叶酸靶向紫杉醇纳米胶束抑制小鼠H22肝癌肺转移的研究
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摘要
叶酸受体是一种在肿瘤细胞表面过表达的蛋白，通过叶酸及其受体的特异结合，而介导胞吞作用，被应用来传递药物活性分子。本研究中，以配体-受体的特异结合为基础，制备了键合叶酸、键合紫杉醇的胶束，经过筛选及校正，依据最合理配比，由两种混合胶束组成新的纳米微粒，而在组装后，复合胶束的叶酸质量比含量1.4%，而同时，紫杉醇（PTX）胶束中PTX活性药物质量比含量25%，然后，将两胶束以质量比1:9的比例，应用相应程序，制备成混合胶束从而同时载有叶酸和PTX。根据本实验室此前研究，证实混合胶束的水溶性良好，动态光散射（DLS）及扫描电镜（TEM）证实，在水媒介中形成特殊的外壳-内核形态的分散的微粒，而将活性药物PTX―包裹‖并保护在聚合物组成的外壳内，以避免/减少PTX在给药后血液循环中的非特异（到达靶区之产胆）释放或非治疗目的相关的释放，因此理论上可以减少毒副作用，同时达到治疗效果。具备有聚合物/纳米微粒、而以EPR效应为基础的―被动靶向‖（EPR）效应，与通过叶酸配体介导的以配体-受体的特异相结合，而形成的主动靶向效应。本实验以动物源性肝癌细胞H22等的体外检测，以及小鼠BALB/c的体内荷瘤抑制、生存分析等实验来评价这一种混合胶束FA-M(PTX)的抗肿瘤疗效是否存在优势。
在本项目研究中，叶酸（folate, FA）作为靶向基元，键合在胶束的侧链上，从而可构建出相应载药聚合物。同时，PTX键合在另一种聚合物的载体上面（M(PTX)）。这样把两种聚合物特异地制备后，构成了同时载有FA及PTX的混合胶束微粒（FA-M(PTX)），通过自组装作用，形成载药的外壳-内核结构，这样的复合纳米微粒有着良好的理化特点，比如说水溶性增加，以及在血液循环中的代谢时间可延长，还有其生物可降解性，最重要的一点是，FR-FA介导的胞吞靶向作用以及细胞摄取增加。
本实验的结果见下：
1.体外进行细胞实验(in vitro)
1.1应用不同剂型的药物PTX, M(PTX)和FA-M(PTX)分别作用12,24和48h后，H22细胞存活率与紫杉醇当量的浓度梯度相关。
1.2作用24h和72h后，药物组凋亡率较空白对照组显著增加；不同剂型药物PTX,M(PTX)和FA-M(PTX)作用24h后H22细胞凋亡率分别为16.8%,8.8%和11%，而在作用72h后，不同剂型药物相应的细胞凋亡纺分别为39.4%,34.9%和37.7%。
1.3肿瘤细胞对载有叶酸的复合胶束的摄取较正常细胞显著增加(Hela细胞摄取阳性率62.1%；H22细胞摄取阳性率55.4%而BEAS-2B细胞为37.6%)。此外，肿瘤细胞对无叶酸胶束的摄取较正常细胞增加（Hela为41.8%，H22为40.1%而BEAS-2B为36.5%）；对实验数据进行统计分析提示，与BEAS-2B细胞比较，Hela和H22这两种类型的肿瘤细胞对载有叶酸的复合胶束的摄取增加(p<0.001和p=0.017)；而且，Hela和H22细胞对载有叶酸的复合胶束的摄取较其对无叶酸胶束的摄取增加(p<0.001)；同时，Hela细胞对载有叶酸的复合胶束的摄取较H22增加(P=0.036)，这种现象可能解释为叶酸-叶酸受体介导的胞吞效应。
2.体内实验
2.1肿瘤转移点的密度在药物治疗组明确低于对照组；荷瘤小鼠的肺组织重量与小鼠体重的比值表示肿瘤转移负担指数，治疗组明显低于对照组(p<0.05)，并呈剂量相关性。
2.2在PTX给药当量为15mg/kg或30mg/kg时，HE染色显示的肺转移抑制率在不同的治疗组中呈现以下趋势：PTX 2.3生存分析：Kaplan-Meier生存曲线；荷瘤小鼠的中位生存时间以及平均生存时间的差异进行log-rank检验；PTX当量为15mg/kg或者30mg/kg时，药物治疗组的小鼠生存期较空白对照组延长，其中，FA-M(PTX)较PTX和M(PTX)对H22肺转移模型的疗效更优，更大程度地延长了荷瘤小鼠模型的存活时间。
The folate receptor (FR) is over-expressed in many types of human cancers. It canmediate endocytosis of folic acid (FA) or FA-carrying drugs. Based on this specific interactionbetween FA and FR, folic acid and paclitaxel (PTX) containing micelles (FA-M(PTX)) wereprepared by co-assembling an FA-polymer conjugate, poly(ethylene glycol)-b-poly(L-lactide-co-2,2-dihydroxylmethyl-propylene carbonate/FA)[PEG-b-P(LA-co-DHP/FA), FAcontent1.4wt%] and a PTX-polymer conjugate, poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-carboxyl-propylene carbonate/PTX)[PEG-b-P(LA-co-DCC/PTX), PTXcontent25wt%] with a mass ratio of1:9. Anti-tumor activity of FA-M(PTX) on H22cancerswere evaluated on BALB/c mice models by pulmonary burden measurements, survival timeanalysis, flow cytometry assay, immunohistochemistry (IHC) and histopathology. The resultsshowed that FA-M(PTX) exhibits significant anti-tumor effects in vivo compared to pure PTXand simple PTX-polymer micelles. This enhanced efficacy of FA-M(PTX) is ascribed to thetargeting effect of FA moieties in the micelles. Therefore, conjugation of both PTX and FAonto the hydrophobic segments of the block copolymer and co-assembling of thePTX-polymer and FA-polymer conjugates are successful strategies to construct cancer celltargeting drug delivery systems.
In this research, folic acid (FA) was chosen as the targeting moiety, and it is attached to acarrier polymer via an ester linkage. Based on our previous work, paclitaxel (PTX) isconjugated to another carrier polymer. These two carrier polymers are co-assembled intocomposite micelles which are expected to have many properties including water solubility,prolonged circulation, biodegradability, folate-receptor targeting and rapid cell uptake. Toexamine the anti-tumor efficacy of these composite micelles, murine H22cancer xenograftnude mice models were constructed and a series of evaluation was performed such as tumorgrowth inhibition rate, survival time analysis, immunohistochemistry (IHC) andhistopathology. The results showed that FA-M(PTX) exhibits significant anti-tumor efficacy in vivo compared to pure PTX and simple PTX-polymer micelles. This enhanced efficacy ofFA-M(PTX) is ascribed to the targeting effect of FA moieties in the micelles.
Results and conclusions of this study:
1. In vitro
1.1The cell viability of H22incubated with PTX, M(PTX), and FA-M(PTX) for12hours,24hours, and48hours are depicted in Figure1as a function of the equivalent PTXconcentration.
1.2The time-dependent apoptosis of H22cells induced by the drugs was observed. As shownin Figure2, the apoptosis of the drug groups were evidently higher when compared with thecontrol at24hours and72hours. The mean apoptosis rate of PTX, M(PTX), and FA-M(PTX)was16.8%,8.8%, and11%at24hours, while it was up to39.4%,34.9%, and37.7%at72hours, respectively.
1.3The three cell lines were exposed to0.1%FA-f-micelles and FA-mixed micelles for2hours,respectively, and a quantitative analysis by FCM was performed. It is presumed and confirmed in this studythat the cellular uptake of FA-mixed micelles was increased in HeLa and H22cells with overexpressed FRwhen compared to nontumorigenic BEAS-2B cells. As shown in Figure3, the obvious preferentialuptake of FA-mixed micelles was shown in cancer cells (HeLa,62.1%; H22,55.4%) compared withBEAS-2B cells (37.6%). Furthermore, an increased uptake of FA-f-micelles by HeLa (41.8%) and H22(40.1%) was observed when compared with BEAS-2B (36.5%). Statistically, HeLa and H22revealed theenhanced cellular uptake of FA-mixed micelles compared with BEAS-2B (P<0.001and P=0.017,respectively). Moreover, the uptake of FA-mixed micelles by the two cancer cells was significantlyincreased compared with that of FA-f-micelles (P<0.001). In addition, HeLa showed the preferential uptakeof FA-mixed-micelles compared with H22(P=0.036), which implicated FA–FR mediated endocytosis.
2. In vivo
2.1The density of the metastatic colonies was visibly decreased in the drug groups comparedwith control. As shown in Figure4, the ratio of wet lung weight to body weight in the druggroups were statistically decreased as an index of metastasis burden when compared with control (P<0.05), and the ratio varied in an almost dose-related manner.
2.2The microscopic tumor metastasis colonies detected by HE decreased in the drug groupsin the order of PTX 2.3The Kaplan–Meier survival curve is shown in Figure6. The median/mean survival time ofthe groups was compared using the log-rank test. The mice in the drug groups showed aprolonged survival time compared with the control with equivalent doses of PTX of15mg/kgas well as30mg/kg. The FA-M(PTX) was significantly more effective than pure PTX and M(PTX)on H22pulmonary metastasis models.
在本项目研究中，叶酸（folate, FA）作为靶向基元，键合在胶束的侧链上，从而可构建出相应载药聚合物。同时，PTX键合在另一种聚合物的载体上面（M(PTX)）。这样把两种聚合物特异地制备后，构成了同时载有FA及PTX的混合胶束微粒（FA-M(PTX)），通过自组装作用，形成载药的外壳-内核结构，这样的复合纳米微粒有着良好的理化特点，比如说水溶性增加，以及在血液循环中的代谢时间可延长，还有其生物可降解性，最重要的一点是，FR-FA介导的胞吞靶向作用以及细胞摄取增加。
本实验的结果见下：
1.体外进行细胞实验(in vitro)
1.1应用不同剂型的药物PTX, M(PTX)和FA-M(PTX)分别作用12,24和48h后，H22细胞存活率与紫杉醇当量的浓度梯度相关。
1.2作用24h和72h后，药物组凋亡率较空白对照组显著增加；不同剂型药物PTX,M(PTX)和FA-M(PTX)作用24h后H22细胞凋亡率分别为16.8%,8.8%和11%，而在作用72h后，不同剂型药物相应的细胞凋亡纺分别为39.4%,34.9%和37.7%。
1.3肿瘤细胞对载有叶酸的复合胶束的摄取较正常细胞显著增加(Hela细胞摄取阳性率62.1%；H22细胞摄取阳性率55.4%而BEAS-2B细胞为37.6%)。此外，肿瘤细胞对无叶酸胶束的摄取较正常细胞增加（Hela为41.8%，H22为40.1%而BEAS-2B为36.5%）；对实验数据进行统计分析提示，与BEAS-2B细胞比较，Hela和H22这两种类型的肿瘤细胞对载有叶酸的复合胶束的摄取增加(p<0.001和p=0.017)；而且，Hela和H22细胞对载有叶酸的复合胶束的摄取较其对无叶酸胶束的摄取增加(p<0.001)；同时，Hela细胞对载有叶酸的复合胶束的摄取较H22增加(P=0.036)，这种现象可能解释为叶酸-叶酸受体介导的胞吞效应。
2.体内实验
2.1肿瘤转移点的密度在药物治疗组明确低于对照组；荷瘤小鼠的肺组织重量与小鼠体重的比值表示肿瘤转移负担指数，治疗组明显低于对照组(p<0.05)，并呈剂量相关性。
2.2在PTX给药当量为15mg/kg或30mg/kg时，HE染色显示的肺转移抑制率在不同的治疗组中呈现以下趋势：PTX
The folate receptor (FR) is over-expressed in many types of human cancers. It canmediate endocytosis of folic acid (FA) or FA-carrying drugs. Based on this specific interactionbetween FA and FR, folic acid and paclitaxel (PTX) containing micelles (FA-M(PTX)) wereprepared by co-assembling an FA-polymer conjugate, poly(ethylene glycol)-b-poly(L-lactide-co-2,2-dihydroxylmethyl-propylene carbonate/FA)[PEG-b-P(LA-co-DHP/FA), FAcontent1.4wt%] and a PTX-polymer conjugate, poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-carboxyl-propylene carbonate/PTX)[PEG-b-P(LA-co-DCC/PTX), PTXcontent25wt%] with a mass ratio of1:9. Anti-tumor activity of FA-M(PTX) on H22cancerswere evaluated on BALB/c mice models by pulmonary burden measurements, survival timeanalysis, flow cytometry assay, immunohistochemistry (IHC) and histopathology. The resultsshowed that FA-M(PTX) exhibits significant anti-tumor effects in vivo compared to pure PTXand simple PTX-polymer micelles. This enhanced efficacy of FA-M(PTX) is ascribed to thetargeting effect of FA moieties in the micelles. Therefore, conjugation of both PTX and FAonto the hydrophobic segments of the block copolymer and co-assembling of thePTX-polymer and FA-polymer conjugates are successful strategies to construct cancer celltargeting drug delivery systems.
In this research, folic acid (FA) was chosen as the targeting moiety, and it is attached to acarrier polymer via an ester linkage. Based on our previous work, paclitaxel (PTX) isconjugated to another carrier polymer. These two carrier polymers are co-assembled intocomposite micelles which are expected to have many properties including water solubility,prolonged circulation, biodegradability, folate-receptor targeting and rapid cell uptake. Toexamine the anti-tumor efficacy of these composite micelles, murine H22cancer xenograftnude mice models were constructed and a series of evaluation was performed such as tumorgrowth inhibition rate, survival time analysis, immunohistochemistry (IHC) andhistopathology. The results showed that FA-M(PTX) exhibits significant anti-tumor efficacy in vivo compared to pure PTX and simple PTX-polymer micelles. This enhanced efficacy ofFA-M(PTX) is ascribed to the targeting effect of FA moieties in the micelles.
Results and conclusions of this study:
1. In vitro
1.1The cell viability of H22incubated with PTX, M(PTX), and FA-M(PTX) for12hours,24hours, and48hours are depicted in Figure1as a function of the equivalent PTXconcentration.
1.2The time-dependent apoptosis of H22cells induced by the drugs was observed. As shownin Figure2, the apoptosis of the drug groups were evidently higher when compared with thecontrol at24hours and72hours. The mean apoptosis rate of PTX, M(PTX), and FA-M(PTX)was16.8%,8.8%, and11%at24hours, while it was up to39.4%,34.9%, and37.7%at72hours, respectively.
1.3The three cell lines were exposed to0.1%FA-f-micelles and FA-mixed micelles for2hours,respectively, and a quantitative analysis by FCM was performed. It is presumed and confirmed in this studythat the cellular uptake of FA-mixed micelles was increased in HeLa and H22cells with overexpressed FRwhen compared to nontumorigenic BEAS-2B cells. As shown in Figure3, the obvious preferentialuptake of FA-mixed micelles was shown in cancer cells (HeLa,62.1%; H22,55.4%) compared withBEAS-2B cells (37.6%). Furthermore, an increased uptake of FA-f-micelles by HeLa (41.8%) and H22(40.1%) was observed when compared with BEAS-2B (36.5%). Statistically, HeLa and H22revealed theenhanced cellular uptake of FA-mixed micelles compared with BEAS-2B (P<0.001and P=0.017,respectively). Moreover, the uptake of FA-mixed micelles by the two cancer cells was significantlyincreased compared with that of FA-f-micelles (P<0.001). In addition, HeLa showed the preferential uptakeof FA-mixed-micelles compared with H22(P=0.036), which implicated FA–FR mediated endocytosis.
2. In vivo
2.1The density of the metastatic colonies was visibly decreased in the drug groups comparedwith control. As shown in Figure4, the ratio of wet lung weight to body weight in the druggroups were statistically decreased as an index of metastasis burden when compared with control (P<0.05), and the ratio varied in an almost dose-related manner.
2.2The microscopic tumor metastasis colonies detected by HE decreased in the drug groupsin the order of PTX
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