Key Laboratory of Smart Drug Delivery of MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, School of Pharmacy, Qinghai Nationalities University, Xining 810007, China.
J Control Release. 2020 Nov 10;327:725-736. doi: 10.1016/j.jconrel.2020.09.024. Epub 2020 Sep 15.
The biological fate of polymeric micelles (PMs) following oral administration was investigated in this study to better understand the contribution of transport of integral PMs to oral absorption. To track integral PMs, near-infrared fluorophores with aggregation-caused quenching properties were utilized to label PMs comprised of methoxy poly(ethylene glycol)-poly(D,L-lactic acid) (mPEG-PDLLA) copolymers and methoxy poly(ethylene glycol)-distearoyl phosphoethanolamine (DSPE-PEG). The particle size of PMs prepared from mPEG-PDLLA, mPEG-PDLLA, mPEG-PDLLA, mPEG-PDLLA and DSPE-PEG was 24.5, 29.5, 34.0, 41.4 and 15.6 nm, respectively. After oral administration by gavage to rats, PMs were retained in the gastrointestinal tract for at least 4 h, and the copolymer block chain lengths did not have significant influence. The emergence of fluorescence in the blood and liver served as direct evidence to support oral absorption of integral PMs. Approximately 1-2% of intact particles were absorbed via the lymphatic pathway, but the total amount of PMs that reach the systemic circulation await further elucidation. Confocal laser scanning microscopy added more evidence to support the penetration of integral PMs into the basolateral tissues of microvilli. Cellular uptake efficiency was about 4-7% in Caco-2 cell lines for all PM groups, but was reduced to 1-3% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 6-12% of integral PMs were transported across Caco-2/HT29-MTX/Raji monolayers, whereas only approximately one-tenth of that amount was transported across Caco-2 and Caco-2/HT29-MTX monolayers. Differences, but not statistically significant, were observed between PM groups in lymphatic uptake, biodistribution, cellular uptake and trans-monolayer transport, possibly owing to difference in block chain lengths as well as particle size. In conclusion, evidence obtained in this study supports penetration of integral PMs across the enteric epithelia, but the total amount may be limited.
本研究旨在探讨口服给药后聚合物胶束（PMs）的生物命运，以更好地了解完整 PMs 的转运对口服吸收的贡献。为了跟踪完整的 PMs，本研究利用具有聚集诱导猝灭特性的近红外荧光团标记由甲氧基聚（乙二醇）-聚（D，L-乳酸）（mPEG-PDLLA）共聚物和甲氧基聚（乙二醇）-二硬脂酰基磷脂酰乙醇胺（DSPE-PEG）组成的 PMs。由 mPEG-PDLLA、mPEG-PDLLA、mPEG-PDLLA、mPEG-PDLLA 和 DSPE-PEG 制备的 PMs 的粒径分别为 24.5、29.5、34.0、41.4 和 15.6nm。经灌胃给予大鼠后，PMs 在胃肠道中至少保留 4h，共聚物嵌段链长无显著影响。血液和肝脏中荧光的出现为完整 PMs 经口吸收提供了直接证据。约 1-2%的完整颗粒通过淋巴途径吸收，但到达体循环的 PMs 总量有待进一步阐明。共聚焦激光扫描显微镜提供了更多证据支持完整 PMs 穿透微绒毛的基底外侧组织。所有 PM 组在 Caco-2 细胞系中的细胞摄取效率约为 4-7%，但在 Caco-2/HT29-MTX 共培养模型中由于黏液层的阻碍降至 1-3%。约 6-12%的完整 PMs 穿过 Caco-2/HT29-MTX/Raji 单层转运，而穿过 Caco-2 和 Caco-2/HT29-MTX 单层的数量约为其十分之一。淋巴摄取、生物分布、细胞摄取和跨单层转运方面，PM 组之间存在差异，但无统计学意义，这可能是由于嵌段链长和粒径的差异所致。总之，本研究获得的证据支持完整 PMs 穿透肠上皮，但总量可能有限。
