细胞和HepG2细胞生长的影响。空白CHGC1纳米粒对MCF-7细胞和HepG2细胞的IC_(50)值分别为0.226 mg/mL和0.351 mg/mL,说明CHGC1纳米粒具有较低的细胞毒性。阿霉素和DCN-16对细胞的毒性均具有浓度依赖性。载药纳米粒DCN-16对MCF-7细胞和HepG2细胞的体外毒性均弱于游离阿霉素。激光共聚焦显微镜结果表明,DCN-16的细胞摄取是通过内吞途径,而游离阿霉素的细胞摄取是通过被动扩散的方式。流式细胞仪测定阿霉素与HepG2细胞孵育05h或4h时的荧光强度强于DCN-16的荧光强度,与CLSM观察结果一致,这也与载药纳米粒DCN-16的体外缓慢释放的有关。体内抗S180肉瘤小鼠实验表明,DCN-16组的抑瘤瘤大于阿霉素组的抑瘤率,并且毒副作用更低。
应用酶降解和超滤膜分离技术制备低分子量的乙二醇壳聚糖。以EDC作为偶联剂,将亚油酸(LA)接枝到低分子量的乙二醇壳聚糖,合成亚油酸疏水改性乙二醇壳聚糖(LALGC)共聚物,利用红外光谱、核磁共振、胶体滴定法对其结构进行表征。通过控制亚油酸的投料比例,合成三种不同取代度(4.5%～13.4%)的聚合物。LALGC共聚物在水溶液中通过探头超声作用下自聚集形成单分散性的纳米粒,纳米粒的形态呈球状,平均粒径在204～289 nm范围内,CAC与纳米粒的粒径大小随着共聚物的疏水基团取代度的增加而降低。应用透析法将紫杉醇包裹LALGC自聚集纳米粒中,载药纳米粒(PTX-LALGC)的载药量与包封率随着聚合物取代度的增加而增加。载药纳米粒的粒子形态呈球形,粒径在238～307 nm范围内。载药纳米粒的体外释放的结果表明,随着纳米粒载药量的增加,药物释放速度减慢,药物从纳米粒中释放呈两相模式,即初始的药物快速释放和后期的药物缓慢释放。应用MTT法研究载药纳米粒PTX-LALGCl对MCF-7细胞生长的影响,结果表明,PTX-LALGC1具有游离紫杉醇相当的细胞毒性。因此,LALGC聚合物纳米粒可以作为潜在的药物传递系统的载体。
Glycol chitosan is a novel chitosan derivative,and can be soluble in water at all pH values.It has chitosan-based structure and physicochemical properties,leading to excellent biocompatibility,biodegradability,low immunogenicity and biological activities.In the present study,a series of novel amphiphilic graft glycol chitosan were synthesized by introducing different hydrophobical groups.These polymeric amphiphiles can form self-aggregated nanoparticles via the intra- and/or intermolecular interactions of hydrophobic segments in aqueous media.These nanoparticles exhibit unique core-shell architecture composed of hydrophobic segments as internal core and hydrophilic segments as surrounding corona in aqueous media.The hydrophobic core serves as a reservoir for water-insoluble drugs.Hence,these nanoparticles can be used as carriers for hydrophobic drugs.
For the synthesis of cholesterol-modified glycol chitosan(CHGC) conjugates,a carboxyl group was initially introduced to cholesterol molecule using succinic anhydride,and then covalently coupled with the primary amino group of glycol chitosan in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxyl succinimide(NHS).These conjuages were characterized by FTIR,1~H NMR and elemental analysis.Three kinds of CHGC conjugates were prepared by controlling the feed ratio of cholesteryl hemisuccinate to glycol chitosan.The degree of substitution(DS),defined as the number of cholesterol groups per 100 sugar residues of glycol chitosan The physicochemical properties of the self-aggregated nanoparticles were studied using dynamic light scattering(DLS),transmission electron microscopy (TEM) and fluorescence spectroscopy.CHGC conjugates were well-dispersed in aqueous media,and formed self-aggregated nanoparticles by probe sonication. Fluorescence measurement using pyrene as fluorescent probe was adopted to determine the critical aggregation concentration(CAC) of amphiphilic copolymers.As the DS of the conjugates increased,the CAC decreased.The CHGC self-aggregated nanoparticles were almost spherical in shape,and the mean diameters of these nanoparticles were in the range of 228-353 nm.Indomethacin(IND) was chosen as a model drug to assess the potential of CHGC self-aggregated nanoparticles as a drug carrier.IND was physically entrapped into the CHGC nanoparticles by a dialysis method.IND-loaded CHGC nanoparticles were almost spherical in shape,and their sizes were larger than blank CHGC nanoparticles.The in vitro release behavior of IND-CHGC nanoparticles was well fitted by Weibull equation and presented a biphasic drug release pattern.Stability experiments revealed that IND-loaded CHGC nanoparticles should be stored at low temperature or in freeze-dried state.
Because the hydrophobic core of CHGC nanoparticles can provide a loading space for water-insoluble drugs,doxorubicin(DOX)-loaded CHGC nanoparticles were prepared.The drug-loaded nanoparticles were hoped to be stealthy nanoparticles, prolong circulation time in plasma and improve antitumor efficacy by enhanced permeability and retention(EPR) effect.The DOX-loaded CHGC1(the DS of CHGC1 was 6.7%) nanoparticles were prepared by a dialysis method.As the weight ratio of feed DOX to CHGC1 nanoparticles increased,the DOX-loading content increased and the DOX entrapment efficiency decreased.The DOX-loaded CHGC1 nanoparticles(DCN) were roughly spherical in shape determined by TEM observation.As the drug-loading content increased,the size of these nanoparticles increased.DOX in the polymer matrix was dispersed in an amorphous or molecular state,which was investigated by differential scanning calorimetry(DSC) and fluorescent quenching studies.The zeta potential of DCN series increased as the pH values of PBS solution decreased.DOX release from DCN in vitro was much faster in PBS at pH 5.5 than in PBS at pH 6.5 and 7.4.As the drug loading content of these nanoparticles increased,the release rate of DOX was much slower under the same condition.A notably slower degradation rate was observed for the encapsulated DOX,while free DOX was subject to rapid decomposition in PBS(pH 7.4) at 37℃.Stability tests indicated that DCN should be freeze-dried in store.
Reversed-phase high performance liquid chromatography(HPLC) was developed to quantify the content of DOX in rate plasma and mice tissues.Intraveneous pharmacokinetic behaviors in rats of DCN-16(drug loading content:9.36%) and free DOX were investigared.DCN-16 could prolong circulation time in rat plasma.In comparison with free DOX,DCN-16 has an increased MRT(P＜0.01) and decreased CL(P＜0.01).The AUC_(0-∞) of DCN-16 was 6.61 times higher than that of free DOX(P＜0.01).Moreover,DCN-16 displayed a much greater systemic circulation time in S180 mice than free DOX.In addition,compared with free DOX,DCN-16 also produced significantly increased AUC in liver(P＜0.05),spleen(P＜0.05),and tumors(P＜0.05).DCN-16 can passively accumulate into the tumor tissues by the long systemic retention in blood circulation and the EPR effect.The AUC_(0-∞) of DCN-16 was lower in heart(P＜0.05),lung(P＜0.05) and kidney(P＜0.05) than that of free DOX,which indicated DCN-16 could show longer circulation time and less toxic effect in S180-bearing mice.The relative tumor tissue exposure(R_e) and the ratio of peak concentration(C_e) were 2.56±0.30 and 1.49±0.24,respectively.It demonstrated that the tumor affinity of DCN-16 was higher than free DOX.
Cytotoxicity of blank CHGC1 nanoparticles and DCN-16 nanoparticles against MCF-7 and HepG2 cells was evaluated by MTT assay.The IC_(50) value of blank CHGC1 nanoparticles on MCF-7 and HepG2 cells was 0.226μg/mL and 0.351μg/mL, respectively.These results indicated that CHGC1 nanoparticles have relatively low cytotoxicity against both MCF-7 and HepG2 cells.Concentration-dependent cytotoxicity on MCF-7 and HepG2 cells was observed for both free DOX and DCN-16. DCN-16 showed a lower cytotoxicity against MCF-7 and HepG2 cells than free DOX. Confocal laser scanning microscopy(CLSM) demonstrated that cellular uptake of DCN-16 was in an endocytosis manner but that of free DOX was in a passive diffusion way.HepG2 ceils incubated with DCN-16 emitted lower fluorescent intensity than the cells incubated with free DOX after 0.5 or 4 h.This result was consistent with confocal microscopic observation and in vitro DOX release behavior.Compared with free DOX, DCN-16 exhibited more efficient tumor growth suppression,and simultaneously showed less toxicity effect in S 180-bearing mice.
Low-molecular-weight glycol chitosan was obtained by enzymatic degradation of glycol chitosan and membrane separation.A series of linoleic acid-modified low-molecular-weight glycol chitosan(LALGC) conjugates were synthesized in the presence of EDC.The chemical structure of LALGC copolymers was characterized by FTIR,1~H NMR and colloidal titration method.The degree of substitution(DS) defined as the number of LA groups per 100 glucosamine units of low-molecular-weight glycol glycol chitosan was 4.5-13.4%.The LALGC conjugates can form mono-dispersed nanoparticles by probe sonication.These nanoaggregates were almost spherical in shape, and the mean diameters of these nanoparticles determined by dynamic light scattering (DLS) were in the range of 204-289 nm.The CAC decreased as the DS of LALGC conjugates increased.Paclitaxel(PTX),as a model drug,was physically entrapped into the LALGC nanoparticles by a dialysis method.The drug loading content and encapsulation efficiency of PTX-loaded LALGC(PTX-LALGC) nanoparticles increased with an increasing ratio of the hydrophobic LA to hydrophilic glycol chitosan in the conjugates.The PTX-LALGC nanoparticles were almost spherical in shape and their size was ranged from 238 to 307 nm.In vitro release revealed that release rate of PTX from the nanoparticles was slower as the drug-loading content increased.PTX appeared to be released in a biphasic way,which characterized by an initial rapid release period followed by a step of slower release.The results of cytotoxicity in vitro showed that PTX-LALGC1 nanoparticles exhibited comparable activity in inhibiting MCF-7 cell proliferation as free PTX.Therefore,these results indicated that LALGC self-aggregated nanoparticles had a potential as a drug carrier.
引文
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