Monoclonal Antibody-conjugated Polyphosphoester-hyd-DOX Prodrug Nanoparticles for Targeted Chemotherapy of Liver Cancer Cells
Monoclonal Antibody-conjugated Polyphosphoester-hyd-DOX Prodrug Nanoparticles for Targeted Chemotherapy of Liver Cancer Cells
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DOI：
10.1007/s10118-021-2582-3
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发表时间：
2021-06-25
影响因子：
4.3
通讯作者：
Ni, Pei-Hong
中科院分区：
文献类型：
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作者：
Huang, Ya-Kui;Tian, Hong-Rui;Ni, Pei-Hong
为了克服传统活性纳米治疗药物在肿瘤靶向效率上的局限性，在体内不能达到足够数量的受体/靶点，在本工作中，我们开发了单克隆抗体（mAb）和聚合物-羟基阿霉素前药偶联物，使自组装的纳米颗粒具有精确靶向、肿瘤组织聚集和ph敏感的药物释放。我们首先通过开环聚合（ROP）和“点击”化学相结合的方法制备了一种两亲性聚合物前药，简称H2N-PEEP-b-PBYP-hyd-DOX，其中PEEP和PBYP代表两种磷酸段，-hyd-是腙键。自组装成直径约93 nm的前药纳米颗粒（PDNPs）后，通过EDC/NHS化学将CD147单抗偶联到PDNPs上，形成单抗-PDNPs。对于PDNPs和单抗-PDNPs，我们还研究了它们的稳定性、体外药物释放行为和细胞摄取。结果表明，ph响应的PDNPs在pb7.4缓冲溶液条件下保持相对稳定。然而，在酸性条件下或在磷酸二酯酶I （PDE I）存在的情况下，DOX的释放量和速度在相同的孵育期内都有所增加。细胞毒试验表明，单克隆抗体-PDNPs对HepG2细胞的IC50为1.12 mg中心点L-1，高于无单克隆抗体的PDNPs （IC50为2.62 mg中心点L-1）。含有抗体mAb- pdnps的纳米颗粒具有相对较好的稳定性，可以直接通过CD147 mAb实现靶向给药。
In order to overcome the limitation of traditional active nano-therapeutic drugs on tumor targeting efficiency which cannot reach the receptor/target in sufficient amount in the body, in this work, we developed a monoclonal antibody (mAb) and a polymer-hyd-doxorubicin prodrug conjugate, which enables the self-assembled nanoparticles to have precise targeting, tumor tissue aggregation and pH-sensitive drug release. We first prepared an amphiphilic polymer prodrug, abbreviated as H2N-PEEP-b-PBYP-hyd-DOX, via a combination of ring-opening polymerization (ROP) and "click" chemistry, in which PEEP and PBYP represent two kinds of phosphoester segmemts, -hyd- is hydrazone bond. After self-assembly into prodrug nanoparticles (PDNPs) with a diameter of about 93 nm, CD147 mAb was conjugated onto the PDNPs by EDC/NHS chemistry to form mAb-PDNPs. For the PDNPs and mAb-PDNPs, we also investigated their stability, in vitro drug release behavior and cellular uptake. The results showed that the pH-responsive PDNPs can remain relatively stable under the condition of PB 7.4 buffer solution. However, under acidic conditions or in the presence of phosphodiesterase I (PDE I), both the amount and rate of DOX release increased at the same incubation period. Cytotoxicity assay showed that mAb-PDNPs exhibited higher cytotoxicity (IC50: 1.12 mg center dot L-1) against HepG2 cells than PDNPs (IC50: 2.62 mg center dot L-1) without monoclonal antibody. The nanoparticles with antibodies mAb-PDNPs have relatively better stability and can directly achieve the targeting drug delivery through CD147 mAb.