Laboratory of Oncology, G. Gaslini Institute, Genoa, Italy.
J Pharm Pharmacol. 2012 Feb;64(2):228-36. doi: 10.1111/j.2042-7158.2011.01403.x. Epub 2011 Nov 18.
The major limitation to successful chemotherapy of neuroblastoma (NB) is the toxicity and the poor bioavailability of traditional drugs.
We synthesised an amphiphilic dextrin derivative (DX-OL) able to host fenretinide (4-HPR) by complexation. In this study, we have investigated the effects of 4-HPR-loaded amphipilic dextrin (DX-OL/4-HPR) in comparison with 4-HPR alone both in vitro on human NB cells and in vivo in pseudometastatic NB models. The haemolysis assay was used as a measure of the potential damage caused by the pharmaceutical formulation in vivo. Pharmacokinetic experiments were performed to assess drug plasma levels in mice treated with free or complexed 4-HPR.
DX-OL/4-HPR exerted a more potent cytotoxic activity on NB cells. Complexed 4-HPR significantly increased the proportion of sub-G1 cells with respect to free 4-HPR. Dextrin derivatives showed no haemolytic activity, indicating their suitability for parenteral administration. DX-OL/4-HPR increased the lifespan and the long-term survival of treated mice over controls. The analysis of drug plasma levels indicates that the complexed drug has a higher AUC due to a reduced clearance from the blood.
Our data suggest that DX-OL/4-HPR is an injectable formulation that is able to improve drug aqueous solubility and bioavailability.
神经母细胞瘤（NB）化疗成功的主要限制因素是传统药物的毒性和生物利用度差。
我们合成了一种两亲性糊精衍生物（DX-OL），能够通过络合作用容纳芬维 A 酯（4-HPR）。在这项研究中，我们研究了负载 4-HPR 的两亲性糊精（DX-OL/4-HPR）与单独的 4-HPR 相比在体外对人 NB 细胞和体内假转移性 NB 模型中的作用。溶血试验被用作衡量药物制剂在体内潜在损伤的指标。进行药代动力学实验以评估用游离或复合 4-HPR 治疗的小鼠中的药物血浆水平。
DX-OL/4-HPR 对 NB 细胞表现出更强的细胞毒性作用。与游离 4-HPR 相比，复合 4-HPR 显著增加了亚 G1 期细胞的比例。糊精衍生物没有溶血活性，表明它们适合于肠胃外给药。DX-OL/4-HPR 增加了治疗小鼠的寿命和长期存活率，超过了对照组。药物血浆水平的分析表明，由于从血液中清除减少，复合药物具有更高的 AUC。
我们的数据表明，DX-OL/4-HPR 是一种可注射制剂，能够提高药物的水溶解度和生物利用度。
