CN105997867B - 功能性药物组合物的制备方法 - Google Patents
功能性药物组合物的制备方法 Download PDFInfo
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- CN105997867B CN105997867B CN201610348663.1A CN201610348663A CN105997867B CN 105997867 B CN105997867 B CN 105997867B CN 201610348663 A CN201610348663 A CN 201610348663A CN 105997867 B CN105997867 B CN 105997867B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明公开了一种功能性药物组合物及其制备方法，利用各自的活性基团，将丙烯酸单元、磷酸酯‑碳酸酯单元、氨基酸单元聚合得到载体；最后，将疏水性抗癌药物、载体分子在溶液中自组装，根据实际需要定容，得到具有酸敏感的功能性药物组合物。本发明公开的功能性药物组合物中，载体具有良好的生物相容性及生物可降解性；化学交联结构有效的延长了体内循环时间，进入癌部位后，释放出所包载药物，可以用作高效可控药物释放体系；特别是本发明的功能性药物组合物还具有缓释功能，解决了现有药物体系释放过快的缺陷，在生物材料及生物医药领域具有良好的应用价值。
Description
技术领域
本发明属于生物医用高分子材料领域，具体涉及一种基于聚磷酸酯-碳酸酯的酸敏感功能性药物组合物的制备方法。
背景技术
众所周知，多数的抗癌药物都具有很强的疏水性，而两亲性共聚物自组装形成的核-壳结构的胶束具有疏水性内核，可以用于包载疏水性抗癌药物，而亲水性的外壳可以起到稳定胶束、增加药物水溶性的作用，并极大地提高了载药胶束在体内的循环时间。胶束交联的方法主要有两种：“物理交联法 (Physical cross-links)”和“化学交联法(Chemicalcross-links)”。物理交联胶束主要通过非共价键作用形成，例如：静电作用、氢键、配位键、疏水作用及超分子络合作用等；而化学交联胶束主要通过共价键作用形成，即功能性共聚物分子链间的相互反应或者添加功能性小分子交联剂与共聚物链发生化学反应。根据胶束交联位置的不同，交联胶束可以分为“核交联胶束(Core cross-linked micelle)”和“壳交联胶束(Shell cross-linked micelle)”，这种交联胶束作为药物载体在体内循环过程中可以稳定存在。两亲性共聚物一般由亲水和疏水链段组成，由于其在水溶液中可以自组装成多种形状纳米粒子，如胶束、囊泡、纳米棒及薄片等，在生物医药、超分子及纳米科技等领域具有广阔的应用前景。
现有两亲性共聚物载药胶束存在一定的热力学不稳定性，在体内循环过程中，使抗癌药物易从胶束内扩散出来，导致药物在癌变组织部位富集程度较低，严重影响治疗效果。同时，药物的毒性对人体带来很多不良反应。生物可降解聚合物具有非常独特的性能，例如它们通常具有良好的生物相容性，能在体内降解，降解产物可被人体吸收或通过人体正常生理途径排出体外，而被广泛应用于生物医学的各个领域，如手术缝合线、骨固定器械、生物组织工程支架材料、和药物控制释放载体等。但是，现有的生物可降解聚合物如PTMC、 PCL、PLA和PLGA等结构比较单一，缺乏可用于修饰的官能团，往往难以提供循环稳定的药物纳米载体或是稳定的表面修饰涂层。理想的药物载体应当具有良好的生物相容性和生物可降解性，并且，作为抗肿瘤药物的载体，还应当能够利用主动或者被动靶向，高效进入癌细胞。因此，需要研发新型的药物载体用于制备药物组合物。
发明内容
本发明的目的是提供一种基于聚磷酸酯-碳酸酯的药物组合物。
为达到上述目的，本发明采取的技术方案是，一种功能性药物组合物的制备方法，包括如下步骤：
(1)将乙二醇二甲基丙烯酸酯、甲基丙烯酸月桂酯、季戊四醇四丙烯酸酯加入丁烷中，搅拌5分钟，再加入二异丙基乙胺，于60℃搅拌15分钟，再加入N，N-二正丁基二硫代氨基甲酸铜，搅拌10分钟，冷却至室温，再加入双 (2，6-二氟-3-(1H-吡咯-1-基)苯基)二茂钛和乙醇，搅拌下，光照反应8小时；反应结束后，反应液加入水中，然后取上层溶液，为丙烯酸预聚物溶液；
(2)氮气气氛中，将磷酸酯单体加入四氢呋喃中，搅拌15分钟，再加入异丙醇，搅拌30分钟，然后加入三亚甲基环碳酸酯，搅拌5分钟，再加入1， 8-二氮杂二环[5.4.0]十一碳-7-烯，于70℃反应10分钟；旋蒸浓缩反应产物，再将浓缩液滴入甲醇/乙醚混合液中沉淀，除去上清液，将剩余物溶于甲醇中，再转移到透析袋内，置于去离子水中透析50小时，然后冷冻干燥，得到磷酸酯-碳酸酯共聚物；所述磷酸酯单体的化学结构式为：
(3)将氨基化合物溶解在二甲基甲酰胺中并置于密闭反应器中，氮气环境下，再滴加γ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的二甲基甲酰胺溶液，然后于40℃反应2小时；反应结束后，将反应液用冰乙醚沉淀，离心，真空干燥，得到氨基酸聚合物；所述氨基化合物为鸟氨酸乙酯或者胱氨酸甲酯；
(4)将磷酸酯-碳酸酯共聚物、氨基酸聚合物分别加入二氯甲烷中得到磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液；然后同时将磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液滴加入丙烯酸预聚物溶液；滴加完成后，加入聚乙二醇以及酞菁锌；于50℃反应20 小时；然后用冰乙酸终止反应，用冰乙醚沉淀反应液，过滤，滤饼干燥即为载体；
(5)将药物溶解在DMSO中，得到药物溶液；将载体溶解在N，N-二甲基甲酰胺中，得到载体溶液；搅拌下，将药物溶液滴加入载体溶液中，混合均匀，然后加入二次水与载体质量0.05％的1，4-二硫代-D，搅拌30分钟，对一次水透析；然后加入缓冲液定容，得到靶向药物组合物。
上述步骤(1)中，乙二醇二甲基丙烯酸酯、甲基丙烯酸月桂酯、季戊四醇四丙烯酸酯、二异丙基乙胺、N，N-二正丁基二硫代氨基甲酸铜、双(2，6-二氟- 3-(1H-吡咯-1-基)苯基)二茂钛的摩尔比为1∶0.8∶0.4∶0.1∶0.01∶0.005。
上述步骤(2)中，磷酸酯单体、异丙醇、三亚甲基环碳酸酯、1，8-二氮杂二环[5.4.0]十一碳-7-烯的摩尔比为1∶0.3∶2∶0.008。
上述步骤(3)中，氨基化合物与γ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的摩尔比为1∶5。
本发明中，乙二醇二甲基丙烯酸酯、三亚甲基环碳酸酯、γ-寡聚乙二醇- L-谷氨酸-N-羧基内酸酐、聚乙二醇以及酞菁锌的摩尔比为3∶6∶1∶0.02∶ 0.0008。如此得到的载体聚合物中丙烯酸单元、磷酸酯-碳酸酯单元、氨基酸单元分布合理，利于聚合物作为药物载体时载药率、释放率的改善。
本发明中，药物为阿霉素、紫杉醇、硼替佐米、阿柔比星、吡柔比星、盐酸柔红霉素、司莫司汀或者普卡霉素；药物溶液浓度为5.0mg/mL。
本发明中，缓冲液为饱和氯化钠磷酸缓冲液；一般PH为10。
本发明进一步公开了上述功能性药物组合物的制备方法制备的功能性药物组合物；其由载体聚合物包裹药物组成，在体内循环具有优异的稳定性，到达病灶处可以缓慢释放药物，达到有效治疗效果，并可以减少用药次数，减少药物副作用，利于患者健康。
本发明进一步公开了上述功能性药物组合物在制备抗癌药物中的应用。
本发明将开环聚合和光引发自由基反应联用，合成酸敏感生物可降解两亲性聚合物载体。首先，利用简单的光催化自由基聚合的方法，以丙烯酸单体为原料，通过逐步添加原料组分，充分混合单体与其他成分，有效的制备了丙烯酸预聚物，尤其是结合加热与光催化，以光催化聚合为主，加热辅助增加各成分的相容性以及反应性，利于丙烯酸单体反应均匀性；然后以小分子醇为引发剂，对环状磷酸酯类单体、碳酸酯单体进行开环聚合，得到两亲性聚磷酸酯-碳酸酯共聚物；随后，用氨基小分子对谷氨酸进行修饰，得到端基带氨基的两亲聚合物；之后，利用各自的活性基团，将丙烯酸单元、磷酸酯-碳酸酯单元、氨基酸单元聚合得到载体；最后，将疏水性抗癌药物、载体分子在溶液中自组装，根据实际需要定容，得到具有酸敏感的功能性药物组合物。
本发明公开的功能性药物组合物中，两亲性共聚物载体具有良好的生物相容性及生物可降解性，其含有亲水和疏水链段，可通过自组装包载疏水性抗癌药物；所形成的载药聚合物结构稳定，在体内循环过程中，化学交联结构有效的延长了体内循环时间，进入癌部位后，载药胶束的化学交联点破坏，在溶酶体内水解酶的存在下，聚磷酸酯部分水解，导致载体结构破坏，释放出所包载药物，可以用作高效可控药物释放体系；特别是本发明的功能性药物组合物还具有缓释功能，解决了现有药物体系释放过快的缺陷，在生物材料及生物医药领域具有良好的应用价值。
具体实施方式
实施例一载体制备方法，包括如下步骤：
(1)将3mmol乙二醇二甲基丙烯酸酯、2.4mmol甲基丙烯酸月桂酯、 1.2mmol季戊四醇四丙烯酸酯加入丁烷中，搅拌5分钟，再加入0.3mmol二异丙基乙胺，于60℃搅拌15分钟，再加入0.03mmol N，N-二正丁基二硫代氨基甲酸铜，搅拌10分钟，冷却至室温，再加入0.015mmol双(2，6-二氟-3-(1H-吡咯-1-基)苯基)二茂钛和乙醇，搅拌下，光照反应8小时；反应结束后，反应液加入水中，然后取上层溶液，为丙烯酸预聚物溶液；
(2)氮气气氛中，将3mmol磷酸酯单体加入四氢呋喃中，搅拌15分钟，再加入0.9mmol异丙醇，搅拌30分钟，然后加入6mmol三亚甲基环碳酸酯，搅拌5分钟，再加入0.024mmol 1，8-二氮杂二环[5.4.0]十一碳-7-烯，于70℃反应 10分钟；旋蒸浓缩反应产物，再将浓缩液滴入甲醇/乙醚混合液中沉淀，除去上清液，将剩余物溶于甲醇中，再转移到透析袋内，置于去离子水中透析50小时，然后冷冻干燥，得到磷酸酯-碳酸酯共聚物；所述磷酸酯单体的化学结构式为：
(3)将0.2mmol鸟氨酸乙酯溶解在二甲基甲酰胺中并置于密闭反应器中，氮气环境下，再滴加1mmolγ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的二甲基甲酰胺溶液，然后于40℃反应2小时；反应结束后，将反应液用冰乙醚沉淀，离心，真空干燥，得到氨基酸聚合物；
(4)将磷酸酯-碳酸酯共聚物、氨基酸聚合物分别加入二氯甲烷中得到磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液；然后同时将磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液滴加入丙烯酸预聚物溶液；滴加完成后，加入0.02mmol聚乙二醇以及0.0008mmol酞菁锌；于50℃反应20小时；然后用冰乙酸终止反应，用冰乙醚沉淀反应液，过滤，滤饼干燥即为载体。
实施例二载体制备方法，包括如下步骤：
(1)将3mmol乙二醇二甲基丙烯酸酯、2.4mmol甲基丙烯酸月桂酯、 1.2mmol季戊四醇四丙烯酸酯加入丁烷中，搅拌5分钟，再加入0.3mmol二异丙基乙胺，于60℃搅拌15分钟，再加入0.03mmol N，N-二正丁基二硫代氨基甲酸铜，搅拌10分钟，冷却至室温，再加入0.015mmol双(2，6-二氟-3-(1H-吡咯-1-基)苯基)二茂钛和乙醇，搅拌下，光照反应8小时；反应结束后，反应液加入水中，然后取上层溶液，为丙烯酸预聚物溶液；
(2)氮气气氛中，将3mmol磷酸酯单体加入四氢呋喃中，搅拌15分钟，再加入0.9mmol异丙醇，搅拌30分钟，然后加入6mmol三亚甲基环碳酸酯，搅拌5分钟，再加入0.024mmol1，8-二氮杂二环[5.4.0]十一碳-7-烯，于70℃反应 10分钟；旋蒸浓缩反应产物，再将浓缩液滴入甲醇/乙醚混合液中沉淀，除去上清液，将剩余物溶于甲醇中，再转移到透析袋内，置于去离子水中透析50小时，然后冷冻干燥，得到磷酸酯-碳酸酯共聚物；
(3)将0.2mmol胱氨酸甲酯溶解在二甲基甲酰胺中并置于密闭反应器中，氮气环境下，再滴加1mmolγ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的二甲基甲酰胺溶液，然后于40℃反应2小时；反应结束后，将反应液用冰乙醚沉淀，离心，真空干燥，得到氨基酸聚合物；
(4)将磷酸酯-碳酸酯共聚物、氨基酸聚合物分别加入二氯甲烷中得到磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液；然后同时将磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液滴加入丙烯酸预聚物溶液；滴加完成后，加入0.02mmol聚乙二醇以及0.0008mmol酞菁锌；于50℃反应20小时；然后用冰乙酸终止反应，用冰乙醚沉淀反应液，过滤，滤饼干燥即为载体。
实施例三载体毒性
以人体成纤维细胞(L929)和人鼻咽癌细胞(KB)为对象，L929细胞培养在加有10％胎牛血清(FBS)的DMEM培养基中，37℃、5％CO2，相对湿度为90％的培养箱中培养。选择处于生长活跃期的细胞接种于每孔含100μL DMEM培养基的96孔板中，培养24小时；KB细胞在RPMI-1640(-)FA培养基中培养两周以上。配置1200mg·L-1的载体溶液，将其加入到96孔板中，继续培养48小时；接着加入25μL的MTT试剂，进一步培养4小时后，用酶标仪(Bio-Rad680)在570纳米下测量对应的吸光度。按照如下公式计算细胞存活率：细胞存活率(Cellviability)(％)＝[A]test/[A]control×100 式中，[A]test为加有待测样品条件下测得的吸光度，[A]control为不加样品空白对照条件下测得的吸光度。每个样品测试五次，取其平均值。
48小时测试结果表明实施例一、实施例二的载体对L929细胞、KB细胞的细胞存活率分别大于92％以及88％，结果表明，本发明的聚合物载体具有较低的毒性和良好的生物相容性。
实施例四药物组合物的制备
将阿霉素溶解在DMSO中，得到5mg/L药物溶液；将载体溶解在N，N-二甲基甲酰胺中，得到载体溶液；搅拌下，将药物溶液滴加入载体溶液中，混合均匀，然后加入二次水与载体质量0.05％的1，4-二硫代-D，搅拌30分钟，对一次水透析；然后加入PH为10的饱和氯化钠磷酸缓冲液定容，得到药物组合物；透射电镜和动态光散射结果表明，药物组合物在水溶液中呈圆形结构，粒径在210纳米左右。
实施例五载药量与包封率
取一定量的药物组合物溶液，先通过冷冻干燥法将溶液中的水除去，然后加入1mL甲酰胺超声0.4h，取溶液20mL，加入3mL甲酰胺，通过荧光测试，结合阿霉素的标准曲线计算包封率及载药量。
包封率＝(药物中阿霉素的质量/投入的阿霉素的质量)×100％
载药量＝(药物中阿霉素的质量/药物中的质量与投入的阿霉素的质量总和) ×100％
当理论载药量为30％时，实施例一、实施例二载体对阿霉素的包封率、实际载药量分别为61.5％、24％，60.8％、23％。
其他药物的结果见表1。
表1 药物包封率、载药量
实施例六药物组合物的释放
将阿霉素药物组合物放入50mL离心管内，加入不同pH值的磷酸盐缓冲溶液(10mL)，并以加去离子水为对照，将离心管置于37℃恒温振荡器中进行释放实验。每隔一段时间取5mL透析(截留分子量为10000～15000g·mol-1)，同时补充5mL相同pH值的缓冲溶液，采用荧光分光光度计检测释放阿霉素的含量，结果表明，药物在pH 5.5条件下释放速率明显快于pH 7.5，同时 20小时阶段，实施例一载体、实施例二载体在对照样本中药物释放率为16％、 17％，说明本发明的药物组合物具有酸敏感性，可以达到药物可控释放效果；实施例一载体药物在1小时、3小时、8小时、12小时、20小时阶段，药物在 pH 5.5条件下释放率为2.5％、16.9％、39.4％、69.4％、80.9％；实施例二载体药物在1小时、3小时、8小时、12小时、20小时阶段，药物在pH 5.5条件下释放率为2％、18.1％、39.1％、67.5％、81.2％；说明本发明的药物组合物具有缓释作用，可以减少用药，避免药物副作用。
将阿霉素换为其他药物，在pH 5.5条件下8小时释放率为35～40％，20 小时释放率为80～83％。
实施例七药物组合物的毒性
配置药物溶液，其中药物浓度为3mg/L；根据实施例三的方法测试对人鼻咽癌细胞(KB)、人脑胶质瘤细胞(U87MG)的毒性，3mg/L游离药物作为参考；表2为毒性结果。
表2 药物组合物对细胞存活率结果(48小时)
结果表明本发明药物组合物杀死癌细胞的能力强，而且，在相同药物浓度下，载药组合物比游离药物具有更强杀死癌细胞的能力。
实施例八小鼠循环结果
将9只体重为20g左右约6周龄的裸鼠随机分为三组，每组分别尾静脉给药(实施例一阿霉素药物组合物、实施例二紫杉醇药物组合物、自由DOX)，药物用量为18mg/kg。在给药后5min、30min、1h、2h、5h、8h、12h、24h各时间点尾部取血8μL，取血结束后将血样称重，并溶解在100μL 1％曲拉通溶液中，后再加入1mL 0.75mol/L的盐酸异丙醇溶液，于-20℃避光条件下静置过夜，离心后取上清液进行荧光测试。
％ID/g＝(FL样品×(V曲拉通+V盐酸))/(M血×FL标样×V标样×标样稀释倍数)×100％。结果表明：药物组合物具有良好的稳定性，可以在小鼠体内实现长循环，8h还可以检测到20％左右，而自由药物在2h之后几乎无法在小鼠血液中检测到。
Claims (3)
1.一种功能性药物组合物的制备方法，其特征在于，包括如下步骤：
（1）将乙二醇二甲基丙烯酸酯、甲基丙烯酸月桂酯、季戊四醇四丙烯酸酯加入丁烷中，搅拌5分钟，再加入二异丙基乙胺，于60℃搅拌15分钟，再加入N,N-二正丁基二硫代氨基甲酸铜，搅拌10分钟，冷却至室温，再加入双(2,6-二氟-3-(1H-吡咯-1-基)苯基)二茂钛和乙醇，搅拌下，光照反应8小时；反应结束后，反应液加入水中，然后取上层溶液，为丙烯酸预聚物溶液；
（2）氮气气氛中，将磷酸酯单体加入四氢呋喃中，搅拌15分钟，再加入异丙醇，搅拌30分钟，然后加入三亚甲基环碳酸酯，搅拌5分钟，再加入1, 8-二氮杂二环[5.4.0]十一碳-7-烯，于70℃反应10分钟；旋蒸浓缩反应产物，再将浓缩液滴入甲醇/乙醚混合液中沉淀，除去上清液，将剩余物溶于甲醇中，再转移到透析袋内，置于去离子水中透析50小时，然后冷冻干燥，得到磷酸酯-碳酸酯共聚物；所述磷酸酯单体的化学结构式为：
（3）将氨基化合物溶解在二甲基甲酰胺中并置于密闭反应器中，氮气环境下，再滴加γ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的二甲基甲酰胺溶液，然后于40℃反应2小时；反应结束后，将反应液用冰乙醚沉淀，离心，真空干燥，得到氨基酸聚合物；所述氨基化合物为鸟氨酸乙酯或者胱氨酸甲酯；
（4）将磷酸酯-碳酸酯共聚物、氨基酸聚合物分别加入二氯甲烷中得到磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液；然后同时将磷酸酯-碳酸酯共聚物的二氯甲烷溶液、氨基酸聚合物的二氯甲烷溶液滴加入丙烯酸预聚物溶液；滴加完成后，加入聚乙二醇以及酞菁锌；于50℃反应20小时；然后用冰乙酸终止反应，用冰乙醚沉淀反应液，过滤，滤饼干燥即为载体；
（5）将药物溶解在DMSO中，得到药物溶液；将载体溶解在N,N-二甲基甲酰胺中，得到载体溶液；搅拌下，将药物溶液滴加入载体溶液中，混合均匀，然后加入二次水与载体质量0.05%的1,4-二硫代-D，搅拌30分钟，对一次水透析；然后加入缓冲液定容，得到靶向药物组合物；
步骤（1）中，乙二醇二甲基丙烯酸酯、甲基丙烯酸月桂酯、季戊四醇四丙烯酸酯、二异丙基乙胺、N,N-二正丁基二硫代氨基甲酸铜、双(2,6-二氟-3-(1H-吡咯-1-基)苯基)二茂钛的摩尔比为1∶0.8∶0.4∶0.1∶0.01∶0.005；
步骤（2）中，磷酸酯单体、异丙醇、三亚甲基环碳酸酯、1, 8-二氮杂二环[5.4.0]十一碳-7-烯的摩尔比为1∶0.3∶2∶0.008；
步骤（3）中，氨基化合物与γ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐的摩尔比为1∶5；
乙二醇二甲基丙烯酸酯、三亚甲基环碳酸酯、γ-寡聚乙二醇-L-谷氨酸-N-羧基内酸酐、聚乙二醇以及酞菁锌的摩尔比为3∶6∶1∶0.02∶0.0008；
药物为阿霉素、紫杉醇、硼替佐米、阿柔比星、吡柔比星、盐酸柔红霉素、司莫司汀或者普卡霉素。
2.根据权利要求1所述功能性药物组合物的制备方法，其特征在于：药物溶液浓度为5.0mg/mL。
3.根据权利要求1所述功能性药物组合物的制备方法，其特征在于：缓冲液为饱和氯化钠磷酸缓冲液。
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