聚乙二醇修饰的可生物降解聚酯药物载体的研究
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摘要
本文设计合成了多种聚乙二醇修饰的可降解酯类聚合物,表征了其结构和性质,并对它们作为抗癌药物载体的性能进行了初步研究。
采用熔融缩聚法合成了聚乙二醇-聚左旋乳酸(PELLA)和聚乙二醇-聚消旋乳酸(PEDLLA)二嵌段共聚物;并以甲苯二异氰酸酯(TDI)为偶联剂,聚己内酯(PCL)和聚乙二醇(PEG)为原料合成了聚乙二醇-聚己内酯-聚乙二醇(PECL)三嵌段共聚物。研究了PEDLLA与PELLA或PECL在水溶液中共混,自组装杂化纳米粒(HNPs)的性能。该HNPs为具有核壳结构的球形(粒径小于100 nm),并且可以有效包载紫杉醇。载药HNPs随着PELLA或PECL含量的增加,药物释放速率逐渐降低,且处于PEDLLA与PELLA或PECL纳米粒的药物释放速率之间。通过调节PEDLLA和PELLA或PECL的比率可以控制紫杉醇的释放速率。WAXD和DSC结果表明HNPs的控制药物释放能力与PLLA或PCL段的结晶相与PDLLA段的无定形相在HNPs的内核中共存有关。
通过二硫醇和聚乙二醇二丙烯酸酯(PEGDA)或聚乙二醇二甲基丙烯酸酯(PEGDMA)缩合聚合得到聚乙二醇修饰的聚硫酯类聚合物(DPEG)。该聚合物具有多个活性基团,如:巯基端基,甲基/丙烯酸端基和侧羟基。运用这些基团成功地和抗癌药物喜树碱形成了前药,还使聚合物端基连接上靶向基团叶酸。调节反应中聚合物,药物的比率,可使聚合物长链带上不同量的药物。所合成的前药具有肿瘤敏感性,而聚合物本身则没有。DPEG的降解速率具有pH依赖性,在pH为7.4的环境中稳定存在,而在酸性环境(pH=6.0,5.0)中快速降解。并且,该聚合物还具有温度敏感性,且相转变范围窄。通过调节大分子单体链长,双键的类型,以及硫醇的类型,可调节相转变温度。其中,有两种聚合物的相转变温度分别为36°C和39°C,与人体温度相近,有应用前景。交联上述直链DPEG可得到具有温度敏感性的凝胶,且通过后交联法得到的凝胶具有和直链聚合物相似的温度敏感特性。
通过PEG和二酸酐缩合聚合得到聚乙二醇修饰的聚碳酸酯类聚合物(PEG-DA)。这种聚合物主链为酯键键接,在每个酯键旁都有一个游离的羧基。在酸性环境(pH=6.0,5.0)中,因羧基对酯键的进攻而快速水解。通过该聚合物与不同的抗癌药物(喜树碱、顺铂)键接,制备出了聚合物前药。通过调节反应中聚合物,药物的比率,可使聚合物长链带上不同量的药物。所合成的前药具有肿瘤敏感性,而聚合物本身则没有。
In this paper, several kinds of PEGylated biodegradable polyesters were designed and synthesized. Their structures and characters were characterized. The pharmaceutical capabilities of these polyesters as anti-cancer drug carriers were also investigated.
A convenient pathway to control drug release from copolymer nanoparticles (NPs) by hybrid assembly of different kinds of copolymers was investigated in this paper. Three kinds of biodegradable amphiphilic copolymers, Methoxy poly(ethylene glycol)-block-poly(L-lactic acid) (PELLA), methoxy poly(ethylene glycol)-block-poly (D,L-lactic acid) (PEDLLA) and poly(ethylene glycol)-block-poly(caprolactone)- block -poly(ethylene glycol) (PECL) were prepared and used to assemble into hybrid nanoparticles (HNPs) as carriers of paclitaxel. The structure and properties of the paclitaxel loaded copolymer NPs and HNPs were characterized by DSC, WAXD, TEM and light scattering. The results show that small spherical HNPs (diameter < 100 nm) with good paclitaxel loading ability and entrapping efficiency were obtained simply by hybrid assembling different copolymers. The in vitro release studies indicate that paclitaxel release rate can be controlled easily by varying the ratio of the hydride copolymers. The release control mechanism of the HNPs is mainly due to the crystallization adjustment by mixing of PEDLLA into PELLA or PECL. The HNPs provide a convenient approach to control drug release for drug-loaded NPs.
PEGylated poly(ester-sulfide)s (DPEGs) were synthesized by condensation polymerization of dithiols and poly(ethylene glycol) diacrylates (PEGDA) or dimethacrylates (PEGDMA). These DPEGs carried functional groups such as terminal thiol or (meth)acrylate groups and pendant hydroxyl groups. Using these functional groups can successfully react with anti-cancer drug camptothecin to form poly-drug conjugate, and connect targeting group folic acid to the end groups of polymer. With different ratio of polymer and drug in conjugation reaction, polymer chain can carry different amount of drugs. The synthesized polymer-drug conjugates have cancer sensitivity, while polymers do not have. DPEGs are pH-dependent degradable. They are stable at pH 7.4 but degraded quickly in acid condition (pH=6.0, 5.0). DPEGs have thermoresponsibility and the phase transition ranges sharp. With changing the PEG chain length, the type of the double bond and the type of dithiol, phase transition temperature can be adjusted. There are two polymers have LCSTs at 36°C and 39°C, respectively, close to the body temperature which make them have promising application potential. Crosslinking DPEG chains produced thermoresponsive hydrogels. And the hydrogels prepared by end-capping method maintain the thermoresponsive properties of the DPEGs.
PEGylated polycarbonates (PEG-DA) were synthesized by condensation polymerization of PEG and dianhydride. This kind of polymers is connected by ester bond and there is a free carbonic acid group near ester bond. Under acid circumstances (pH=6.0,5.0), polymers are hydrolysized quickly by the attack of acid group. PEG-DA can effectively conjugate anti-cancer drugs (camptothecin, cisplatin). With different ratio of polymer and drug in conjugation reaction, polymer chain can carry different amount of drugs. The synthesized polymer-drug conjugates have cancer sensitivity, while polymers do not have.
采用熔融缩聚法合成了聚乙二醇-聚左旋乳酸(PELLA)和聚乙二醇-聚消旋乳酸(PEDLLA)二嵌段共聚物;并以甲苯二异氰酸酯(TDI)为偶联剂,聚己内酯(PCL)和聚乙二醇(PEG)为原料合成了聚乙二醇-聚己内酯-聚乙二醇(PECL)三嵌段共聚物。研究了PEDLLA与PELLA或PECL在水溶液中共混,自组装杂化纳米粒(HNPs)的性能。该HNPs为具有核壳结构的球形(粒径小于100 nm),并且可以有效包载紫杉醇。载药HNPs随着PELLA或PECL含量的增加,药物释放速率逐渐降低,且处于PEDLLA与PELLA或PECL纳米粒的药物释放速率之间。通过调节PEDLLA和PELLA或PECL的比率可以控制紫杉醇的释放速率。WAXD和DSC结果表明HNPs的控制药物释放能力与PLLA或PCL段的结晶相与PDLLA段的无定形相在HNPs的内核中共存有关。
通过二硫醇和聚乙二醇二丙烯酸酯(PEGDA)或聚乙二醇二甲基丙烯酸酯(PEGDMA)缩合聚合得到聚乙二醇修饰的聚硫酯类聚合物(DPEG)。该聚合物具有多个活性基团,如:巯基端基,甲基/丙烯酸端基和侧羟基。运用这些基团成功地和抗癌药物喜树碱形成了前药,还使聚合物端基连接上靶向基团叶酸。调节反应中聚合物,药物的比率,可使聚合物长链带上不同量的药物。所合成的前药具有肿瘤敏感性,而聚合物本身则没有。DPEG的降解速率具有pH依赖性,在pH为7.4的环境中稳定存在,而在酸性环境(pH=6.0,5.0)中快速降解。并且,该聚合物还具有温度敏感性,且相转变范围窄。通过调节大分子单体链长,双键的类型,以及硫醇的类型,可调节相转变温度。其中,有两种聚合物的相转变温度分别为36°C和39°C,与人体温度相近,有应用前景。交联上述直链DPEG可得到具有温度敏感性的凝胶,且通过后交联法得到的凝胶具有和直链聚合物相似的温度敏感特性。
通过PEG和二酸酐缩合聚合得到聚乙二醇修饰的聚碳酸酯类聚合物(PEG-DA)。这种聚合物主链为酯键键接,在每个酯键旁都有一个游离的羧基。在酸性环境(pH=6.0,5.0)中,因羧基对酯键的进攻而快速水解。通过该聚合物与不同的抗癌药物(喜树碱、顺铂)键接,制备出了聚合物前药。通过调节反应中聚合物,药物的比率,可使聚合物长链带上不同量的药物。所合成的前药具有肿瘤敏感性,而聚合物本身则没有。
In this paper, several kinds of PEGylated biodegradable polyesters were designed and synthesized. Their structures and characters were characterized. The pharmaceutical capabilities of these polyesters as anti-cancer drug carriers were also investigated.
A convenient pathway to control drug release from copolymer nanoparticles (NPs) by hybrid assembly of different kinds of copolymers was investigated in this paper. Three kinds of biodegradable amphiphilic copolymers, Methoxy poly(ethylene glycol)-block-poly(L-lactic acid) (PELLA), methoxy poly(ethylene glycol)-block-poly (D,L-lactic acid) (PEDLLA) and poly(ethylene glycol)-block-poly(caprolactone)- block -poly(ethylene glycol) (PECL) were prepared and used to assemble into hybrid nanoparticles (HNPs) as carriers of paclitaxel. The structure and properties of the paclitaxel loaded copolymer NPs and HNPs were characterized by DSC, WAXD, TEM and light scattering. The results show that small spherical HNPs (diameter < 100 nm) with good paclitaxel loading ability and entrapping efficiency were obtained simply by hybrid assembling different copolymers. The in vitro release studies indicate that paclitaxel release rate can be controlled easily by varying the ratio of the hydride copolymers. The release control mechanism of the HNPs is mainly due to the crystallization adjustment by mixing of PEDLLA into PELLA or PECL. The HNPs provide a convenient approach to control drug release for drug-loaded NPs.
PEGylated poly(ester-sulfide)s (DPEGs) were synthesized by condensation polymerization of dithiols and poly(ethylene glycol) diacrylates (PEGDA) or dimethacrylates (PEGDMA). These DPEGs carried functional groups such as terminal thiol or (meth)acrylate groups and pendant hydroxyl groups. Using these functional groups can successfully react with anti-cancer drug camptothecin to form poly-drug conjugate, and connect targeting group folic acid to the end groups of polymer. With different ratio of polymer and drug in conjugation reaction, polymer chain can carry different amount of drugs. The synthesized polymer-drug conjugates have cancer sensitivity, while polymers do not have. DPEGs are pH-dependent degradable. They are stable at pH 7.4 but degraded quickly in acid condition (pH=6.0, 5.0). DPEGs have thermoresponsibility and the phase transition ranges sharp. With changing the PEG chain length, the type of the double bond and the type of dithiol, phase transition temperature can be adjusted. There are two polymers have LCSTs at 36°C and 39°C, respectively, close to the body temperature which make them have promising application potential. Crosslinking DPEG chains produced thermoresponsive hydrogels. And the hydrogels prepared by end-capping method maintain the thermoresponsive properties of the DPEGs.
PEGylated polycarbonates (PEG-DA) were synthesized by condensation polymerization of PEG and dianhydride. This kind of polymers is connected by ester bond and there is a free carbonic acid group near ester bond. Under acid circumstances (pH=6.0,5.0), polymers are hydrolysized quickly by the attack of acid group. PEG-DA can effectively conjugate anti-cancer drugs (camptothecin, cisplatin). With different ratio of polymer and drug in conjugation reaction, polymer chain can carry different amount of drugs. The synthesized polymer-drug conjugates have cancer sensitivity, while polymers do not have.
引文
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