摘要
肿瘤微环境响应性聚合物药物载体具有长血液循环,良好的水溶性和易于多功能集成整合的特点,已经成为生物医学领域的重要研究方向。本论文集中研究了肿瘤微环境响应性,特别是酸性和还原性响应药物载体的设计以及特殊纳米结构的构筑及其对功能的影响。第一章简要介绍了响应性聚合物药物载体近几年的发展和面临的挑战。第二章中介绍了利用双响应动态共价壳交联胶束用于物理包埋抗肿瘤药物,实现刺激响应性释放。第三章中介绍了将光响应断键的喜树碱前药和靶向分子引入动态共价壳交联胶束体系,探讨其光响应药物传输和细胞毒性增加。第四章提出“聚前药两性分子(polyprodrug amphiphiles)"概念,通过自组装方法,实现聚前药两性分子特殊纳米结构制备,研究不同纳米结构的生物效应。第五章探讨了聚前药两性分子的复合功能化,用于造影剂传输和纳米结构微调控；首先发展了一种长血液循环带有细胞穿膜功能的支化结构聚前药两性分子,用于还原性响应磁共振造影信号增强和抗癌药物传输。其次介绍了一种“关窗一开门”策略用于聚前药两性分子囊泡的渗透性调节,负载疏水药物和亲水药物／蛋白实现协同抗肿瘤作用。具体来说,本论文的工作包括以下几个方面：
1.通过原子转移自由基聚合(ATRP)、开环聚合(ROP)成功地合成了生物相容的两亲性嵌段聚合物聚(ε-己内酯)-b-聚(寡聚环氧乙烷甲基丙烯酸酯-co-对苯甲醛基氧乙基甲基丙烯酸酯)(PCL-b-P(OEGMA-co-MAEBA))。在水溶液中,PCL-b-P(OEGMA-co-MAEBA)可以组装得到以PCL为内核,外壳含有悬垂醛基的胶束。在pH6.2以及苯胺催化下,采用二硫代丙二酰肼(DTP)交联剂与壳层的醛基反应产生酰腙键,得到壳交联胶束,提高了胶束的稳定性。该壳交联胶束的交联点含有二硫键和酰腙键,在还原性环境或酸性环境中可以分别断裂,从而实现双重控制。该动态共价壳交联胶束的疏水PCL内核可以用来包埋喜树碱和阿霉素等疏水抗肿瘤药物。在正常生理环境中,壳交联胶束可以大大降低药物的泄露,在肿瘤细胞酸性或还原性微环境中,壳层交联解离,能实现可控释放被包埋的药物。细胞实验发现,未包药的胶束本身没有明显毒性,包埋药物的壳交联胶束的细胞毒性接近小分子药物。细胞成像实验发现,壳交联胶束能够将抗癌药物输运到细胞内部,交联解离后药物释放加快,抗肿瘤药物能够在细胞核富集,发挥抗肿瘤效果。
2.结合原子转移自由基聚合(ATRP)、开环聚合(ROP)成功地合成了生物相容的两亲性嵌段聚合物聚(ε-己内酯)-b-聚(寡聚环氧乙烷甲基丙烯酸酯-co-对苯甲醛基氧乙基甲基丙烯酸酯-co-叠氮丙基甲基丙烯酸酯)(PCL-b-P(OEGMA-co-MAEBA-co-AzPMA))。通过点击化学反应,将含炔基的具有肿瘤靶向功能的叶酸分子接到聚合物的亲水链上制备亲水链标记有靶向分子的两亲性嵌段聚合物PCL-b-P(OEGMA-co-MAEBA-co-FA).此外,先通过ATRP方法合成末端含有羟基的聚(寡聚环氧乙烷甲基丙烯酸酯-co-对苯甲醛基氧乙基甲基丙烯酸酯)HO-P(OEGMA-co-MAEBA)),然后利用末端羟基开环己内酯和alfa-溴代己内酯共聚得到两亲性嵌段聚合物聚(ε-己内酯-co-溴代己内酯)-b-聚(寡聚环氧乙烷甲基丙烯酸酯-co-对苯甲醛基氧乙基甲基丙烯酸酯)(P(CL-co-CLBr)-b-P(OEGMA-co-MAEBA)),然后与叠氮化钠反应制备(PCL-g-N3)-b-P(OEGMA-co-MAEBA)-N3,然后通过点击化学反应,将炔基化的含有邻硝基苄基元的喜树碱前药共价接到聚合物链上制备得到含有喜树碱抗肿瘤前药的两亲性嵌段共聚物(PCL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT。在水溶液中,上述含有靶向分子的两亲性嵌段聚合物PCL-b-P(OEGMA-co-MAEBA-co-FA)和含有光响应前药的两亲性嵌段聚合物(PCL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT发生共组装得到混合胶束。在pH6.2以及苯胺催化下,采用二硫代丙二酰肼(DTP)交联剂与壳层的醛基反应产生酰腙键,得到壳交联胶束,胶束的壳层含有靶向分子叶酸,疏水内核含有光敏感抗肿瘤前药喜树碱。动态共价键交联壳层有效地消除了血液循环中的药物泄露,同时该药物传输系统具有很好的内涵／溶酶体逃逸能力。含有靶向分子叶酸标记的壳交联胶束可以有效地将药物输送到表达叶酸受体的肿瘤细胞内部,同时在光照刺激下,有效释放出喜树碱原药,细胞毒性提高约-9.7倍。这些结果表明,我们可以进一步结合其它靶向基元,抗肿瘤药物和响应性断键机制实现载体稳定性提高,肿瘤微环境信号响应性原药释放,同时毒性显现。
3.采用三光气和羟乙基二硫醚为基本原料,对喜树碱的20-位羟基进行改性,引入二硫键基元,制备一种含二硫键的还原性响应喜树碱前药单体CPTM。利用可逆加成断裂链转移(RAFT)聚合,采用聚乙二醇(PEG)的大分子RAFT试剂,成功合成了亲水链为PEG,疏水链为聚喜树碱前药的两亲性嵌段聚合物PEG-b-PCPTM。此类含有亲水链且含有聚合前药嵌段的两亲性分子被命名为“聚前药两性分子(polyprodrug amphiphiles)"。本体系中,PEG-b-PCPTM作为聚合前药两性分子的典型代表,具有极高的载药量(>50wt%),提高了水溶性,稳定性,具备肿瘤细胞还原性环境响应释放喜树碱原药特点。非常意外地发现,通过组装条件调控,PEG-b-PCPTM可以组装得到多种复杂纳米结构,其中四种典型的结构为：球(spheres)、花状复合囊泡(flower-like large compound vesicles)、光滑盘状结构(smooth disks)阳错列堆积的片层结构(staggered lamellae)。其中光滑盘状结构在经典嵌段聚合物自组装中难以得到,错列堆积的片层结构更没有实现。研究不同形貌的生物效应时发现,错列堆积的片层结构具有最长的血液循环时间,光滑盘状结构血液循环时间其次。错列堆积的片层结构和花状复合囊泡以独特的不依赖于网格蛋白和小窝体的内吞方式进入细胞,具有最快和其次的细胞内吞速率。四种结构的纳米粒子具有不同的降解速率,药物释放速率以及体外细胞毒性。聚合前药两性分子PEG-b-PCPTM的可控分级自组装和形状依赖的生物功能表现是自组装和抗肿瘤材料的重要突破,开辟了新一代药物自传输和共传输的新领域。
4.针对聚前药两性分子的复合功能化,特别是造影剂传输和纳米结构微调控。首先,我们通过可逆加成断裂链转移(RAFT)聚合方法,在单体链转移剂存在下,无规共聚还原性响应的喜树碱前药单体(CPTM)和甲基丙烯酸缩水甘油酯(GMA)得到支化结构聚前药分子聚(喜树碱前药-co-甲基丙烯酸缩水甘油酯)(P(CPTM-co-GMA))。然后以此支化内核为大分子链转移剂无规共聚亲水单体寡聚环氧乙烷甲基丙烯酸酯(OEGMA)和胍基单体3-胍基丙基甲基丙烯酰胺(GPMA)得到支化结构的聚前药两性分子P(CPTM-co-GMA)-b-P(OEGMA-co-GPMA)。进一步经过叠氮化钠改性支化结构疏水内核的环氧基元,然后再与炔基化的MRI增强对比剂DOTA(Gd)发生点击化学反应制备得到疏水内核标记有DOTA(Gd),亲水链标记有具有细胞穿膜功能胍基的两性支化分子P(CPTM-co-DOTA(Gd))-b-P(OEGMA-co-GPMA)。该支化结构聚前药两性分子具有极好的细胞膜穿透能力。在肿瘤细胞还原性环境中,释放喜树碱原药的同时,MRI信号增强效果明显。同时,该支化结构聚前药两性分子具有较好的血液循环时间。这些都表明我们得到的多功能支化结构聚前药两性分子在细胞穿膜,可控释放抗肿瘤原药以及可视化治疗上有着很大的潜在应用价值。另外,针对聚合前药两性分子在聚集体微结构功能调控,如囊泡渗透性调节与药物协同传输方面,我们进行了如下设计与探索。通过可逆加成断裂链转移(RAFT)聚合方法,在聚乙二醇(PEG)大分子RAFT试剂存在下,共聚喜树碱前药单体CPTM和甲基丙烯酰氧丙基三甲氧基硅烷(TMSPMA)得到含有硅基可交联基元的聚前药两性分子PEG-b-P(TMSPMA-co-CPTM).通过分子自组装方法,制备得到囊泡,弱碱条件下是囊泡双分子膜里面的硅烷水解发生原位交联,得到交联囊泡,伴随此过程的是囊泡渗透性降低。在还原性环境中,喜树碱原药从囊泡双层膜释放出来,同时囊泡渗透性大大提高。这种“关窗—开门”囊泡渗透性调控策略可被用于抗癌药物/蛋白的协同传输。
The research on tumor microenvironments-responsive polymeric vectors has been increasingly regarded as an important area in biomedicine due to their long blood circulation, improved water solubility, and facile integration of functionalities. This dissertation mainly focuses on the design, complicated nanostructural fabrication, and related functional performance of tumor microenvironments-responsive polymeric vectors, especially acid-and reduction-responsive polymers. The first chapter gave a brief introduction concerning the development and challenges of stimuli-responsive polymeric carriers in recent years. In the second chapter, dual-responsive dynamic covalent shell cross-linked micelles for triggered release of chemotherapeutic drugs were explored. The third chapter demonstrated the targeting ligand folic acid-decorated dual-responsive dynamic covalent shell cross-linked micelles conjugated with photo-responsive camptothecin prodrug for photo-triggered drug release and photoactiviated cytotoxicity. The forth chapter reported a novel kind of polymeric drug vectors, termed as polyprodrug amphiphiles, affording multiple hierarchical nanostructures through facile solution self-assembly, exhibiting shape-modulated biological performances. The fifth chapter described some integrated multifunctional application of polyprodrug amphiphiles. Firstly, one type of long blood circulating branched polyprodrug amphiphiles with cell-penetrating ability for reduction-responsive enhancement of magnetic resonance imaging signals and anticancer ability. Secondly, one kind of "windows closing-doors opening" strategy was investigated to regulate the permeability of polymeric vesicles fabricated from polyprodrug amphiphiles, realizing the synergetic delivery of hydrophobic drugs and hydrophilic drugs or proteins. This dissertation can be further clarified as described below:
1. Well-defined amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-MAEBA), was synthesized via ring-opening polymerization (ROP) of ε-caprolactone (CL) and then atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers. In aqueous solution, the diblock copolymer self-assembles into micelles consisting of hydrophobic PCL cores and hydrophilic P(OEGMA-co-MAEBA) coronas covalently anchored with pendent aldehyde groups. The subsequent shell cross-linking reaction was conducted at pH6.2upon addition of difunctional dithiolbis(propanoicdihydrazide)(DTP). The formation of dynamic acylhydrazone cross-linking linkages was facilitated under the catalysis of aniline. The obtained SCL micelles can be de-crosslinked via two biologically relevant modes, namely, acidic pH-triggered cleavage of acylhydrazone bonds into aldehyde and hydrazide and reduction-triggered cleavage of disulfide linkages, which have been utilized for triggered release of physically encapsulated chemotherapeutic drugs. Camptothecin (CPT)-loaded SCL micelles were used to investigate reduction and pH-modulated CPT release profiles. Compared with CPT-loaded non-crosslinked (NCL) micelles, CPT-loaded SCL micelles can largely minimize drug leakage under physiological conditions, whilst exhibiting accelerated drug release under mildly acidic or reductive microenvironments, which are relevant to those of acidic organelles (endosomes and lysosomes) or cytosol within tumor cells. Cell cytotoxicity studies revealed that drug-free SCL micelles are almost nontoxic, whereas CPT-loaded SCL micelles can efficiently deliver chemotherapeutic drug (CPT) into HepG2cells, leading to considerable nucleic accumulation at extended incubation duration. The reported dynamic covalent shell crosslinking strategy can exert intricate control concerning the micellar stability and the release profile of encapsulated drugs in response to biological microenvironments, which augurs well for their potential use as novel smart nanocarriers for drug delivery in cancer chemotherapy.
2. Two types of amphiphilic diblock copolymers, P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT and PCL-b-P(OEGMA-co-MAEBA-co-FA), were synthesized via the combination of ring-opening copolymerization (ROP) of ε-caprolactone (CL) and2-bromo-e-caprolactone (CL-Br), atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers, and "click" post-functionalization with photocaged camptothecin (CPT) prodrug and alkynyl-functionalized folic acid (FA) moieties, respectively. Mixed micelles coassembled from PCL-b-P(OEGMA-co-MAEBA-co-FA) and P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT possess hydrophobic cores conjugated with photocaged CPT prodrugs and hydrophilic outer coronas covalently attached with aldehyde groups and FA moieties for subsequent shell cross-linking and cancer cell targeting. Shell cross-linking was performed at pH6.2upon addition of difunctional crosslinker, dithiol bis(propanoic dihydrazide)(DTP), under the catalysis of aniline. The obtained FA-decorated SCL micelles contain acylhydrazone and disulfide linkages in the outer coronas, which can be de-crosslinked under mildly acidic or reductive microenvironments, that is, endosomal/lysosomal pH or high GSH level in the cytosol. The cleavage of caged CPT drug within the cores of SCL micelles can be effectively actuated under photo irradiation, whereas its diffusion out of micellar nanocarriers can be further modulated by pH and thiol levels due to the dually responsive nature of DTP cross-linker. Compared with the control, FA-decorated SCL micelles can more efficiently enter folate-receptor expressing cancer cells than folate-receptor deficient ones. Cell viability assays revealed that SCL micelles displayed at least-9.7-fold enhanced cytotoxicity upon light irradiation. The reported targeting ligand decorated and prodrug-conjugated dynamic covalent SCL micelles exert intricate control concerning micellar stability, cancer cell targeting, photo-triggered parent drug release with photoactivated cytotoxicity, and tunable drug release profiles. All of these augur well for their potential application as a novel integrated platform for targeted drug delivery in cancer chemotherapy.
3. Camptothecin (CPT) prodrug monomer with a disulfide linkage, CPTM, was synthesized from2,2'-dithiodiethanol and triphosgene via fuctionalizing the20-hydroxy of CPT parent drug. We employed reversible addition-fragmentation transfer (RAFT) technique to polymerize CPTM prodrug monomer using hydrophilic PEG-based macroRAFT agent, affording PEG-b-PCPTM diblock copolymers with CPT moieties in the hydrophobic block. This kind of amphiphiles with hydrophilic chain and polymerized block of prodrug monomer were termed as polyprodrug amphiphiles. In this system, PEG-b-PCPTM, a typical representation of polyprodrug amphiphiles, possess>50wt%drug loading content, improved water solubility, drug stability and reduction-responsive parent drug release characteristics. It's very accidental to find that the solution self-assembly of PEG-b-PCPTM can afford multiple hierarchical nanostructures. Among these, four typical nanostructures, including spheres, flower-like large compound vesicles, and in particular smooth disks and staggered lamellae with spiked periphery, with the latter being unprecedented. Amongst these, staggered lamellae exhibit the longest blood circulation duration, and smooth disks possess slightly faster blood elimination than staggered lamellae. Staggered lamellae and large compound vesicles show quite fast cellular uptake, may follow unique internalization pathways. Reductive milieu-triggered release kinetics of parent CPT drugs and nanostructure degradation, and shape-modulated in vitro cytotoxicity were also explored. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological functions open up new horizons for exploring next-generation drug self-delivery and co-delivery systems with further improved efficiency.
4. In terms of potential applications of polymeric assemblies from polyprodrug amphiphiles in clinical diagnosis (magnetic resonance imaging, MRI), we explored the following design. RAFT polymerization was employed to prepare branched P(CPTM-co-GMA) in the presence of RAFT chain transfer agent monomer, prodrug monomer CPTM, and glycidyl methacrylate (GMA). Then, branched P(CPTM-co-GMA) was further used as macro RAFT agent to copolymerize oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and3-guanidinopropyl methacrylamide (GPMA), affording branched polyprodrug amphiphiles, P(CPTM-co-GMA)-b-P(OEGMA-co-GPMA). Subsequent treatment with sodium azide to functionalize the epoxy groups in the branched core and click conjugation with alkynyl-containing MRI contrast agent, alkynyl-DOTA(Gd) afforded branched P(CPTM-co-DOTA(Gd))-b-P(OEGMA-co-GPMA). This type of branched polyprodrug amphiphiles with caged MRI contrast agent in the branched core possess good cell-penetrating ability and extended blood circulation. Upon treatment with tumor cells'reductive milieu, CPT parent drugs were released as the active form accompanied with the great enhancement of MRI signals. These observations demonstrate that our obtained multi-functional combined branched polyprodrug platforms have great potential applications in cell-penetrating, controlled parent drug release and in-situ therapeutic monitoring. In terms of the permeability regulation of vesicle nanostructures from polyprodrug amphiphiles and the demand for synergetic drug delivery, we conceived the following design to regulate vesicular permeability for biomedical application. RAFT polymerization was employed to prepare PEG-b-P(TMSPMA-co-CPTM) in the presence of PEG macroRAFT agent, prodrug monomer CPTM, and3-(trimethoxysilyl)propyl methacrylate (TMSPMA). Polymeric vesicles were fabricated via solution self-assembly of PEG-b-P(TMSPMA-co-CPTM). Upon treating under weak alkaine milieu, the bilayer of vesicles was crossliked by the sol-gel reaction of silane moieties, affording crosslinked vesicles with decreased permeability of vesicle bilayer. Thus, the permeability of bilayer was enhanced under the tumor cell's reduction microenvirnoments, accopanied with CPT parent drug release from the vesicle bilayer. This kind of "windows closing-doors opening" strategy was further investigated to realize the synergetic delivery with hydrophilic drugs or proteins.
引文
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