刺激响应型微胶囊的可控释放研究进展

刺激响应型微胶囊由于具有独有的高稳定性、多功能性、膜结构的可调性、以及对不同芯材的运送能力,在药物封装和释放、人造细胞、催化、化学传感器等领域具有广阔的应用前景.本文综述了近年来不同刺激响应型复合微胶囊的可控释放的研究进展,包括温敏型、pH响应型、磁响应型、生物响应型、电响应型,以及光响应型微胶囊,根据释放机理的不同着重对光响应型微胶囊的释放过程进行了总结,并对微胶囊可控释放在未来的发展趋势进行了展望.     

新型结合阿霉素的聚乙二醇嵌段共聚树枝状聚赖氨酸的合成及其药物缓释行为的研究

采用液相多肽合成方法, 成功制备得到窄分子量分布、结构确定的聚乙二醇嵌段共聚四代树枝状聚赖氨酸 (MPEG-block-DPL4). 在此基础上, 进一步将其DPL4的端氨基转化为端肼基, 并通过其与抗肿瘤药物阿霉素(DOX) C＝O的反应形成C＝N键, 实现在DPL4表面的阿霉素药物分子化学结合, 最终得到新型pH敏感性的高分子药物MPEG-block-DPL4-CONHN＝DOX. 运用紫外分光光度(UV-Vis)法, 对MPEG-block-DPL4-CONHNH₂与阿霉素的负载效率进行了定量分析. 高分子药物MPEG-block-DPL4-CONHN＝DOX在生理条件(pH＝7.4)下相对稳定, 而弱酸性条件(pH＝4.5, 5.5)下, C＝N键能较快水解, 释放阿霉素药物分子. 体外细胞毒性评价结果表明(细胞株SMMC-7721和SPCA-1), 所得新型高分子药物MPEG-block-DPL4-CONHN＝DOX的细胞毒性显著地低于游离阿霉素药物分子, 因此, 可进一步研究发展成为新型pH敏感性可控缓释高分子抗肿瘤药物载体体系.     

Green Algae as a Drug Delivery System for the Controlled Release of Antibiotics

New strategies to efficiently treat bacterial infections are crucial to circumvent the increase of resistant strains and to mitigate side effects during treatment. Skin and soft tissue infections represent one of the areas suffering the most from these resistant strains. We developed a new drug delivery system composed of the green algae, Chlamydomonas reinhardtii, which is generally recognized as safe, to target specifically skin diseases. A two-step functionalization strategy was used to chemically modify the algae with the antibiotic vancomycin. Chlamydomonas reinhardtii was found to mask vancomycin and the insertion of a photocleavable linker was used for the release of the antibiotic. This living drug carrier was evaluated in presence of Bacillus subtilis and, only upon UVA1-mediated release, growth inhibition of bacteria was observed. These results represent one of the first examples of a living organism used as a drug delivery system for the release of an antibiotic by UVA1-irradiation.     

上转换纳米粒子结合DNA链式扩增技术在阿霉素光控释放中的应用

纳米技术的发展使得纳米材料可以通过不同的表面包覆和修饰而在生物医药中发挥应用。 构建简单、经济、药物释放可控的生物相容性纳米药物仍是纳米生物化学领域的重点。 我们构建的纳米载药体系(DDS)以NaYF₄：Yb/Tm上转换纳米粒子为载体,在其表面通过光致断键型小分子4,5-二甲氧基-2-硝基苯基乙酮(DMNPE)连接一段短单链DNA,利用DNA链式扩增技术(HCR)来调节纳米粒子最终修饰的双链DNA的总量,从而控制对抗癌药物阿霉素(Dox)的担载量,在980 nm激光照射下上转换纳米粒子发射可切断DMNPE连接的近紫外光,协同胞内DNA酶的作用达到对药物的可控释放。 由于近红外光照对生物组织具有较好的穿透能力,此体系能够对病灶位置有更好的光靶向性从而减少药物的毒副作用。     

Protein Capsules with Cross‐Linked,Semipermeable, and Enzyme‐Degradable Surface Barriers for Controlled Release

This paper describes a method for fabricating protein‐based capsules with semipermeable and enzyme‐degradable surface barriers. It involves the use of a simple fluidic device to generate water‐in‐oil emulsion droplets, followed by cross‐linking of proteins at the water–oil interface to generate a semipermeable surface barrier. The capsules can be readily fabricated with uniform and controllable sizes and, more importantly, show selective permeability toward molecules with different molecular weights: small molecules like fluorescein sodium salt can freely diffuse through the surface barrier while macromolecules such as proteins can not. The proteins, however, can be released by digesting the surface barrier with an enzyme such as pepsin. Taken together, the capsules hold great potential for applications in controlled release, in particular, for the delivery of protein drugs.

     

Ion Exchange Controlled Drug Release from Polymerized Ionic Liquids

In this work ion functionalized hydrogels as potent drug delivery systems are presented. The ion functionalization of the hydrogel enables the retention of ionic drug molecules and thus a reduction of burst release effects. Timolol maleate in combination with polymerized anionic 3‐sulfopropylmethacrylate potassium and ibuprofen combined with cationic poly‐[2‐(methacryloyloxy)ethyl] trimethylammonium chloride are investigated in respect to their drug release profile. The results are showing an ion exchange depending release behavior instead of a diffusion‐controlled drug release as it is known from common drug delivery systems. Furthermore, the suitability of such hydrogels for standard methods for sterilization is investigated.     

控制释放技术

综述药物控制释放的种类，机理，高分子材料在控制释放技术中的应用。     

Novel Carboxymethyl Chitosan Microspheres for Controlled Delivery of Chelerythrine

Novel carboxymethyl chitosan (O-CMCS) microspheres containing an anti-tumor drug chelerythrine (CHE) have been successfully prepared by an emulsion crosslinking method using glutaraldehyde. The optimized microsphere formulation was characterized for particle size, shape, morphology, crystallinity and in vitro drug release. Results for mean particle size, drug loading content, entrapment efficiency and in vitro drug release of chelerythrine loaded microspheres were found to be 12.18 μm, 4.08%, 54.78% and 35.30% at pH 7.4 in 20 h, respectively. The optimized microspheres had an imperfect crystalline lattice and a spherical, rough morphology and the CHE release from O-CMCS microspheres followed the Higuchi matrix model. All these results suggested that O-CMCS microspheres are a promising carrier system for controlled drug delivery.     

Mesoporous γ‐Iron Oxide Nanoparticles for Magnetically Triggered Release of Doxorubicin and Hyperthermia Treatment

Mesoporous iron‐oxide nanoparticles (mNPs) were prepared by using a modified nanocasting approach with mesoporous carbon as a hard template. mNPs were first loaded with doxorubicin (Dox), an anticancer drug, and then coated with the thermosensitive polymer Pluronic F108 to prevent the leakage of Dox molecules from the pores that would otherwise occur under physiological conditions. The Dox‐loaded, Pluronic F108‐coated system (Dox@F108‐mNPs) was stable at room temperature and physiological pH and released its Dox cargo slowly under acidic conditions or in a sudden burst with magnetic heating. No significant toxicity was observed in vitro when Dox@F108‐mNPs were incubated with noncancerous cells, a result consistent with the minimal internalization of the particles that occurs with normal cells. On the other hand, the drug‐loaded particles significantly reduced the viability of cervical cancer cells (HeLa, IC₅₀=0.70 μm ), wild‐type ovarian cancer cells (A2780, IC₅₀=0.50 μm ) and Dox‐resistant ovarian cancer cells (A2780/AD, IC₅₀=0.53 μm ). In addition, the treatment of HeLa cells with both Dox@F108‐mNPs and subsequent alternating magnetic‐field‐induced hyperthermia was significantly more effective at reducing cell viability than either Dox or Dox@F108‐mNP treatment alone. Thus, Dox@F108‐mNPs constitute a novel soft/hard hybrid nanocarrier system that is highly stable under physiological conditions, temperature‐responsive, and has chemo‐ and thermotherapeutic modes of action.     

Thermo-Responsive MOF/Polymer Composites for Temperature-Mediated Water Capture and Release

We report an in situ polymerization strategy to incorporate a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNIPAM), with controlled loadings into the cavity of a mesoporous metal–organic framework (MOF), MIL-101(Cr). The resulting MOF/polymer composites exhibit an unprecedented temperature-triggered water capture and release behavior originating from the thermo-responsive phase transition of the PNIPAM component. This result sheds light on the development of stimuli-responsive porous adsorbent materials for water capture and heat transfer applications under relatively mild operating conditions.     

Chitosan Nanoparticle-Based System: A New Insight into the Promising Controlled Release System for Lung Cancer Treatment

Lung cancer has been recognized as one of the most often diagnosed and perhaps most lethal cancer diseases worldwide. Conventional chemotherapy for lung cancer-related diseases has bumped into various limitations and challenges, including non-targeted drug delivery, short drug retention period, low therapeutic efficacy, and multidrug resistance (MDR). Chitosan (CS), a natural polymer derived from deacetylation of chitin, and comprised of arbitrarily distributed β-(1-4)-linked d-glucosamine (deacetylated unit) and N-acetyl-d-glucosamine (acetylated unit) that exhibits magnificent characteristics, including being mucoadhesive, biodegradable, and biocompatible, has emerged as an essential element for the development of a nano-particulate delivery vehicle. Additionally, the flexibility of CS structure due to the free protonable amino groups in the CS backbone has made it easy for the modification and functionalization of CS to be developed into a nanoparticle system with high adaptability in lung cancer treatment. In this review, the current state of chitosan nanoparticle (CNP) systems, including the advantages, challenges, and opportunities, will be discussed, followed by drug release mechanisms and mathematical kinetic models. Subsequently, various modification routes of CNP for improved and enhanced therapeutic efficacy, as well as other restrictions of conventional drug administration for lung cancer treatment, are covered.     

智能响应型水凝胶药物控释体系及其应用

药物控释体系可改善药物分子在机体内的释放、吸收、代谢和排泄过程,显著提高药物利用率并减弱药物的毒副作用。智能响应型水凝胶凭借其刺激响应性、亲水性和无毒性在药物控释方面得到了广泛的关注。本文介绍了智能响应型水凝胶药物控释体系的概念、机理和应用,详细归纳了智能响应型水凝胶药物控释体系的研究进展。按照刺激源不同将智能响应型水凝胶药物控释体系分为pH响应型、温度响应型、光响应型、生物分子(如葡萄糖、酶)响应型、外场(如电场、磁场)响应型、压力响应型、氧化还原响应型及多重响应型水凝胶药物控释体系。进一步介绍了智能响应型水凝胶药物控释体系在治疗癌症、急性肾损伤、眼病、糖尿病等疾病及抗菌、防止伤口感染等方面的应用。最后,基于目前智能响应型水凝胶药物控释体系存在的一些问题(如生物相容性差、存在突释或滞释现象、不可降解等)对其发展做出了展望。     

Smart Approach for In Situ One‐Step Encapsulation and Controlled Delivery of a Chemotherapeutic Drug using Metal–Organic Framework–Drug Composites in Aqueous Media

Controlled release of an anticancer drug, doxorubicin (dox), from metal–organic framework (MOF)–drug composites is demonstrated under different external stimuli. 1,3,5‐Benzenetricarboxylic acid (H₃BTC) is used as an organic ligand, and iron acetate and zinc nitrate are used as metal sources to synthesize Fe–BTC and Zn–BTC MOFs, which are known to be biocompatible. The in situ formation of MOF–drug composites demonstrates high drug loading capacity compared to conventional methods. The present methodology is devoid of any extra steps for loading the drug after synthesis. Moreover, the drug loading is also independent of pore size of the MOF as the drug molecules are embedded inside the MOF during their in situ formation. The drug release was monitored under external stimuli including change to acidic pH and the presence of biocompatible liposomes for a period of more than 72 h. Steady‐state fluorescence spectroscopy is used to monitor the drug release as a function of time and confocal laser scanning microscopy is used to unravel the post‐release fate of doxorubicin in the presence of liposomes. It is found that drug release rate is higher for the Zn–BTC–dox composite than for the Fe–BTC–dox composite. This is attributed to the stronger binding between dox and Fe‐BTC than that between dox and Zn–BTC. This study highlights a novel approach for the preparation of MOF–drug composites in an aqueous medium for future biomedical applications.     

聚合物/SiO2杂化材料在药物控制释放中的应用*

聚合物用作药物控制释放载体时,具有释药浓度可控、药物的生物利用率高、可实现靶向治疗等优点。但有些聚合物也存在机械强度低、化学稳定性差、生物相容性不理想等缺点。二氧化硅(SiO₂)具有多孔、无毒、生物相容性好、化学和机械稳定性高、表面易功能化等优点。但SiO₂用作药物控制释放载体时,有时也存在载药量低、不能装载大分子药物、不能实现靶向释放等缺点。聚合物/SiO₂杂化材料作为药物控制释放载体,可有效结合二者的优点,并克服二者的缺陷。根据聚合物的种类和杂化体系性质的不同,我们分别对温敏性聚合物/SiO₂杂化材料、聚电解质/SiO₂杂化材料、生物高分子/SiO₂杂化材料以及其它一些聚合物/SiO₂杂化材料体系在药物控制释放中的应用进行了介绍,并展望了该领域今后的研究发展方向。     

基于透明质酸的缺氧响应型胶束的制备及性能研究

以透明质酸（HA）及硝基咪唑（NI）衍生物为原料,通过酰胺反应合成了一种两亲性接枝聚合物（HA-NI）.该聚合物具有缺氧响应性和肿瘤靶向性.利用傅里叶红外光谱（FT-IR）和核磁共振（NMR）对接枝聚合物的结构进行了表征,同时基于¹H NMR计算出接枝聚合物中NI的取代度.HA-NI在水中自组装形成胶束,利用动态光散射仪（DLS）表征胶束大小并对胶束的稳定性进行了研究,利用原子力显微镜（AFM）和透射电镜（TEM）观察胶束形貌.载药胶束的载药率（DL）和包封率（EE）通过紫外-可见吸收光谱（UV）测试并计算得到.胶束的缺氧响应性利用DLS、AFM、TEM、UV等探究.实验证明,该聚合物胶束具有缺氧响应性并对药物表现出良好的控制释放能力,在常氧环境下,胶束稳定存在;而在缺氧环境下,胶束散开,药物快速且完全地释放.     

The Cyclodextrins as Modelling Agents of Drug Controlled Release

The controlled release of nicardipine (NC) was achieved by hybridizing its hydrophilic and hydrophobic cyclodextrin (CDs) complexes, i.e., those with hydroxypropyl--cyclodextrin (HPCD) andtriacetyl--cyclodextrin (TACD),respectively. ¹H-nuclearmagnetic resonance (¹H-NMR) was performed to examine the interaction between both CDs and NC in solution. The solid complexes of NC : HPCD and NC : TACD were prepared, in a 1 : 1 molar ratio by the spray-drying method. Complexation in the solid state was demonstrated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In vitro dissolution studies were carried out in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, according to the USP basket method. The ¹H-NMR studies provided clear evidence of an interaction between the CDs and the aromatic rings of NC. The DSC thermograms of the solid complexes showed no endothermic peak due to NC melting and their diffraction pattern was completely diffuse, which suggested the formation of a novel type solid phase with an amorphous character. The low dissolution rate of NC, a weak basic drug, in alkaline medium was significantly improved by complexation with HPCD. In contrast, the in vitro release of this drug from the NC : TACD complexes was markedly retarded in both dissolution media. An optimal formulation was then designed by the combination, in different molar ratios, of these two complexes. The release behavior of these preparations was investigated and it was observed that the retarding effect was dependent on the amount of the NC : TACD complex. In addition, the initial release rate became faster as the molar ratio of the NC : HPCD complex increased.     

Zeolitic Imidazolate Framework-8 as pH-Sensitive Nanocarrier for “Arsenic Trioxide” Drug Delivery

Previous results revealed that arsenic trioxide might be used as promising therapeutic agent for the treatment of some solid tumours as atypical teratoid rhabdoid tumours (ATRT). However, in order to become an approved drug for solid tumour treatment, the active formulation has to get more efficient and feasible—but at the same time less toxic. One of the possibilities to achieve this dichotomy is to use nanomedicine tools. Herein, we report on the Zn-based metal–organic framework ZIF-8 (Zeolitic Imidazolate Framework-8) which turned out to be a promising candidate for the delivery of As^III species. It conjointly features a high drug loading capacity and a prominent pH-triggered release behaviour. As^III-loaded ZIF-8 nanoparticles coated and non-coated with polyethylene glycol were studied by XRPD, IR, Raman, TGA, TEM, EDX, CHN-elemental analysis, sorption analysis and ICP-OES, and their cytotoxicity was evaluated in vitro.