Tuning core vs. shell dimensions to adjust the performance of nanoscopic containers for the loading and release of doxorubicin.
Tuning core vs. shell dimensions to adjust the performance of nanoscopic containers for the loading and release of doxorubicin.
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DOI：
10.1016/j.jconrel.2011.01.009
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发表时间：
2011-05-30
期刊：
影响因子：
--
通讯作者：
Wooley KL
中科院分区：
文献类型：
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作者：
Lin LY;Lee NS;Zhu J;Nyström AM;Pochan DJ;Dorshow RB;Wooley KL
进行了详细的研究以探测两亲性壳交联的膝状聚合物纳米颗粒（SCKs）的核和壳尺寸对阿霉素（DOX）（一种广泛使用的化疗剂）在水性缓冲液中的负载和释放的影响，作为溶液pH的函数。通过使用由单一类型的两亲性二嵌段共聚物构建的SCKs，聚（丙烯酸）-b-聚苯乙烯（PAA-b-PS）。由具有不同相对嵌段长度和绝对聚合度的四种嵌段共聚物制备数均流体动力学直径范围为14-30 nm的一系列四种SCK纳米颗粒样品。丙烯酸与苯乙烯嵌段长度的比率在0.65至3.0的范围内，得到壳与核体积的比率在0.44至2.1的范围内的SCKs。尽管计算出的外壳厚度（通过透射电子显微镜（TEM）计算为1.5-3.1 nm，通过小角中子散射（SANS）分析为3.5-4.9 nm），两种SCK纳米颗粒具有相对大的核直径（TEM为19 ± 2和20 ± 2 nm; SANS为17.4和15.3 nm），而两种具有相似的较小的核直径（TEM为11 ± 2和13 ± 2 nm; SANS为9.0和8.9 nm）。SCK每个颗粒能够负载1500-9700个DOX分子，较大数量的DOX分子包装在较大的核心SCK内。它们的壳与核体积比显示出对DOX释放速率和程度的影响，其中聚（丙烯酸）壳所占据的体积相对于聚苯乙烯核所占据的体积与DOX的基于扩散的释放成反比。考虑到相同量的聚合物用于构建每个SCK样品，具有较小核和较高丙烯酸与苯乙烯体积比的SCK以比较大核SCK更高的浓度存在，并且给出较低的最终释放程度。对于所有装载DOX的颗粒样品，在pH 5.0相对于pH 7.4下分别观察到较高的最终释放程度和较快的释放速率，约100%。在60小时时，60%对40%，表明有望增强肿瘤和细胞内的递送。通过将数据拟合到Higuchi模型，进行释放动力学的定量测定，在pH 7.4下给出的速率常数范围为0.0431至0.0540 h− 1/2，在pH 5.0下给出的速率常数范围为0.106至0.136 h− 1/2。相比之下，非交联聚合物胶束类似物在pH 7.4和5.0下释放DOX的速率常数分别为0.245和0.278 h-1/2。这些研究指出了未来的方向，以工艺复杂的设备控制药物释放。
Detailed studies were performed to probe the effects of the core and shell dimensions of amphiphilic, shell crosslinked, knedel-like polymer nanoparticles (SCKs) on the loading and release of doxorubicin (DOX), a widely-used chemotherapy agent, in aqueous buffer, as a function of the solution pH. Effects of the nanoparticle composition were held constant, by employing SCKs constructed from a single type of amphiphilic diblock copolymer, poly(acrylic acid)-b-polystyrene (PAA-b-PS). A series of four SCK nanoparticle samples, ranging in number-average hydrodynamic diameter from 14–30 nm, was prepared from four block copolymers having different relative block lengths and absolute degrees of polymerization. The ratios of acrylic acid to styrene block lengths ranged from 0.65 to 3.0, giving SCKs with ratios of shell to core volumes ranging from 0.44 to 2.1. Although the shell thicknesses were calculated to be similar (1.5–3.1 nm by transmission electron microscopy (TEM) calculations and 3.5–4.9 nm by small angle neutron scattering (SANS) analyses), two of the SCK nanoparticles had relatively large core diameters (19 ± 2 and 20 ± 2 nm by TEM; 17.4 and 15.3 nm by SANS), while two had similar, smaller core diameters (11 ± 2 and 13 ± 2 nm by TEM; 9.0 and 8.9 nm by SANS). The SCKs were capable of being loaded with 1500–9700 DOX molecules per each particle, with larger numbers of DOX molecules packaged within the larger core SCKs. Their shell-to-core volume ratio showed impact on the rates and extents of release of DOX, with the volume occupied by the poly(acrylic acid) shell relative to the volume occupied by the polystyrene core correlating inversely with the diffusion-based release of DOX. Given that the same amount of polymer was used to construct each SCK sample, SCKs having smaller cores and higher acrylic acid vs. styrene volume ratios were present at higher concentrations than were the larger core SCKs, and gave lower final extents of release., Higher final extents of release and faster rates of release were observed for all DOX-loaded particle samples at pH 5.0 vs. pH 7.4, respectively, ca. 60% vs. 40% at 60 h, suggesting promise for enhanced delivery within tumors and cells. By fitting the data to the Higuchi model, quantitative determination of the kinetics of release was made, giving rate constants ranging from 0.0431 to 0.0540 h−½ at pH 7.4 and 0.106 to 0.136 h−½ at pH 5.0. In comparison, the non-crosslinked polymer micelle analogs exhibited rate constants for release of DOX of 0.245 and 0.278 h−½ at pH 7.4 and 5.0, respectively. These studies point to future directions to craft sophisticated devices for controlled drug release.