多功能聚乳酸微囊的制备与性能研究
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摘要
近年来,高分子微囊因其在药物传输、人工红细胞、超声造影等生物医学领域广泛的应用前景而倍受关注。包埋无机纳米颗粒后的高分子微囊,除了具有微型载体功能,还能兼备无机纳米颗粒的声、磁、光、热等优异性能。本文将超顺磁性的Fe_3O_4纳米颗粒分别复合在聚乳酸微囊的壳层和空腔中,不仅能使微囊具备磁共振造影的潜力,还能提高微囊的超声响应性,获得一种兼备磁共振造影和超声造影的多功能载体。
首先,本文通过调节双乳化法的工艺参数,研究微囊粒径和内部结构的变化规律。鉴于空心结构对实现载体功能的重要性,我们提出了“空心率”和“空心程度”两个概念来半定量地表征微囊的空心结构。研究表明,第一次乳化水油比是影响微囊空心率的关键因素,太高或太低都不利于获得空心微囊;此外,合适的外水相乳化剂浓度是高空心率的保证;微囊的粒径与内水相液滴的尺寸关系密切,较低的第二次乳化能量能获得多腔结构的大粒径微囊。在深入理解微囊结构特征和粒径的影响机理后,我们成功地制得了平均粒径分别为12μm、10μm、8μm、6μm、5μm和4μm的高空心率单腔聚乳酸微囊。
在上述工作的基础上,将热分解制得的油溶性Fe_3O_4纳米颗粒与聚乳酸大分子复合,通过双重乳液-溶剂蒸发法制得Fe_3O_4纳米颗粒复合在壳层中的磁壳聚乳酸微囊,磁含量为13 wt.%时对应的饱和磁化强度为4.6 emu/g。通过对壳结构的控制,首次发现了复合微囊壳结构的变化规律:随着第二次乳化转速的提高或时间的延长,微囊从蜂窝结构依次转变为多腔、同心、偏心、碗形和弹坑形,最后变成实心结构,并伴随着平均粒径的逐渐减小。
本文还发明了一种新型的界面共沉淀联合双乳化法,实现了将Fe_3O_4纳米颗粒复合在聚乳酸微囊的空腔中。该法将铁盐水溶液作为内水相,二正丙胺溶于聚乳酸的二氯甲烷溶液作为油相,使生成水溶性Fe_3O_4纳米颗粒的界面共沉淀反应在双重乳液的油包水界面进行。Fe_3O_4纳米颗粒在油包水界面生成后,因其亲水性而转入内水相,内水相作为微囊空腔的前体,在冷冻干燥升华内水相后,Fe_3O_4纳米颗粒留在微囊的空腔中,从而成功地获得磁腔聚乳酸微囊。该法实现了磁性纳米颗粒的合成与磁性高分子微囊的制备同步进行,大大简化了复合微囊的制备流程。研究发现铁盐投料量和超声振荡时间是影响复合微囊磁含量和磁性能的关键因素,提高铁盐投料量和延长超声振荡时间能获得磁含量达38 wt.%、相应饱和磁化强度达22 emu/g磁腔聚乳酸微囊。通过对合成机理的探讨,认为是超声振荡促进了界面共沉淀反应的进行,使生成的Fe_3O_4纳米颗粒的饱和磁化强度达78 emu/g,最终提高了复合微囊的磁性能。
最后,我们通过覆盖医学超声频率(0-10 MHz)的声衰减谱研究不同粒径、不同壳结构、不同复合结构及其磁含量的聚乳酸微囊的声学行为。发现:随着平均粒径的增大,微囊共振频率有所升高,而整个频率范围的声衰减变化不明显;同心微囊的共振频率和整个频率范围的声衰减均高于弹坑和多腔微囊,多腔微囊因其壳结构多孔疏松,共振频率最低;随着壳中磁含量从0 wt.%增大到13 wt.%,磁壳聚乳酸微囊的共振频率和声衰减逐渐升高,而当腔中磁含量从12 wt.%增大到38 wt.%时,微囊的共振频率几乎未变,整个频率范围的声衰减却有所下降;壳中磁含量和腔中磁含量的变化所带来的不同影响,反映出复合结构对微囊声学性能的影响。体外超声造影检查表明,磁含量13 wt.%的磁壳聚乳酸微囊的视频强度明显高于聚乳酸微囊,与它们声衰减的测量结果吻合。
Polymeric microcapsules have attracted increasing attention in recent years due to their wide application prospects in biomedical fields, such as drug delivery systems, blood substitutes, ultrasound contrast agents and so forth. On this basis, incorporation of different inorganic nanoparticles into polymeric microcapsules can provide the desired acoustic, magnetic, optical, thermal or other property to the microcapsules. Polymeric microcapsules incorporating superparamagnetic Fe_3O_4 nanoparticles in its shell or cavity can serve as a dual functional contrast agents both for magnetic resonance imaging (MRI) and ultrasound imaging. In this dissertation, poly(lactic acid) (PLA) was chosen to be the shell material for FDA’s approval of clinical use, and appropriate method was adopted to fabricate PLA microcapsules with controllable size, shell structures, composite structures and magnetite loading. Sound attenuation spectra covering the medical ultrasound frequency were used to investigate the sound attenuation and resonance frequency of the microcapsules.
Firstly, poly(lactic acid) microcapsules with controllable average size were fabricated by the improved double emulsion– solvent evaporation technique. Considering the importance of hollow structure to the function of microcarrier, we introduced the concept of“hollow ratio”and“hollow degree”to semi-quantitatively evaluate the hollow structure of the microcapsules. It was demonstrated that the W1/O volume ratio in the first emulsification process was of vital significance to the hollow ratio, and a too high or too low W1/O volume ratio was not favorable to the output of hollow microcapsules. Moreover, a suitable concentration of emulsifier in the outer aqueous phase can guarantee a high hollow ratio. It was also found that the size of inner aqueous droplets has great effect on the size of the microcapsules, and lower energy input of the second emulsification process could obtain bigger microcapsules with multicavities. With a good comprehension of the mechanism on structure formation and size variation, we successfully fabricated poly(lactic acid) microcapsules with high hollow ratio, single cavity and adjustable average size of 12μm, 10μm, 8μm, 6μm, 5μm and 4μm. On the basis of the work mentioned above, oil-soluble Fe_3O_4 nanoparticles synthesized by thermal decomposition were compounded with poly(lactic acid) macromolecular by double emulsion– solvent evaporation method to obtain magnetic poly(lactic acid) microcapsules with Fe_3O_4 nanopartilces composited in the shell. When the magnetite loading was 13 wt.%, the corresponding saturation magnetization was 4.6 emu/g. Through carefully adjusting the parameters in the second emulsification, the regularity in the transformation of shell structures was firstly explored. With the increase of the energy or the time of the second emulsification, the composite microcapsules transformed from honeycomb gradually to multicavity, concentric, eccentric, bowl, crater and finally to solid structures, accompanied by the decrease of average size. The variation of shell structure caused the change of surface morphology. The concentric microcapsules had smooth and tight surface, which had no difference from that of solid microspheres. While eccentric and multicavity microcapsules had holes on the surface which led to the inner cavities.
In order to obtain the magnetic poly(lactic acid) microcapsules with Fe_3O_4 nanoparticles composited in the cavity, a novel interfacial coprecipitation joint double emulsification method was designed and verified. In this method, iron salts aqueous solution served as the inner aqueous phase, di-n-propylamine was dissolved in PLA/dichloromethane solution and served as the oil phase. The interfacial coprecipitation which generated water-soluble Fe_3O_4 nanoparticles performed at the water in oil (W1/O) interface of double emulsion. After Fe_3O_4 nanoparticles generated at the water in oil (W1/O) interface, they would transfer into the inner aqueous phase due to their hydrophilicity. The inner aqueous phase was the precursor of cavities, so the Fe_3O_4 nanoparticles remained in the cavities after the inner aqueous phase was sublimated by freeze drier, and poly(lactic acid) microcapsules with magnetic cavity were obtained finally. This approach realized the simultaneous synthesis of magnetic nanoparticles and polymeric microcapsules and greatly simplified the fabrication process of magnetic composite microcapsules. It was demonstrated that increasing the input of iron salts and prolonging the time of ultrasonic vibration could obtain magnetic poly(lactic acid) microcapsules with a magnetite loading of 38 wt.% and a relevant saturation magnetization of 22 emu/g. Through investigating the mechanism of synthesis, we considered that the ultrasonic vibration accelerated the performance of interfacial coprecipitation and caused the saturation magnetization of the generated Fe_3O_4 nanoparticles to achieve 78 emu/g, and finally enhanced the magnetic properties of composite microcapsules.
Sound attenuation spectra covering the medical ultrasound frequency (0-10 MHz) were used to investigate the influence of size, shell structure, composite structure and magnetite loading on the sound attenuation and resonance frequency of the poly(lactic acid) microcapsules. With the average size increased, the resonance frequency improved accordingly, but the sound attenuation did not change obviously. The resonance frequency and the sound attenuation in the entire spectrum of concentric microcapsules were higher than that of crater and multicavity. Microcapsules with multicavities had the lowest resonance frequency due to their porous and loose shell structures. With the magnetite loading in shell improved from 0 wt.% to 13 wt.%, the resonance frequency and sound attenuation improved gradually. When the magnetite loading in cavity increased from 12 wt.% to 38 wt.%, the resonance frequency had no variation, but the sound attenuation in the entire spectrum decreased. The different influence of magnetite loading in shell and magnetite loading in cavity reflected the influence of composite structures on the acoustical properties of microcapsules. In vitro ultrasonography demonstrated that poly(lactic acid) microcapsules with 13 wt.% magnetite loading in shell had higher video intensity than pure poly(lactic acid) microcapsules, which was consistent with the measured results of their sound attenuation.
首先,本文通过调节双乳化法的工艺参数,研究微囊粒径和内部结构的变化规律。鉴于空心结构对实现载体功能的重要性,我们提出了“空心率”和“空心程度”两个概念来半定量地表征微囊的空心结构。研究表明,第一次乳化水油比是影响微囊空心率的关键因素,太高或太低都不利于获得空心微囊;此外,合适的外水相乳化剂浓度是高空心率的保证;微囊的粒径与内水相液滴的尺寸关系密切,较低的第二次乳化能量能获得多腔结构的大粒径微囊。在深入理解微囊结构特征和粒径的影响机理后,我们成功地制得了平均粒径分别为12μm、10μm、8μm、6μm、5μm和4μm的高空心率单腔聚乳酸微囊。
在上述工作的基础上,将热分解制得的油溶性Fe_3O_4纳米颗粒与聚乳酸大分子复合,通过双重乳液-溶剂蒸发法制得Fe_3O_4纳米颗粒复合在壳层中的磁壳聚乳酸微囊,磁含量为13 wt.%时对应的饱和磁化强度为4.6 emu/g。通过对壳结构的控制,首次发现了复合微囊壳结构的变化规律:随着第二次乳化转速的提高或时间的延长,微囊从蜂窝结构依次转变为多腔、同心、偏心、碗形和弹坑形,最后变成实心结构,并伴随着平均粒径的逐渐减小。
本文还发明了一种新型的界面共沉淀联合双乳化法,实现了将Fe_3O_4纳米颗粒复合在聚乳酸微囊的空腔中。该法将铁盐水溶液作为内水相,二正丙胺溶于聚乳酸的二氯甲烷溶液作为油相,使生成水溶性Fe_3O_4纳米颗粒的界面共沉淀反应在双重乳液的油包水界面进行。Fe_3O_4纳米颗粒在油包水界面生成后,因其亲水性而转入内水相,内水相作为微囊空腔的前体,在冷冻干燥升华内水相后,Fe_3O_4纳米颗粒留在微囊的空腔中,从而成功地获得磁腔聚乳酸微囊。该法实现了磁性纳米颗粒的合成与磁性高分子微囊的制备同步进行,大大简化了复合微囊的制备流程。研究发现铁盐投料量和超声振荡时间是影响复合微囊磁含量和磁性能的关键因素,提高铁盐投料量和延长超声振荡时间能获得磁含量达38 wt.%、相应饱和磁化强度达22 emu/g磁腔聚乳酸微囊。通过对合成机理的探讨,认为是超声振荡促进了界面共沉淀反应的进行,使生成的Fe_3O_4纳米颗粒的饱和磁化强度达78 emu/g,最终提高了复合微囊的磁性能。
最后,我们通过覆盖医学超声频率(0-10 MHz)的声衰减谱研究不同粒径、不同壳结构、不同复合结构及其磁含量的聚乳酸微囊的声学行为。发现:随着平均粒径的增大,微囊共振频率有所升高,而整个频率范围的声衰减变化不明显;同心微囊的共振频率和整个频率范围的声衰减均高于弹坑和多腔微囊,多腔微囊因其壳结构多孔疏松,共振频率最低;随着壳中磁含量从0 wt.%增大到13 wt.%,磁壳聚乳酸微囊的共振频率和声衰减逐渐升高,而当腔中磁含量从12 wt.%增大到38 wt.%时,微囊的共振频率几乎未变,整个频率范围的声衰减却有所下降;壳中磁含量和腔中磁含量的变化所带来的不同影响,反映出复合结构对微囊声学性能的影响。体外超声造影检查表明,磁含量13 wt.%的磁壳聚乳酸微囊的视频强度明显高于聚乳酸微囊,与它们声衰减的测量结果吻合。
Polymeric microcapsules have attracted increasing attention in recent years due to their wide application prospects in biomedical fields, such as drug delivery systems, blood substitutes, ultrasound contrast agents and so forth. On this basis, incorporation of different inorganic nanoparticles into polymeric microcapsules can provide the desired acoustic, magnetic, optical, thermal or other property to the microcapsules. Polymeric microcapsules incorporating superparamagnetic Fe_3O_4 nanoparticles in its shell or cavity can serve as a dual functional contrast agents both for magnetic resonance imaging (MRI) and ultrasound imaging. In this dissertation, poly(lactic acid) (PLA) was chosen to be the shell material for FDA’s approval of clinical use, and appropriate method was adopted to fabricate PLA microcapsules with controllable size, shell structures, composite structures and magnetite loading. Sound attenuation spectra covering the medical ultrasound frequency were used to investigate the sound attenuation and resonance frequency of the microcapsules.
Firstly, poly(lactic acid) microcapsules with controllable average size were fabricated by the improved double emulsion– solvent evaporation technique. Considering the importance of hollow structure to the function of microcarrier, we introduced the concept of“hollow ratio”and“hollow degree”to semi-quantitatively evaluate the hollow structure of the microcapsules. It was demonstrated that the W1/O volume ratio in the first emulsification process was of vital significance to the hollow ratio, and a too high or too low W1/O volume ratio was not favorable to the output of hollow microcapsules. Moreover, a suitable concentration of emulsifier in the outer aqueous phase can guarantee a high hollow ratio. It was also found that the size of inner aqueous droplets has great effect on the size of the microcapsules, and lower energy input of the second emulsification process could obtain bigger microcapsules with multicavities. With a good comprehension of the mechanism on structure formation and size variation, we successfully fabricated poly(lactic acid) microcapsules with high hollow ratio, single cavity and adjustable average size of 12μm, 10μm, 8μm, 6μm, 5μm and 4μm. On the basis of the work mentioned above, oil-soluble Fe_3O_4 nanoparticles synthesized by thermal decomposition were compounded with poly(lactic acid) macromolecular by double emulsion– solvent evaporation method to obtain magnetic poly(lactic acid) microcapsules with Fe_3O_4 nanopartilces composited in the shell. When the magnetite loading was 13 wt.%, the corresponding saturation magnetization was 4.6 emu/g. Through carefully adjusting the parameters in the second emulsification, the regularity in the transformation of shell structures was firstly explored. With the increase of the energy or the time of the second emulsification, the composite microcapsules transformed from honeycomb gradually to multicavity, concentric, eccentric, bowl, crater and finally to solid structures, accompanied by the decrease of average size. The variation of shell structure caused the change of surface morphology. The concentric microcapsules had smooth and tight surface, which had no difference from that of solid microspheres. While eccentric and multicavity microcapsules had holes on the surface which led to the inner cavities.
In order to obtain the magnetic poly(lactic acid) microcapsules with Fe_3O_4 nanoparticles composited in the cavity, a novel interfacial coprecipitation joint double emulsification method was designed and verified. In this method, iron salts aqueous solution served as the inner aqueous phase, di-n-propylamine was dissolved in PLA/dichloromethane solution and served as the oil phase. The interfacial coprecipitation which generated water-soluble Fe_3O_4 nanoparticles performed at the water in oil (W1/O) interface of double emulsion. After Fe_3O_4 nanoparticles generated at the water in oil (W1/O) interface, they would transfer into the inner aqueous phase due to their hydrophilicity. The inner aqueous phase was the precursor of cavities, so the Fe_3O_4 nanoparticles remained in the cavities after the inner aqueous phase was sublimated by freeze drier, and poly(lactic acid) microcapsules with magnetic cavity were obtained finally. This approach realized the simultaneous synthesis of magnetic nanoparticles and polymeric microcapsules and greatly simplified the fabrication process of magnetic composite microcapsules. It was demonstrated that increasing the input of iron salts and prolonging the time of ultrasonic vibration could obtain magnetic poly(lactic acid) microcapsules with a magnetite loading of 38 wt.% and a relevant saturation magnetization of 22 emu/g. Through investigating the mechanism of synthesis, we considered that the ultrasonic vibration accelerated the performance of interfacial coprecipitation and caused the saturation magnetization of the generated Fe_3O_4 nanoparticles to achieve 78 emu/g, and finally enhanced the magnetic properties of composite microcapsules.
Sound attenuation spectra covering the medical ultrasound frequency (0-10 MHz) were used to investigate the influence of size, shell structure, composite structure and magnetite loading on the sound attenuation and resonance frequency of the poly(lactic acid) microcapsules. With the average size increased, the resonance frequency improved accordingly, but the sound attenuation did not change obviously. The resonance frequency and the sound attenuation in the entire spectrum of concentric microcapsules were higher than that of crater and multicavity. Microcapsules with multicavities had the lowest resonance frequency due to their porous and loose shell structures. With the magnetite loading in shell improved from 0 wt.% to 13 wt.%, the resonance frequency and sound attenuation improved gradually. When the magnetite loading in cavity increased from 12 wt.% to 38 wt.%, the resonance frequency had no variation, but the sound attenuation in the entire spectrum decreased. The different influence of magnetite loading in shell and magnetite loading in cavity reflected the influence of composite structures on the acoustical properties of microcapsules. In vitro ultrasonography demonstrated that poly(lactic acid) microcapsules with 13 wt.% magnetite loading in shell had higher video intensity than pure poly(lactic acid) microcapsules, which was consistent with the measured results of their sound attenuation.
引文
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