Photo-Triggered Release of Caged Camptothecin Prodrugs from Dually Responsive Shell Cross-Linked Micelles
Photo-Triggered Release of Caged Camptothecin Prodrugs from Dually Responsive Shell Cross-Linked Micelles
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光触发从双重响应壳交联胶束中释放笼状喜树碱前药
DOI：
10.1021/ma400691j
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发表时间：
2013-08-13
期刊：
影响因子：
5.5
通讯作者：
Liu, Shiyong
中科院分区：
文献类型：
--
作者：
Hu, Xianglong;Tian, Jie;Liu, Shiyong
我们报道了动态共价壳交联（SCL）胶束与疏水核共轭与光笼化疗药物和冠功能化配体的肿瘤细胞靶向的制造。两类两亲性嵌段共聚物，P（CL-g-CPT）-b-P（OEGMA-co-MAEBA）-CPT和PCL-b-P-通过ε-己内酯（CL）和2-溴-ε-己内酯（CL-Br）的开环共聚（ROP）的组合合成了（OEGMA-co-MAEBA-co-FA），原子转移自由基聚合（ATRP）（乙二醇）单甲醚甲基丙烯酸酯（OEGMA）和p（甲基丙烯酰氧基乙氧基）苯甲醛（MAEBA）共聚单体，和分别用光笼化的喜树碱（CPT）前药和炔基官能化的叶酸（FA）部分进行“点击”后官能化。由PCL-b-P（OEGMA-co-MAEBA-co-FA）和P（CL-g-CPT）-b-P（OEGMA-co-MAEBA）-CPT共组装的混合胶束具有与光笼化CPT前药缀合的疏水核和与醛基和FA部分共价连接的亲水外冠，用于随后的壳交联和癌细胞靶向。壳交联在pH 6.2时进行，在添加双官能交联剂，二硫醇双（丙酸二酰肼）（DTP），在苯胺的催化下。所获得的FA-修饰的SCL胶束含有酰腙和二硫键的外部冠，这可以在两个生物相关的条件下，弱酸性或还原性微环境，即，内体/溶酶体pH值或高GSH水平的胞质溶胶中去交联。在SCL胶束的核心内的笼状CPT药物的裂解可以在光照射下被有效地致动，而其从胶束纳米载体中的扩散可以通过pH和硫醇水平进一步调节，这是由于DTP交联剂的双重响应性质。与对照相比，FA修饰的SCL胶束可以更有效地进入叶酸受体表达的癌细胞比叶酸受体缺陷的。细胞活力测定显示，SCL胶束显示至少类似于9.7倍增强的细胞毒性后，光照射。报道的靶向配体修饰和前药缀合的动态共价SCL胶束对胶束稳定性、癌细胞靶向、具有光活化细胞毒性的光触发母体药物释放和可调药物释放曲线施加复杂的控制。所有这些都预示着它们作为一种新型的整合平台在癌症化疗中的靶向给药的潜在应用。
We report on the fabrication of dynamic covalent shell cross-linked (SCL) micelles with hydrophobic cores conjugated with photocaged chemotherapeutic drugs and coronas functionalized with ligands for tumor cell targeting. Two types of amphiphilic diblock copolymers, P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT and PCL-b-P-(OEGMA-co-MAEBA-co-FA),were synthesized via the combination of ring-opening copolymerization (ROP) of epsilon-caprolactone (CL) and 2-bromo-epsilon-caprolactone (CL-Br), atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers, and "click" post-functionalization with photocaged camptothecin (CPT) prodrug and alkynyl-functionalized folic acid (FA) moieties, respectively. Mixed micelles coassembled from PCL-b-P(OEGMA-co-MAEBA-co-FA) and P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT possess hydrophobic cores conjugated with photocaged CPT prodrugs and hydrophilic outer coronas covalently attached with aldehyde groups and FA moieties for subsequent shell cross-linking and cancer cell targeting. Shell cross-linking was performed at pH 6.2 upon addition of difunctional cross-linker, dithiol bis(propanoic dihydrazide) (DTP), under the catalysis of aniline. The obtained FA-decorated SCL micelles contain acylhydrazone and disulfide linkages in the outer coronas, which can be de-cross-linked under two biologically relevant conditions, mildly acidic or reductive microenvironments, that is, endosomal/lysosomal pH or high GSH level in the cytosol. The cleavage of caged CPT drug within the cores of SCL micelles can be effectively actuated under photo irradiation, whereas its diffusion out of micellar nanocarriers can be further modulated by pH and thiol levels due to the dually responsive nature of DTP cross-linker. Compared with the control, FA-decorated SCL micelles can more efficiently enter folate-receptor expressing cancer cells than folate-receptor deficient ones. Cell viability assays revealed that SCL micelles displayed at least similar to 9.7-fold enhanced cytotoxicity upon light irradiation. The reported targeting ligand decorated and prodrug-conjugated dynamic covalent SCL micelles exert intricate control concerning micellar stability, cancer cell targeting, photo-triggered parent drug release with photoactivated cytotoxicity, and tunable drug release profiles. All of these augur well for their potential application as a novel integrated platform for targeted drug delivery in cancer chemotherapy.