恩度PLGA缓释微球磷酸钙骨水泥复合物治疗骨肉瘤实验研究
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摘要
研究目的:重组人血管内皮抑素(rh-Endostatin)是一种特异的多靶点血管内皮细胞生长抑制因子,具有抑制人内皮细胞的迁移的作用,能特异性强效抑制肿瘤新生血管内皮细胞增殖,阻止肿瘤新生血管的形成,进而抑制肿瘤生长和转移,而对正常组织和结构无影响。恩度(Endostar)是一种新型重组人血管内皮抑素注射液,通过在Endostatin氨基末端增加9个氨基序列(MGGSHHHHH),从而简化了蛋白纯化程序、有效增加了蛋白质的稳定性,并可水溶性应用,更重要的是增强了抑制血管形成的作用。磷酸钙骨水泥(CPC)是目前唯一能自行固化并产生骨再生效果的骨骼修复材料,同时由于其固化条件温和,以及内部存在的孔隙结构,成为良好的药物载体。本研究构建恩度的聚乳酸-乙醇酸共聚物poly(lactic-co-glycolic acid) (PLGA)缓释微球,并与磷酸钙骨水泥(Calcium Phosphate Cement,CPC)相复合,研究复合后复合骨水泥的理化性质、药物体外缓释、缓释后的生物学活性和应用于荷骨肉瘤裸鼠体内对骨肉瘤生长抑制情况。
研究方法:利用乳化溶剂挥发法(w/o/o)制备出相应粒径的恩度PLGA缓释微球,观察其形态以及粒径分布,并研究了该方法制备缓释微球的制备工艺及其影响因素,优选载药量和包封率高的处方以制备微球;将恩度PLGA缓释微球分别以5%、8%、10%的质量百分比与磷酸钙骨水泥复合,检测复合物的凝结时间、抗压强度、孔隙率及微结构的改变等理化性质,研究不同质量配比的载药微球复合磷酸钙骨水泥后是否对骨水泥的结构产生重要影响;体外测定恩度PLGA缓释微球磷酸钙骨水泥复合物药物缓释情况,并以人脐静脉内皮细胞(Human Umbilical Vein Endothelial Cells HUVESc)增殖抑制试验(MTT)法检测缓释后的药物活性;将恩度PLGA缓释微球磷酸钙骨水泥复合物植入荷骨肉瘤裸鼠模型,并进行对照实验,明确恩度PLGA缓释微球磷酸钙骨水泥复合物对裸鼠骨肉瘤的治疗作用。
结果:1、选用PLGA微球作为药物载体材料,采用乳化溶剂挥发法制备恩度PLGA缓释微球,制备工艺简便易行,稳定性好,包封率和载药量较高。同时,该法制备的缓释微球的初始突释较小,前期释放较快,后期稳定,且缓慢溶蚀释放为其主释药过程,时间可达3周以上,能够满足骨肿瘤病灶清除后缺损修复中抗肿瘤药物局部持续释放要求。2、CPC作为一种理想的提供局部负荷力学重建与药物缓释的载体,其理化特性可能随着加入药物的量而改变。不同配比的恩度PLGA缓释微球对磷酸钙骨水泥的凝结时间、抗压强度及孔隙率均有影响,三者的关系是统一的。恩度PLGA缓释微球磷酸钙骨水泥复合物的固化时间及材料性能产生负面的影响;5%、8%恩度PLGA缓释微球磷酸钙骨水泥复合物的固化时间及材料性能无显著改变。3、以CPC为载体的药物缓释体系可以达到药物缓释过程可控、局部药物高效、稳定、长期释放的目的。恩度PLGA缓释微球磷酸钙骨水泥复合物是一种集骨修复和药物治疗于一体的较理想的新型功能人工骨,作为Endostar的控释载体,该体系能有效缓释具有生物活性的Endostar超过28天,且突释较小。恩度PLGA缓释微球磷酸钙骨水泥复合物的缓释液具有良好的生物活性,可有效抑制HUVECs的增殖,其抑制作用与其浓度呈正相关。4、恩度PLGA缓释微球磷酸钙骨水泥复合物在体内可抑制骨肉瘤移植瘤的生长、侵袭和转移,恩度可望作为骨肉瘤综合治疗的组成部分。
结论:采用可生物降解的聚合物PLGA作为载体材料,可将rh-endostatin制备成缓释微球。较低质量百分比(5%以下)PLGA包裹的rh-endostatin缓释微球复合磷酸钙骨水泥对CPC固化及材料性能未产生负面的影响,CPC的凝结时间无明显延长,抗压强度无明显改变。rh-endostatin缓释后各组CPC的抗压强度无明显降低,rh-endostatin从骨水泥中的缓释情况与其从缓释微球中缓释相近,稳定性、重现性良好。含有rh-endostatin的缓释液可有效抑制HUVECs的增殖,其抑制作用与其浓度呈正相关,浓度越高对细胞增殖的抑制越大,具有剂量依赖抑制关系。rh-endostatin/PLGA微球复合CPC骨水泥具有较好的抑制裸鼠骨肉瘤新生血管形成,诱导肿瘤凋亡的作用。以上结果提示恩度PLGA缓释微球磷酸钙骨水泥复合物能应用于骨肉瘤的局部治疗,本研究将对载药CPC的临床应用一定的具有指导作用。
本研究创新点:
首次合成抗新生血管形成药物(恩度,Endostar)PLGA缓释微球磷酸钙骨水泥复合物,既具有骨肉瘤术中的重建作用,同时也具有持久的局部缓释抗肿瘤作用。不仅能用于脊柱肿瘤术中重建,同时也能应用于四肢肿瘤,具有广泛的临床应用前景,为后期其他研究奠定了基础。
It was confirmed by many studies at home and abroad that the solid tumor could not develop if there were not new endothelial cells to supplement and the formation of neogenesis blood capillary was the cause of the amplification and metastasis of tumors. Rh-Endostatin was discovered by Folkman et al at 1997 and it is the fragment of non-collegenous dormain which is at the C-terminal of extracellular matrix(ECM) collagen protein XVIII. It exerts a negative effect on the angiogenesis of tumor. And it is a specific kind of angiogenic inhibitor. The experiment in vitro indicated that it can inhibit the proliferation and migration of vascular endothelial cells effectively and inhibit the angiogenesis of carcinoma. So the nutrition supply of tumor cells was obstructed and the proliferation and migration of tumor were inhibited. Therefore rh-Endostatin is featured in broad-spectrum, high-efficiency and no resistance to prevent neoplasm of tumor blood vessels. Calcium phosphates possess good biocompatibility and osteoconductivity as the filling materials for repairing bone defects. When solidified, CPC produces strong compressive strength without releasing much heat and has good plasticity, biocompatibility, osteoconductivity and degradability in vivo. Currently, CPC is the only material available capable of spontaneous solidification and inducing bone regeneration, and has been widely used in dental and orthopedic surgeries. The mild condition required for solidification and the porous structure of CPC suggest great potential of CPC as a drug carrier for sustained drug release in vivo to maintain sufficient local drug concentration and minimize potential systemic adverse effects of the drugs, especially the agents for tumor therapy.
Endostar is a neotype self-designed rh-Endostatin and it is produced by using escherichia coli as expression vectors. Endostar raise the stability of the protein efficiently and the antiangiogenenic effect, and make the purification of protein easy. As shown in these researchs, the inhibitory effect of Endostar to new vessels is greater two times than Endostatin at least. PhaseⅢclinical trials confirm that the efficacy of Endostar combined with NP regimen in treating advanced non-small-cell lung cancer(NSCLC) is raised significantly and the treatment prolong the live time and improve the quality of life. At present in home and abroad many researchers are attempting to use Endostar combined chemotherapy to treatment many kinds of advanced malignant tumour. Calcium phosphates possess good biocompatibility and osteoconductivity as the filling materials for repairing bone defects. When solidified, CPC produces strong compressive strength without releasing much heat and has good plasticity, biocompatibility, osteoconductivity and degradability in vivo. Currently, CPC is the only material available capable of spontaneous solidification and inducing bone regeneration, and has been widely used in dental and orthopedic surgeries. The mild condition required for solidification and the porous structure of CPC suggest great potential of CPC as a drug carrier for sustained drug release in vivo to maintain sufficient local drug concentration and minimize potential systemic adverse effects of the drugs, especially the agents for tumor therapy.
At present, the research of the pharmaceutical dosage form of Endostar is very seldom and there is no report about sustained-release dosage form of Endostar. Because Endostar is easy to be degradated and inactivated and has a very short half-life in vivo, it is required to inject many times and the promising prospects in utilization are restricted. In this study we design to prepare controlled release of Endostar encapsulated within poly(D,L-lactide-co-glycolide)(PLGA).The lasting time of the drug is 4 weeks and the quality of drug and the compliance of patients are raised. The delayed release microspheres are used to combinate with calcium phosphate cement (CPC), then the complex is used to fill the defect after the focal cleaning of bone tumor. Because the diameter of Osteoblast is about 100～150um, in this study the particle diameter of these microspheres are controlled about 100～150um. After delayed release the cellules are profit to osteoblast to enter and newly formed bone tissue to deposite.
This study is divided into 4 parts. The first part begun with the preparation of PLGA microspheres by W/O/O phase separation method and observed the appearance and the size and distribution of PLGA microspher. Single-factor experiment was designed to investigate the influential factors of the size and encapsulation efficiency of microspheres. The influential factors include stirring rate when preparing double emulsion, polyvinyl alcohol (PVA) volume, PLGA concentration, the volume of inner water phase. Adjusting all kinds of influential factors, the encapsulation efficiency of microspheres are usually high(more than 45%). In vitro test confirmed that PLGA microspheres for Endostar delivery systems prepared by the solvent evaporation with W/O/O phase separation method have better functions of sustained releasing Endostar, moreover, their stability and reproducibility are favorable, and encapsulation efficiency are high, which could provide the local sustained releasing Endostar.
The second part of this study researched on the properties of CPC combined with PLGA microspheres for Endostar. We studied the properties of CPC combined with different content of PLGA microspheres, including the setting time, compressive strength, microstructural development and the interval porosity. The result showed that high content of PLGA microspheres(10%) affected the properties of CPC that had the longer setting time and lower compressive strength. On the other hand, the properties of CPC combined with low content of PLGA microspheres(5% and 8%) were not influenced.
The third part of this study researched on the release characteristics in vitro of the PLGA microspheres for Endostar combined with CPC and the biological activities of Endostar delayed release from CPC. The experimental result showed that the delayed release of Endostar from CPC is like as the delayed release of Endostar from PLGA, their stability and reproducibility are favorable, and it could meet the need of the local controlled releasing.
The last part of this study is the in vivo research of the PLGA microspheres for Endostar combined with CPC on tumor. Implanted the PLGA microspheres for Endostar combined with CPC and MTX CPC into osteosarcoma model of the nude mouse. It has shown that the PLGA microspheres for Endostar combined with CPC has the stronger ability of inhibiting the growth and inducing the apoptosis of the of the tumor cell.
Conclusion:Endostar can be encapsulated in microspheres to yield continuous release when using biodegradable polymers PLGA as carrier material, and this technique will have a favorable perspective in the near future. The properties of CPC combined with low content of PLGA microspheres(5% and 8%) were not influenced negatively. The delayed release of Endostar from CPC is like as the delayed release of Endostar from PLGA, their stability and reproducibility are favorable, and it could meet the need of the local controlled releasing. The compressive strength of three groups CPC after Endostar delayed release from them did not cut down, and the porosity of CPC (8% and 10%) raised obviously. In summary, the composite cement serves as an ideal drug carrier and Endostar released from the composites retains good bioactivity. The composite cement may find potential clinical application in bone defect reconstruction with sustained release of therapeutic agents to improve the therapeutic effect, simplify the drug administration and minimize the adverse effects of the drugs.
All aboved experimental result suggested that the PLGA microspheres for Endostar combined with CPC could be used for local treatment of malignant bone tumor. And this research has certain instructive function to the clinical application of drug-loaded CPC.
The new ideas of this study:
1、Discuss the feasibility of CPC on the spinal tumor.
2、Compounded the PLGA microspheres for Endostar combined with CPC for the first time and carried out the basic research.
研究方法:利用乳化溶剂挥发法(w/o/o)制备出相应粒径的恩度PLGA缓释微球,观察其形态以及粒径分布,并研究了该方法制备缓释微球的制备工艺及其影响因素,优选载药量和包封率高的处方以制备微球;将恩度PLGA缓释微球分别以5%、8%、10%的质量百分比与磷酸钙骨水泥复合,检测复合物的凝结时间、抗压强度、孔隙率及微结构的改变等理化性质,研究不同质量配比的载药微球复合磷酸钙骨水泥后是否对骨水泥的结构产生重要影响;体外测定恩度PLGA缓释微球磷酸钙骨水泥复合物药物缓释情况,并以人脐静脉内皮细胞(Human Umbilical Vein Endothelial Cells HUVESc)增殖抑制试验(MTT)法检测缓释后的药物活性;将恩度PLGA缓释微球磷酸钙骨水泥复合物植入荷骨肉瘤裸鼠模型,并进行对照实验,明确恩度PLGA缓释微球磷酸钙骨水泥复合物对裸鼠骨肉瘤的治疗作用。
结果:1、选用PLGA微球作为药物载体材料,采用乳化溶剂挥发法制备恩度PLGA缓释微球,制备工艺简便易行,稳定性好,包封率和载药量较高。同时,该法制备的缓释微球的初始突释较小,前期释放较快,后期稳定,且缓慢溶蚀释放为其主释药过程,时间可达3周以上,能够满足骨肿瘤病灶清除后缺损修复中抗肿瘤药物局部持续释放要求。2、CPC作为一种理想的提供局部负荷力学重建与药物缓释的载体,其理化特性可能随着加入药物的量而改变。不同配比的恩度PLGA缓释微球对磷酸钙骨水泥的凝结时间、抗压强度及孔隙率均有影响,三者的关系是统一的。恩度PLGA缓释微球磷酸钙骨水泥复合物的固化时间及材料性能产生负面的影响;5%、8%恩度PLGA缓释微球磷酸钙骨水泥复合物的固化时间及材料性能无显著改变。3、以CPC为载体的药物缓释体系可以达到药物缓释过程可控、局部药物高效、稳定、长期释放的目的。恩度PLGA缓释微球磷酸钙骨水泥复合物是一种集骨修复和药物治疗于一体的较理想的新型功能人工骨,作为Endostar的控释载体,该体系能有效缓释具有生物活性的Endostar超过28天,且突释较小。恩度PLGA缓释微球磷酸钙骨水泥复合物的缓释液具有良好的生物活性,可有效抑制HUVECs的增殖,其抑制作用与其浓度呈正相关。4、恩度PLGA缓释微球磷酸钙骨水泥复合物在体内可抑制骨肉瘤移植瘤的生长、侵袭和转移,恩度可望作为骨肉瘤综合治疗的组成部分。
结论:采用可生物降解的聚合物PLGA作为载体材料,可将rh-endostatin制备成缓释微球。较低质量百分比(5%以下)PLGA包裹的rh-endostatin缓释微球复合磷酸钙骨水泥对CPC固化及材料性能未产生负面的影响,CPC的凝结时间无明显延长,抗压强度无明显改变。rh-endostatin缓释后各组CPC的抗压强度无明显降低,rh-endostatin从骨水泥中的缓释情况与其从缓释微球中缓释相近,稳定性、重现性良好。含有rh-endostatin的缓释液可有效抑制HUVECs的增殖,其抑制作用与其浓度呈正相关,浓度越高对细胞增殖的抑制越大,具有剂量依赖抑制关系。rh-endostatin/PLGA微球复合CPC骨水泥具有较好的抑制裸鼠骨肉瘤新生血管形成,诱导肿瘤凋亡的作用。以上结果提示恩度PLGA缓释微球磷酸钙骨水泥复合物能应用于骨肉瘤的局部治疗,本研究将对载药CPC的临床应用一定的具有指导作用。
本研究创新点:
首次合成抗新生血管形成药物(恩度,Endostar)PLGA缓释微球磷酸钙骨水泥复合物,既具有骨肉瘤术中的重建作用,同时也具有持久的局部缓释抗肿瘤作用。不仅能用于脊柱肿瘤术中重建,同时也能应用于四肢肿瘤,具有广泛的临床应用前景,为后期其他研究奠定了基础。
It was confirmed by many studies at home and abroad that the solid tumor could not develop if there were not new endothelial cells to supplement and the formation of neogenesis blood capillary was the cause of the amplification and metastasis of tumors. Rh-Endostatin was discovered by Folkman et al at 1997 and it is the fragment of non-collegenous dormain which is at the C-terminal of extracellular matrix(ECM) collagen protein XVIII. It exerts a negative effect on the angiogenesis of tumor. And it is a specific kind of angiogenic inhibitor. The experiment in vitro indicated that it can inhibit the proliferation and migration of vascular endothelial cells effectively and inhibit the angiogenesis of carcinoma. So the nutrition supply of tumor cells was obstructed and the proliferation and migration of tumor were inhibited. Therefore rh-Endostatin is featured in broad-spectrum, high-efficiency and no resistance to prevent neoplasm of tumor blood vessels. Calcium phosphates possess good biocompatibility and osteoconductivity as the filling materials for repairing bone defects. When solidified, CPC produces strong compressive strength without releasing much heat and has good plasticity, biocompatibility, osteoconductivity and degradability in vivo. Currently, CPC is the only material available capable of spontaneous solidification and inducing bone regeneration, and has been widely used in dental and orthopedic surgeries. The mild condition required for solidification and the porous structure of CPC suggest great potential of CPC as a drug carrier for sustained drug release in vivo to maintain sufficient local drug concentration and minimize potential systemic adverse effects of the drugs, especially the agents for tumor therapy.
Endostar is a neotype self-designed rh-Endostatin and it is produced by using escherichia coli as expression vectors. Endostar raise the stability of the protein efficiently and the antiangiogenenic effect, and make the purification of protein easy. As shown in these researchs, the inhibitory effect of Endostar to new vessels is greater two times than Endostatin at least. PhaseⅢclinical trials confirm that the efficacy of Endostar combined with NP regimen in treating advanced non-small-cell lung cancer(NSCLC) is raised significantly and the treatment prolong the live time and improve the quality of life. At present in home and abroad many researchers are attempting to use Endostar combined chemotherapy to treatment many kinds of advanced malignant tumour. Calcium phosphates possess good biocompatibility and osteoconductivity as the filling materials for repairing bone defects. When solidified, CPC produces strong compressive strength without releasing much heat and has good plasticity, biocompatibility, osteoconductivity and degradability in vivo. Currently, CPC is the only material available capable of spontaneous solidification and inducing bone regeneration, and has been widely used in dental and orthopedic surgeries. The mild condition required for solidification and the porous structure of CPC suggest great potential of CPC as a drug carrier for sustained drug release in vivo to maintain sufficient local drug concentration and minimize potential systemic adverse effects of the drugs, especially the agents for tumor therapy.
At present, the research of the pharmaceutical dosage form of Endostar is very seldom and there is no report about sustained-release dosage form of Endostar. Because Endostar is easy to be degradated and inactivated and has a very short half-life in vivo, it is required to inject many times and the promising prospects in utilization are restricted. In this study we design to prepare controlled release of Endostar encapsulated within poly(D,L-lactide-co-glycolide)(PLGA).The lasting time of the drug is 4 weeks and the quality of drug and the compliance of patients are raised. The delayed release microspheres are used to combinate with calcium phosphate cement (CPC), then the complex is used to fill the defect after the focal cleaning of bone tumor. Because the diameter of Osteoblast is about 100～150um, in this study the particle diameter of these microspheres are controlled about 100～150um. After delayed release the cellules are profit to osteoblast to enter and newly formed bone tissue to deposite.
This study is divided into 4 parts. The first part begun with the preparation of PLGA microspheres by W/O/O phase separation method and observed the appearance and the size and distribution of PLGA microspher. Single-factor experiment was designed to investigate the influential factors of the size and encapsulation efficiency of microspheres. The influential factors include stirring rate when preparing double emulsion, polyvinyl alcohol (PVA) volume, PLGA concentration, the volume of inner water phase. Adjusting all kinds of influential factors, the encapsulation efficiency of microspheres are usually high(more than 45%). In vitro test confirmed that PLGA microspheres for Endostar delivery systems prepared by the solvent evaporation with W/O/O phase separation method have better functions of sustained releasing Endostar, moreover, their stability and reproducibility are favorable, and encapsulation efficiency are high, which could provide the local sustained releasing Endostar.
The second part of this study researched on the properties of CPC combined with PLGA microspheres for Endostar. We studied the properties of CPC combined with different content of PLGA microspheres, including the setting time, compressive strength, microstructural development and the interval porosity. The result showed that high content of PLGA microspheres(10%) affected the properties of CPC that had the longer setting time and lower compressive strength. On the other hand, the properties of CPC combined with low content of PLGA microspheres(5% and 8%) were not influenced.
The third part of this study researched on the release characteristics in vitro of the PLGA microspheres for Endostar combined with CPC and the biological activities of Endostar delayed release from CPC. The experimental result showed that the delayed release of Endostar from CPC is like as the delayed release of Endostar from PLGA, their stability and reproducibility are favorable, and it could meet the need of the local controlled releasing.
The last part of this study is the in vivo research of the PLGA microspheres for Endostar combined with CPC on tumor. Implanted the PLGA microspheres for Endostar combined with CPC and MTX CPC into osteosarcoma model of the nude mouse. It has shown that the PLGA microspheres for Endostar combined with CPC has the stronger ability of inhibiting the growth and inducing the apoptosis of the of the tumor cell.
Conclusion:Endostar can be encapsulated in microspheres to yield continuous release when using biodegradable polymers PLGA as carrier material, and this technique will have a favorable perspective in the near future. The properties of CPC combined with low content of PLGA microspheres(5% and 8%) were not influenced negatively. The delayed release of Endostar from CPC is like as the delayed release of Endostar from PLGA, their stability and reproducibility are favorable, and it could meet the need of the local controlled releasing. The compressive strength of three groups CPC after Endostar delayed release from them did not cut down, and the porosity of CPC (8% and 10%) raised obviously. In summary, the composite cement serves as an ideal drug carrier and Endostar released from the composites retains good bioactivity. The composite cement may find potential clinical application in bone defect reconstruction with sustained release of therapeutic agents to improve the therapeutic effect, simplify the drug administration and minimize the adverse effects of the drugs.
All aboved experimental result suggested that the PLGA microspheres for Endostar combined with CPC could be used for local treatment of malignant bone tumor. And this research has certain instructive function to the clinical application of drug-loaded CPC.
The new ideas of this study:
1、Discuss the feasibility of CPC on the spinal tumor.
2、Compounded the PLGA microspheres for Endostar combined with CPC for the first time and carried out the basic research.
引文
[1] Zetter BR.Angiogenesis and tumor metastasis[J].Annu Rev Med,1998,49:4O7-424.
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