Zhu Xun, Lu Lichun, Currier Bradford L, Windebank Anthony J, Yaszemski Michael J
Department of Orthopedic Surgery and Bioengineering, Mayo Clinic, Rochester, MN 55905, USA.
Biomaterials. 2002 Jul;23(13):2683-92. doi: 10.1016/s0142-9612(01)00409-4.
The objective of this study was to evaluate a poly(DL-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) delivery system for nuclear factor-kappa B (NFkappaB) decoy phosphorothioated oligonucleotides (ODNs). PLGA/PEG microparticles loaded with ODNs were fabricated with entrapment efficiencies up to 70%. The effects of PEG contents (0, 5, and l0 wt%), ODN loading densities (0.4, 4, and 40 microg/mg), and pH of the incubation medium (pH 5, 7.4. and 10) on ODN release kinetics from the PLGA/PEG microparticles were investigated in vitro for up to 28 days. The release profiles in pH 7.4 phosphate buffered saline (PBS) were characterized by an initial burst during the first 2 days, a linear release phase until day 18, and a final release phase for the rest of the period. Up to 85% of the ODNs were released after 28 days in pH 7.4 PBS regardless of the ODN loading density and PEG content. Higher ODN loading densities resulted in lower entrapment efficiencies and greater initial burst effects. The bulk degradation of PLGA was not significantly affected by the PEG content and ODN loading density, but significantly accelerated at acidic buffer pH. Under acidic and basic conditions, the aggregation of microparticles resulted in significantly lower cumulative mass of released ODNs than that released at neutral pH. The effects of pH were reduced by the incorporation of PEG into PLGA microparticles. Since the PLGA degradation products are acidic, PLGA/PEG microparticles might provide a better ODN delivery vehicle than PLGA microparticles. These results suggest that PLGA/PEG microparticles are useful as delivery vehicles for controlled release of ODNs and merit further investigation in cell culture and animal models of glioblastoma.
本研究的目的是评估一种用于核因子-κB（NFκB）诱饵硫代磷酸化寡核苷酸（ODN）的聚（DL-乳酸-共-乙醇酸）/聚（乙二醇）（PLGA/PEG）递送系统。制备了负载ODN的PLGA/PEG微粒，包封率高达70%。体外研究了聚乙二醇（PEG）含量（0、5和10 wt%）、ODN负载密度（0.4、4和40 μg/mg）以及孵育介质的pH值（pH 5、7.4和10）对PLGA/PEG微粒中ODN释放动力学的影响，长达28天。pH 7.4磷酸盐缓冲盐水（PBS）中的释放曲线特征为：前2天有初始突释，直到第18天为线性释放阶段，之后为最终释放阶段。在pH 7.4 PBS中，无论ODN负载密度和PEG含量如何，28天后高达85%的ODN会释放出来。较高的ODN负载密度导致较低的包封率和更大的初始突释效应。PLGA的本体降解不受PEG含量和ODN负载密度的显著影响，但在酸性缓冲液pH下会显著加速。在酸性和碱性条件下，微粒的聚集导致释放的ODN累积质量显著低于中性pH下释放的质量。将PEG掺入PLGA微粒中可降低pH的影响。由于PLGA降解产物呈酸性，PLGA/PEG微粒可能比PLGA微粒提供更好的ODN递送载体。这些结果表明，PLGA/PEG微粒可作为ODN控释的递送载体，值得在胶质母细胞瘤的细胞培养和动物模型中进一步研究。
