Heparin-folate-retinoic acid bioconjugates for targeted delivery of hydrophobic photosensitizers.
Heparin-folate-retinoic acid bioconjugates for targeted delivery of hydrophobic photosensitizers.
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DOI：
10.1016/j.carbpol.2012.10.075
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发表时间：
2013-02
影响因子：
11.2
通讯作者：
T. Tran;Byoung-chan Bae;Yong-kyu Lee;K. Na;K. Huh
中科院分区：
文献类型：
--
作者：
T. Tran;Byoung-chan Bae;Yong-kyu Lee;K. Na;K. Huh
通过将疏水性抗癌剂全反式维甲酸（all-trans-retinoic acid，RA）和靶向配体叶酸（folic acid，FA）化学偶联到高分子量肝素骨架上，合成了两亲性肝素-维甲酸（heparin-retinoic acid，HR）和肝素-叶酸-维甲酸（heparin-folate-retinoic acid，HFR）生物偶联物。HR和HFR生物缀合物具有高RA含量（22%，w/w），并且可以自组装成具有疏水光敏剂脱镁叶绿酸a（PhA）的有效包封的纳米颗粒。与HR生物缀合物相比，HFR生物缀合物表现出更高的PhA负载含量和负载效率。负载PHA的HR和HFR纳米颗粒具有约70 nm的平均直径、带负电荷的表面、持续释放模式和在缓冲溶液中的自猝灭效应。此外，在叶酸受体阳性HeLa细胞中，PhA负载的HFR纳米颗粒的细胞摄取高于PhA负载的HR纳米颗粒。在照射后，HFR纳米颗粒选择性地增强了HeLa细胞中PhA的光毒性，而在没有光处理的情况下，纳米颗粒的暗毒性是最小的。HFR纳米颗粒还表现出靶向抗癌作用，在RA浓度≥50μg/mL时，与HR纳米颗粒相比，改善了RA在HeLa细胞中的细胞毒性。在叶酸受体阴性的HT-29细胞中未观察到HFR和PhA负载的HFR纳米颗粒的靶向作用。结果表明，HFR纳米颗粒可用于疏水性PDT药物的靶向递送，并可作为化学和光动力双重治疗的潜在纳米载体。
Amphiphilic heparin-retinoic acid (HR) and heparin-folate-retinoic acid bioconjugates (HFR) were synthesized by chemical conjugation of a hydrophobic anticancer agent all-trans-retinoic acid (RA) and a targeting ligand, folic acid (FA), to the high molecular weight heparin backbone. The HR and HFR bioconjugates had a high RA content (22%, w/w) and could self-assemble into nanoparticles with efficient encapsulation of a hydrophobic photosensitizer, pheophorbide a (PhA). The HFR bioconjugate demonstrated higher PhA loading content and loading efficiency compared to HR bioconjugate. The PhA-loaded HR and HFR nanoparticles had an average diameter of about 70nm, a negatively charged surface, a sustained release pattern and self-quenching effect in a buffered solution. Furthermore, the cellular uptake of PhA-loaded HFR nanoparticles in folate receptor-positive HeLa cells was higher than that of PhA-loaded HR nanoparticles. Upon irradiation, HFR nanoparticles selectively enhanced the phototoxicity of PhA in HeLa cells while the dark-toxicity of the nanoparticles was minimal without light treatment. HFR nanoparticles also demonstrated targeted anti-cancer effect, improving the cytotoxicity of RA in HeLa cells compared to HR nanoparticles at RA concentration ≥50μg/mL. The targeting effect of HFR and PhA-loaded HFR nanoparticles was not observed in folate receptor-negative HT-29 cells. The results indicated that HFR nanoparticles may be useful for targeted delivery of hydrophobic PDT agents and as a potential nanocarrier for dual chemo-and photodynamic therapies.