He Xuezhong, Ma Junyu, Mercado Angel E, Xu Weijie, Jabbari Esmaiel
Biomimetic Materials and Tissue Engineering Laboratories, Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina, 29208, USA.
Pharm Res. 2008 Jul;25(7):1552-62. doi: 10.1007/s11095-007-9513-z. Epub 2008 Jan 15.
Biodegradable core-shell polymeric nanoparticles (NPs), with a hydrophobic core and hydrophilic shell, are developed for surfactant-free encapsulation and delivery of Paclitaxel to tumor cells.
Poly (lactide-co-glycolide fumarate) (PLGF) and Poly (lactide-fumarate) (PLAF) were synthesized by condensation polymerization of ultra-low molecular weight poly(L: -lactide-co-glycolide) (ULMW PLGA) with fumaryl chloride (FuCl). Similarly, poly(lactide-co-ethylene oxide fumarate) (PLEOF) macromer was synthesized by reacting ultra-low molecular weight poly(L: -lactide) (ULMW PLA) and PEG with FuCl. The blend PLGF/PLEOF and PLAF/PLEOF macromers were self-assembled into NPs by dialysis. The NPs were characterized with respect to particle size distribution, morphology, and loading efficiency. The physical state and miscibility of Paclitaxel in NPs were characterized by differential scanning calorimetry. Tumor cell uptake and cytotoxicity of Paclitaxel loaded NPs were measured by incubation with HCT116 human colon carcinoma cells. The distribution of NPs in vivo was assessed with Apc(Min/+)mouse using infrared imaging.
PLEOF macromer, due to its amphiphilic nature, acted as a surface active agent in the process of self-assembly which produced core-shell NPs with PLGF/PLAF and PLEOF macromers as the core and shell, respectively. The encapsulation efficiency ranged from 70 to 56% and it was independent of the macromer but decreased with increasing concentration of Paclitaxel. Most of the PLGF and PLAF NPs degraded in 15 and 28 days, respectively, which demonstrated that the release was dominated by hydrolytic degradation and erosion of the matrix. As the concentration of Paclitaxel was increased from 0 to 10, and 40 mug/ml, the viability of HCT116 cells incubated with free Paclitaxel decreased from 100 to 65 and 40%, respectively, while those encapsulated in PLGF/PLEOF NPs decreased from 93 to 54 and 28%.
Groups with Paclitaxel loaded NPs had higher cytotoxicity compared to Paclitaxel directly added to the media at the same concentration. NPs acted as reservoirs to protect the drug from epimerization and hydrolysis while providing a sustained dose of Paclitaxel with time. Infrared image of the Apc(Min/+) mouse injected with NPs showed significantly higher concentration of NPs in the intestinal tissue.
开发具有疏水核心和亲水外壳的可生物降解核壳聚合物纳米颗粒（NPs），用于在无表面活性剂的情况下将紫杉醇包封并递送至肿瘤细胞。
通过超低分子量聚（L-丙交酯-共-乙交酯）（ULMW PLGA）与富马酰氯（FuCl）的缩聚反应合成聚（丙交酯-共-乙交酯富马酸酯）（PLGF）和聚（丙交酯-富马酸酯）（PLAF）。同样，通过使超低分子量聚（L-丙交酯）（ULMW PLA）和聚乙二醇（PEG）与FuCl反应合成聚（丙交酯-共-环氧乙烷富马酸酯）（PLEOF）大分子单体。PLGF/PLEOF和PLAF/PLEOF大分子单体的共混物通过透析自组装成纳米颗粒。对纳米颗粒的粒径分布、形态和负载效率进行了表征。通过差示扫描量热法表征紫杉醇在纳米颗粒中的物理状态和混溶性。通过与HCT116人结肠癌细胞孵育来测量负载紫杉醇的纳米颗粒的肿瘤细胞摄取和细胞毒性。使用红外成像评估Apc(Min/+)小鼠体内纳米颗粒的分布。
由于其两亲性，PLEOF大分子单体在自组装过程中充当表面活性剂，分别产生以PLGF/PLAF和PLEOF大分子单体为核心和外壳的核壳纳米颗粒。包封效率在70%至56%之间，且与大分子单体无关，但随紫杉醇浓度的增加而降低。大多数PLGF和PLAF纳米颗粒分别在15天和28天内降解，这表明释放主要由基质的水解降解和侵蚀主导。随着紫杉醇浓度从0增加到10和40μg/ml，与游离紫杉醇孵育的HCT116细胞的活力分别从100%降至65%和40%，而包封在PLGF/PLEOF纳米颗粒中的细胞活力从93%降至54%和28%。
与以相同浓度直接添加到培养基中的紫杉醇相比，负载紫杉醇的纳米颗粒组具有更高的细胞毒性。纳米颗粒充当储存库，保护药物免受差向异构化和水解，同时随着时间提供持续剂量的紫杉醇。注射纳米颗粒的Apc(Min/+)小鼠的红外图像显示肠道组织中纳米颗粒的浓度明显更高。
