Dufes Christine, Muller Jean-Marc, Couet William, Olivier Jean-Christophe, Uchegbu Ijeoma F, Schätzlein Andreas G
Laboratoire de Biologie des Interactions Cellulaires, CNRS UMR 6558, Faculté des Sciences, Poitiers, France.
Pharm Res. 2004 Jan;21(1):101-7. doi: 10.1023/b:pham.0000012156.65125.01.
The study reports the initial biological evaluation of targeted polymeric glycol chitosan vesicles as carrier systems for doxorubicin (Dox).
Transferrin (Tf) was covalently bound to the Dox-loaded palmitoylated glycol chitosan (GCP) vesicles using dimethylsuberimidate (DMSI). For comparison, glucose targeted niosomes were prepared using N-palmitoyl glucosamine. Biological properties were studied using confocal microscopy, flow cytometry, and cytotoxicity assays as well as a mouse xenograft model.
Tf vesicles were taken up rapidly with a plateau after 1-2 h and Dox reached the nucleus after 60-90 min. Uptake was not increased with the use of glucose ligands, but higher uptake and increased cytotoxicity were observed for Tf targeted as compared to GCP Dox alone. In the drug-resistant A2780AD cells and in A431 cells, the relative increase in activity was significantly higher for the Tf-GCP vesicles than would have been expected from the uptake studies. All vesicle formulations had a superior in vivo safety profile compared to the free drug.
The in vitro advantage of targeted Tf vesicles did not translate into a therapeutic advantage in vivo. All vesicles reduced tumor size on day 2 but were overall less active than the free drug.
本研究报告了靶向聚合物糖基化壳聚糖囊泡作为阿霉素（Dox）载体系统的初步生物学评价。
使用辛二酸二甲酯（DMSI）将转铁蛋白（Tf）共价结合到负载阿霉素的棕榈酰化糖基化壳聚糖（GCP）囊泡上。作为对照，使用N-棕榈酰葡萄糖胺制备葡萄糖靶向脂质体。使用共聚焦显微镜、流式细胞术、细胞毒性测定以及小鼠异种移植模型研究生物学特性。
Tf囊泡在1-2小时后迅速摄取并达到平台期，阿霉素在60-90分钟后到达细胞核。使用葡萄糖配体并未增加摄取，但与单独的GCP阿霉素相比，Tf靶向的摄取更高且细胞毒性增加。在耐药的A2780AD细胞和A431细胞中，Tf-GCP囊泡的活性相对增加明显高于摄取研究预期。与游离药物相比，所有囊泡制剂在体内均具有更好的安全性。
靶向Tf囊泡的体外优势并未转化为体内治疗优势。所有囊泡在第2天均减小了肿瘤大小，但总体活性低于游离药物。
