非甾体类药物含糖乙烯醇酯共聚物制备及药物释放研究

分别利用化学法和酶促法合成了三种药物(萘普生、酮洛芬、布洛芬)乙烯酯和葡萄糖丁二酸乙烯酯(6-O-乙烯丁二酰-D-葡萄糖)两种聚合单体, 通过两种单体的自由基聚合反应制备了具有较高分子量的含糖聚合物前药. 通过IR、NMR对聚合物的结构进行了表征, 用GPC测定共聚物分子量. 含糖聚合物前药的体外释放研究表明, 将小分子原药制备成含糖聚合物前药后, 药物的释放时间大大延长, 达到了缓释的目的. 三种含糖聚合物的药物释放研究表明, 酮洛芬含糖高分子前药的药物释放速率较快, 萘普生含糖高分子前药的药物释放速率较慢. 不同的pH条件下的含糖聚合物的药物释放研究表明, 碱性环境下的药物释放较快, 酸性环境下的药物释放较慢.     

对二氧环己酮—乙交酯共聚物的合成及性能研究

本文研究了对二氧环己酮与乙交酯无规共聚物的化学结构，热性能。体外降解性能及共聚反应动力学。研究结果表明，随着单体配比中乙交酯含量的增加，共聚物中乙交酯含量增加，共聚物结晶能力下降，玻璃化转变温度升高，降解速率加快。随着聚合反应时间的延长，单体转化率及聚合物分子量不断增加。聚合时间超过96小时后，转化率及分子量变化趋于平缓。     

本体共聚合制备丙烯/1-丁烯合金及表征

以球形高效负载的TiCl₄/MgCl₂/邻苯二甲酸二异丁酯(DIBP)为催化剂, 采用本体聚合方法进行丙烯与1-丁烯共聚合研究. 考察了共单体效应对共聚活性及聚合物立构规整性的影响; 表征了共聚物的结构. 结果表明, 随着1-丁烯/丙烯投料比的增加, 聚合活性呈先升高后降低的趋势, 在1-丁烯/丙烯摩尔投料比为0.26条件下聚合活性达到最高, 并随着共聚物中1-丁烯含量的增加, 共聚物的熔点明显下降, 分子量降低, 分子量分布变窄, 同时共聚物力学性能有明显提高, 透明度逐渐增加.     

两亲性杂臂星型嵌段共聚物胶束的制备、表征及载药性能研究

以溴代异丁酰溴与3,5-二羟基苯甲酸制备3,5-二(2-溴-2丙酰氧基)苯甲酸,再与聚乙二醇单甲醚酯化,合成含溴大分子引发剂PEG-Br2。以苯乙烯为单体,利用原子转移自由基聚合方法(ATRP)合成了两种不同亲疏水段比例的两亲性星型杂臂嵌段共聚物PEG-b-(PS)2。本实验利用FTIR、1H-NMR、GPC等技术对聚合物的分子结构及分子量进行表征,利用透析法制备聚合物胶束;采用AFM对聚合物胶束的纳米结构进行观察;采用荧光探针法测得其临界胶束浓度(CMC)分别为0.99 mg·L-1和0.59 mg·L-1;利用DLS测得聚合物胶束粒径为150 nm左右;以疏水型抗肿瘤药物氨甲喋呤(MTX)为模型药物,对载药胶束的体外释药行为进行了研究,测得聚合物胶束的载药量分别为为13.32%和10.00%,包封率分别为61.75%和46.82%。结果表明,随着疏水段的增大,星型杂臂嵌段共聚物胶束药物包载量及CMC随之降低,且在人体pH条件下药物释放较低;同时发现两种载药胶束在肿瘤细胞酸性条件下释药速率增加。综上,此类结构的聚合物胶束作为抗肿瘤药物MTX的载体分子具有很好的应用前景。     

丙交酯-乙交酯共聚物的亲水性能研究

以丙交酯和乙交酯为原料,PEG-800为引发剂,采用开环聚合方法合成了具有不同单体比例的共聚物。通过IR、1 H-NMR表征了聚合物的结构,应用GPC技术分析了不同单体组成对共聚物分子量及其分布的影响;通过接触角测定的方法考察了不同单体比例组成对其共聚物的亲水性能影响;通过吸水实验,表明随着乙交酯含量的增强,共聚物的吸水性增强。只要引发剂的含量一定,单体丙交酯、乙交酯摩尔比为3∶1的聚合物膜的吸水性能较好。     

聚(碳酸酯-co-磷酸酯)的酶促合成及性能

以猪胰脂肪酶或假丝酵母皱褶酶为催化剂, 100℃下通过本体聚合成功地合成了三亚甲基碳酸酯(TMC)和2-乙氧基-2-氧-1,3-二氧磷杂环戊烷(EEP)的无规共聚物(poly(TMC-co-EEP)). 研究了酶浓度, 聚合反应时间以及共聚单体投料比等因素对共聚物分子量和产率的影响. 随着酶(PPL或CL)浓度的增加, 共聚物分子量降低. 同时, 随着EEP投料比的增加, 共聚物的分子量也降低. 共聚物数均分子量最大可达到10200. 随着共聚单体投料摩尔比(EEP/TMC)从0增加到5︰10, 共聚物的玻璃化温度从-28℃降低到-41.7℃. 体外降解实验表明: 共聚物中磷酸酯含量越高, 降解速率越快.     

聚苯乙烯大单体与乙酸乙烯酯的共聚及其接枝共聚物的表征

研究了聚苯乙烯大单体与乙酸乙烯酯的溶液聚合,结果表明,接枝效率随引发剂用量、聚合温度及小单体与大单体的投料比的增加而增加,随大单体的分子量增加而减少,而随单体浓度的变化呈现一最大值。共聚过程中大单体的转化率开始较小单体的增加快,后期变慢。用萃取法纯化的接枝共聚物经GPC、IR、~1H-NMR及PGC等表征,并算得平均接枝数为4—7。透射电镜表明接枝共聚物中存在微观相分离。     

聚苯乙烯大单体与乙酸乙烯酯的共聚及其接枝共聚物的表征

 研究了聚苯乙烯大单体与乙酸乙烯酯的溶液聚合,结果表明,接枝效率随引发剂用量、聚合温度及小单体与大单体的投料比的增加而增加,随大单体的分子量增加而减少,而随单体浓度的变化呈现一最大值。共聚过程中大单体的转化率开始较小单体的增加快,后期变慢。用萃取法纯化的接枝共聚物经GPC、IR、¹H-NMR及PGC等表征,并算得平均接枝数为4—7。透射电镜表明接枝共聚物中存在微观相分离。     

基于Maple软件辅助绘制自由基二元共聚曲线的研究

运用数据处理软件(maple)对经典的自由基二元聚合公式进行图形绘制,得到了二元单体之间共聚关系的三组图。一是二元单体的自由基共聚曲线图F1-f1,二是聚合物中单体平均组成(Fp)与投料单体浓度(f1)的关系曲线图,三是聚合物转化率(C)与投料单体(f1)的关系曲线图。通过二组具有代表性的共聚实例,分别是有恒比点的非理想共聚(苯乙烯-丙烯腈共聚物)和非理想非恒比共聚(苯乙烯-乙酸乙烯酯共聚物)展现了绘图步骤和分析了不同竞聚率情况下的聚合物转化过程。     

含有三氟乙烯基芳基醚侧基的聚丙烯酸酯的合成与表征

研究了聚丙烯酸酯侧基上引入三氟乙烯基芳基醚结构单元的方法. 首先, 合成了含有三氟乙烯基芳基醚侧基的丙烯酸酯单体, 然后通过原子转移自由基聚合实现了该单体的均聚和无规共聚, 得到了含有三氟乙烯基芳基醚侧基的聚丙烯酸酯聚合物, 聚合物的分子量分布较窄. 通过控制共聚投料比, 可以得到具有不同含量三氟乙烯基芳基醚侧基的无规共聚物.     

Mechanochemical solid-state polymerization (XI): effect of water-insoluble pharmaceutical aids on drug release from mechanically synthesized polymeric prodrugs

We discuss here the effect of water-insoluble pharmaceutical aids on the nature of drug release from composite polymeric prodrugs synthesized by mechanochemical solid-state polymerization. Magnesium stearate (Mgst) and hydrogen castor oil (HCO) were used as water-insoluble pharmaceutical aids. Composite polymeric prodrugs were synthesized by the mechanochemical solid-state polymerization of a vinyl monomer of 5-fluorouracil (I) in the presence of Mgst or HCO. The molecular weight of the resulting polymeric prodrugs increased with increasing the content of Mgst or HCO. Prodrug hydrolysis was carried out in a heterogeneous system in phosphate buffer at pH 6.8 and 37 degrees C. The rate of drug release from the composite polymeric prodrug containing Mgst (Poly-Mgst) was faster than that from polymeric prodrug containing no pharmaceutical aids (Poly-Non), while hydrolysis of the composite polymeric prodrug containing HCO (Poly-HCO) was slower than Poly-Non. Scanning electron microscope (SEM) photos showed the surface of Poly-HCO was smoother than that of Poly-Non and Poly-Mgst. It was suggested that the slower drug release from Poly-HCO may be responsible for the smaller specific surface area than that of Poly-Non. It was also shown that the rate of drug release from the composite polymeric prodrugs decreases with increasing the content of Mgst or HCO. Hence, novel composite polymeric prodrugs with a variety of drug release rates can be prepared by mechanochemical solid-state polymerization in a totally dry process.     

Synthesis of water-soluble polymeric prodrugs possessing 4-methylcatechol derivatives by mechanochemical solid-state copolymerization and nature of drug release

In this study we synthesized the water-soluble polymeric prodrugs possessing a 4-methylcatechol (4MC) derivative as a side chain by mechanochemical solid-state copolymerization. 1-benzoyl-4-methylcatechol (Bz4MC) was selected as a model compound of 4MC, and its methacryloyl derivative (1) was synthesized. 6-O-methacryloyl-D-galactose (2) was also prepared as a water-soluble monomer. The mechanochemical solid-state copolymerization of 1 and 2 was carried out to obtain the water-soluble polymeric prodrug possessing the Bz4MC as a side chain. The mechanochemical copolymerization of 1 and 2 proceeded to completion, and the polymeric prodrug produced possessed a narrow molecular weight distribution. Three kinds of polymeric prodrugs, whose compositions were different from one another, were hydrolyzed in vitro. The hydrolysis of these polymeric prodrugs proceeded to completion. The rate constants of hydrolysis decreased with increasing the mole fraction of 1 in polymeric prodrug. It was suggested that the rate constant of hydrolysis could be controlled by the composition, the mole fraction of 1 in the polymeric prodrug.     

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

The acid-cleavable amphiphilic prodrug DOX-PEG-DOX self-assemble to form nanoparticles and enter the cell by endocytosis for the pH-triggered intracellular delivery of DOX.     

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

PEGylated prodrug, covalent attaching polyethylene glycol (PEG) polymer chains to therapeutic drugs, is one of the most promising techniques to improve the water-solubility, stability, and therapeutic effect of drugs. In this study, three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights, were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin (DOX). This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution. The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. It turned out that the nanoparticles could be kept stable in the physiological environment, but degraded in acidic medium. Subsequently, we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property. The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells, which have the potential for use in cancer therapy.     

Mechanochemical solid-state polymerization (X): the influence of copolymer structure in copolymeric prodrugs on the nature of drug release

From the standpoint of the mechanism of mechanochemical polymerization, two kinds of copolymeric prodrug, whose monomer sequence distribution (MSD) is different from each other, can be prepared by this polymerization under appropriate operational conditions: one is a random copolymer abundant in the longer block consisting of the same repeating units (multi-block copolymer), and the other is a block copolymer. To confirm the difference of MSD, the 13C-NMR spectra of poly(acrylamide-co-sodium acrylate) prepared by mechanochemical polymerization were measured and compared with the spectrum of that synthesized by a conventional radical-initiated solution polymerization, which produces the random copolymer normally. The results show that MSD in copolymers depends on the polymerization method (operational condition). We prepared three kinds of copolymeric prodrug consisting of acrylamide and vinyl monomer of 5-fluorouracil, whose MSD is different from one another. These copolymeric prodrugs had almost the same number average molecular weight, particle diameter and composition, and differed only in MSD. We compared the rate of drug release of these copolymeric prodrugs. The rate of drug release was the highest with the random copolymer, followed by the mechanochemically produced multi-block copolymer and the block copolymer. This result suggests that the rate of drug release depends on MSD of copolymeric prodrugs. These results are useful as they give a fundamental insight into the synthesis of copolymeric prodrugs having the desired rate of drug release.     

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation

N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.     

Long conjugated 2-nitrobenzyl derivative caged anticancer prodrugs with visible light regulated release: preparation and functionalizations

A series of anticancer prodrugs with different chemical functional groups were prepared, in which the styryl conjugated 2-nitrobenzyl derivatives were introduced as the phototrigger to regulate the drug (chlorambucil) release. Compared to the common 4,5-dimethoxy-2-nitrobenzyl caged compounds, most of the prodrugs exhibited large and redshifted one-photon absorption within the visible range. One-photon excitation for the drug release was studied by measuring UV-vis absorption, FT-IR, and HPLC spectra, which suggested that chlorambucil was released effectively and precisely by manipulating external light conditions. And the introduction of different functional groups made this type of prodrug a good platform to further react with some typical drug carriers and to further form excellent visible light responsive drug delivery systems. Moreover, the drug also could be effectively released under the excitation of two-photon at 800 nm with comparable photorelease efficiencies.     

Targeting Cancer with PCPA‐Drug Conjugates: LSD1 Inhibition‐Triggered Release of 4‐Hydroxytamoxifen

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer‐targeting methods. Herein, we focused on lysine‐specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans‐2‐phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA‐drug conjugate (PDC) prototypes, we designed PCPA‐tamoxifen conjugates 1 a and 1 b , which released 4‐hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.     

Polymeric prodrugs of mitomycin C

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the cytotoxic agent Mitomycin C were synthesized using peptidyl spacers to link the drug to the polymeric carrier. The influence on the length and detailed structure of the oligopeptide on the rate of drug release was investigated in buffer, in the presence of lysosomal enzymes (tritosomes, cathepsin B and D) and metalloprotease type IV collagenase. It was observed that tetra- and hexapeptide based conjugates generally release Mitomycin C (MMC) more effectively than tripeptide derivatives. The gly-phe-ala-leu conjugate released MMC very rapidly both in presence of lysosomal enzymes and collagenase IV. Only in the presence of the aspartic protease cathepsin D, the gly-phe-leu-gly-phe-leu derivative turned out to be a better substrate. In vivo studies against C26 solid tumour bearing mice suggest that PHEG-spacer-MMC conjugates act as prodrugs of MMC: antitumour efficacy of the macromolecular prodrugs was better than free MMC both in inhibition of tumour growth and increasing survival.