双重敏感的磺酸甜菜碱-姜黄素药物载体的合成和表征

合成了聚姜黄素-二硫键-聚甲基丙烯酸二乙胺基乙酯-聚磺酸甜菜碱(Cur-DA-ss-PDEA-PS,或简写为Cur-ss-PDEA-PS),采用核磁、红外对聚合物结构进行了表征,用示差扫描量热法测试了聚合物热性能.用溶剂挥发法制备聚合物胶束,形成了聚磺酸甜菜碱为亲水壳层、聚姜黄素为疏水核、二硫键作为还原敏感基团和聚甲基丙烯酸二乙氨基乙酯为p H敏感基团的胶束.用荧光分光光度计测定了临界胶束浓度,动态光散射以及扫描电镜对胶束结构及性质进行了表征.结果显示,胶束稳定性良好,粒径分布较窄,且具有p H敏感性和还原敏感性.胶束载药量及包封率测试结果显示,相比于聚己内酯为内核的聚合物胶束,聚姜黄素的引入提高了胶束对药物的封装效果.     

嵌段共聚物核交联胶束的制备与载药性能研究

在DMAP的催化和DIPC的作用下,丙烯酸的双键被引入聚乙二醇-聚己内酯嵌段共聚物的疏水链段上,制备胶束过程中使用过硫酸铵催化位于胶束内核部分的双键交联,得到的核交联胶束。在包载甲氨喋呤释放过程中,核交联胶束的累积释放率明显比非核交联胶束的小,具有良好的缓释效果。     

交联聚天冬氨酸基聚离子胶束的制备与表征

通过胺端基聚乙二醇(CH3O-PEG-NH2)开环聚琥珀酰亚胺(PSI), 进一步碱解和胺解制备了聚乙二醇接枝聚天冬氨酸(PEG-g-PAsp)和聚乙二醇接枝聚乙二胺基天冬酰胺(PEG-g-PDEA)两种聚天冬氨酸衍生物. 利用它们之间的静电相互作用, 在磷酸缓冲液中形成了以PEG为壳、聚天冬氨酸复合物为核的聚离子胶束. 研究发现, 该聚离子胶束粒子呈球形, 粒径约为70 nm, 且粒径分布较窄. 然而, 体系的稳定性受溶液的pH和盐离子强度影响较大. 通过戊二醛交联PEG-g-PDEA中的伯胺可以有效提高该聚离子胶束对pH和盐离子强度的稳定性.     

具有还原刺激响应的聚氨酯胶束的制备和表征

以聚ε-己内酯二元醇(PCL)为软段,赖氨酸二异氰酸酯(LDI)和胱胺(cystamine)为硬段,合成了以胱胺封端的线性聚氨酯预聚体,然后利用α-甲氧基-ω-环氧丙基聚乙二醇(EO-MPEG)的环氧基与胱胺的胺基反应,制备了含有二硫键的双亲性聚氨酯.利用GPC测试了聚氨酯的分子量,1H-NMR及FTIR表征了聚氨酯的结构.利用透析法制备了聚氨酯胶束,荧光探针技术测得其临界胶束浓度为5.6×10-3g/L,TEM分析表明胶束形貌为球形,DLS分析表明胶束的平均粒径为82 nm.还原响应实验表明胶束在10 mmol/L的谷胱甘肽的作用下粒径明显增大,表明胶束具有还原刺激响应特性.最后,以抗肿瘤疏水药物氨甲喋呤(MTX)为模型药物,研究了载药胶束在谷胱甘肽作用下的药物释放,结果表明谷胱甘肽的存在可刺激药物的释放,该材料可作为细胞内还原响应的载体材料使用.     

pH敏感型mPEG-Hz-PLA聚合物纳米载药胶束的制备

以合成的含有腙键的聚乙二醇大分子(mPEG-Hz-OH)为引发剂,以丙交酯为单体引发开环聚合反应,并通过调整投料比,制备出3种不同分子量的含腙键的生物可降解嵌段聚合物(mPEG-Hz-PLA).将腙键引入到聚合物的骨架中,以此构建聚合物胶束并作为pH敏感型纳米药物载体.制备的pH敏感型胶束的CMC值等于或低于5.46×10-4 mg/m L,DLS和TEM显示粒径均小于100 nm,且粒径分布均匀.非pH敏感型胶束在不同pH下的粒径变化不明显,而pH敏感型胶束在酸性环境下(pH=4.0和pH=5.0)胶束粒径出现了明显变化.以阿霉素为模型药物制备了pH敏感型载药胶束,其粒径比空白胶束大(100~200 nm),且粒径分布均匀.药物释放实验表明pH敏感型载药胶束随着释放介质pH降低累积释药量增高.MTT实验表明空白胶束对HeLa细胞和RAW264.7细胞几乎没有抑制作用,而载阿霉素的胶束对2种细胞的抑制作用都随着剂量的增大和时间的延长而增强.     

磺酸基甜菜碱共聚物的合成及其界面活性研究

以N-[3-(二甲氨基)丙基]丙烯酰胺与1,3-丙磺酸内酯为原料,制备了3-[(3-丙烯酰胺)丙基-二甲氨基]丙磺酸钠甜菜碱型单体,并将其与丙烯基聚乙二醇通过自由基聚合物反应合成了磺酸基甜菜碱和聚乙二醇的共聚物.利用红外光谱(FT-IR)和凝胶渗透色谱仪(GPC)对共聚物进行表征,并考察了在高浓度CaCl2条件下该共聚...     

荧光标记pH敏感胶束的制备及其药物控释

利用原子转移自由基聚合方法（ATRP）合成了pH敏感的两亲性嵌段共聚物mPEG-b-PDPA_n（聚合度n=100-200）及荧光修饰的嵌段聚合物异硫氰酸荧光素-聚乙二醇-聚N,N-二异丙胺基甲基丙烯酸乙酯（FITCPEG₄₅-PDPA₁₀₀）。采用溶剂挥发的方法制备胶束,此胶束呈现均一的球形分布,平均粒径180-240 nm（0.3 mg·mL^-1）。以阿霉素（DOX）为模拟药物,其胶束载药量约11%（w,质量分数）左右,外环境pH对载药胶束的粒径和体外释放行为有显著影响。在弱酸环境下,胶束核质子化发生膨胀甚至解体,在2-3 h内药物可释放80%左右。体外毒性试验表明,空白胶束与人类肝癌细胞（Huh7）有良好的生物相容性。同时,与此细胞共同孵育5 h的荧光聚合物胶束体现了较好的转染效果。因此,这类荧光标记胶束可能会为实时跟踪化疗药物的输送或分布打开新的视角。     

芥酸酰胺丙基羟基磺酸甜菜碱的合成及其表面活性

以芥酸,N,N-二甲基丙胺和环氧氯丙烷为原料,经酰胺化和季胺化等反应合成了芥酸酰胺丙基羟基磺酸甜菜碱(1),其结构经1H NMR和IR确证。表面活性研究结果表明:1的临界胶束浓度为0.037 4 mmol·L-1(20.6 mg·L-1),表面张力为24.604 mN·m-1。     

基于有机硅组分交联稳定纳米胶束的研究进展

综述了基于有机硅组分交联稳定纳米胶束的研究进展,对制备方法和交联区域的选择以及应用领域的研究进行了较为详细的阐述.指出将有机硅引入双亲性高分子链中,利用有机硅部分的溶胶-凝胶转变对双亲高分子胶束的具体区域进行交联,能够使其胶束结构固定下来并形成杂化材料,在提高高分子胶束稳定性的同时又赋予其无机材料的刚性、低生理毒性、便于纯化等优点,为双亲性高分子的制备以及药物的运载、控制释放等带来极大的帮助.     

交联度对原位聚合法制备聚合物胶束性质的影响及相应的空心球制备

用原位聚合法成功地制备出不同响应温度的温敏性聚乳酸/聚(异丙基丙烯酰胺-co-丙烯酰胺)[P(D,L-LA)/P(NIPAM-co-AM)]核壳胶束. 实验中发现, 壳层的交联剂含量对粒子的尺寸有很大的影响, 当交联剂的摩尔分数从5%提高到15%时, 粒子在25 ℃时的流体力学直径从170.2 nm增加到886.5 nm. 通过对胶束粒子的核进行生物降解, 方便地得到了相应的空心球. 用FTIR监测核的降解过程, 用SEM和AFM检测核降解完全后粒子的外在形貌和内在结构变化. DLS结果表明, 空心球粒子同样具有良好的温度响应性, 其响应温度可通过改变原位聚合时单体AM的含量加以调节.     

Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates

A dilemma exists between the circulation stability and cargo release/mass diffusion at desired sites when designing delivery nanocarriers and in vivo nanoreactors. Reported herein are disulfide‐crosslinked (DCL) micelles exhibiting reduction‐triggered switching of crosslinking modules and synchronized hydrophobic‐to‐hydrophilic transition. Tumor cell targeted DCL micelles undergo cytoplasmic milieu triggered disulfide cleavage and self‐immolative decaging reactions at chemically adjustable rates, generating primary amine moieties. Extensive amidation reactions with neighboring ester moieties then occur because of the high local concentration and suppression of the apparent amine pK_a value within the hydrophobic cores, thus leading to the transformation of crosslinking modules and formation of tracelessly crosslinked (TCL) micelles, with hydrophilic cores, inside live cells. We further integrate this design principle with theranostic nanocarriers for selective intracellular drug transport guided by enhanced magnetic resonance (MR) imaging performance.     

不同内核结构PEG-b-PCL胶束的制备及其载药性能的研究

以聚乙二醇单甲醚作大分子引发剂,异辛酸亚锡作催化剂,将不同比例的ε-己内酯(CL)与4-甲基-ε-己内酯(MCL)单体开环共聚,并通过控制CL和MCL的投料比以及投料方式,得到了疏水链段上CL和MCL不同比例和分布的4组聚合物.核磁和凝胶渗透色谱法表征了聚合物的结构,示差扫描量热法,广角X射线衍射和红外光谱表征了聚合物的结晶性.采用透析的方法,制备了4种聚合物的纳米胶束,以及载药(阿霉素DOX)胶束,并研究了胶束的自组装行为以及对阿霉素的包裹和释放情况.结果表明MCL单体的引入降低了聚合物的结晶性,提高了对DOX的载药量,加快了DOX的释放.通过激光共聚焦显微镜和流式细胞仪研究了Hep G2肝癌细胞对不同内核结构载药胶束的内吞情况,并用MTT法考察了胶束对细胞的毒害作用,细胞实验发现,Hep G2细胞对载DOX胶束的内吞以及载DOX胶束对细胞的杀伤能力和胶束内核的结构相关.     

Polymeric Micelles for Multidrug Delivery and Combination Therapy

The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called “combination therapy”, based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re‐enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug‐loaded micelles as carriers in drug‐releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given.     

淀粉基聚合物胶束用作药物载体

两亲性聚合物能通过亲疏水作用自组装为核-壳结构,而这独特的优势已使其成为在肿瘤靶向药物缓释方面具有很好发展前景的药物载体.淀粉原材料来源丰富,价格低廉,同时具有良好的生物相容性和生物可降解性,故基于淀粉的两亲性聚合物胶束正引起越来越多研究者极大的关注.作为药物载体,淀粉基聚合物胶束不仅可以提高药物的水溶性、延长药物在体内的循环时间、降低副作用和通过增强渗透与滞留(EPR)效应提高药物在靶向部位的优先累积,还可以在淀粉骨架上引入一些刺激响应型的官能团实现胶束快速靶向释药的功能.因此,淀粉基聚合物胶束在用作药物载体方面有着广阔的发展潜力.本文结合本课题组目前的研究工作和近几年的相关报道对淀粉基聚合物胶束作为药物载体的最新研究进展做简要综述.     

Targeted Antithrombotic Protein Micelles

Activated platelets provide a promising target for imaging inflammatory and thrombotic events along with site‐specific delivery of a variety of therapeutic agents. Multifunctional protein micelles bearing targeting and therapeutic proteins were now obtained by one‐pot transpeptidation using an evolved sortase A. Conjugation to the corona of a single‐chain antibody (scFv), which binds to the ligand‐induced binding site (LIBS) of activated GPIIb/IIIa receptors, enabled the efficient detection of thrombi. The inhibition of thrombus formation was subsequently accomplished by incorporating the catalytically active domain of thrombomodulin (TM) onto the micelle corona for the local generation of activated protein C, which inhibits the formation of thrombin. An effective strategy has been developed for the preparation of protein micelles that can be targeted to sites of activated platelets with broad potential for treatment of acute thrombotic events.     

Preparation and drug controlled-release of polyion complex micelles as drug delivery systems

Block copolymers, poly(N-vinylprrolidone)-block-poly(styrene-alter-maleic anhydride) (PVP-b-PSMA) and poly(N-vinylprrolidone)-block-poly(N,N-dimethylaminoethyl methacrylate) (PVP-b-PDMAEMA), were synthesized by reversible addition- fragmentation chain transfer (RAFT) polymerization. In aqueous media, this a pair of oppositely-charged diblock copolymers could self-assemble into stable and narrow distribution polyion complex micelles (PICMs). Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that the micelles to be spherically shaped with mean hydrodynamic diameter around 70 nm. In addition, the PICMs display ability to response to external stimuli. All of theses features are quite feasible for utilizing it as a novel intelligent drug delivery system. In order to assess its application in biomedical area, release profiles of coenzyme A (Co A) from PICMs were studied under both simulated gastric and intestinal pH conditions. The release was much quicker in pH 7.4 buffer than in pH 2.0 solution. Based on these results, these PICMs could be a potential pH-sensitive carrier for colon-specific drug delivery system.     

含胆汁酸和胆固醇的双亲性聚合物的研究进展

胆固醇和胆汁酸是广泛存在于自然界中的天然物质 ,生物相容性好 ,被广泛地用于高分子的疏水性改性 ,得到的双亲性聚合物 ,在水相中可以自组装或自聚集成纳米粒子。本文综述了含胆固醇或胆汁酸的双亲性聚合物的最新研究进展以及它们在药物载体系统中的应用。