Sorafenib在近期的研究已被證實是一個具有潛在抗纖維化試劑的一種酪胺酸激酶抑制劑。然而，sorafenib本身的狹窄治療窗口限制了其在臨床上的應用以及治療功效。因此，我們利用聚乙二醇-聚乳酸聚乙醇酸(PEG-PLGA)共聚物以及聚乳酸聚乙醇酸(PLGA)的混合物開發及最優化的奈米粒子輸送sorafenib於利用四氯化碳誘導肝纖維化小鼠模型。我們比較了兩種不同的PLGA奈米粒子的藥物以及生物學的特性：PEG-PLGA奈米粒子(PEG-PLGA / PLGA = 10/0)和PEG-PLGA / PLGA奈米粒子(PEG-PLGA / PLGA = 5/5 )。增加PLGA在PEG-PLGA/PLGA中的含量會導致奈米粒子的大小增加、增加藥物包覆率以及降低藥物釋放速率。兩種奈米粒子皆可以顯著的延長血液中藥物濃度，並且增加了纖維化肝臟組織的吸收。透過包覆sorafenib的PEG-PLGA和PEG-PLGA/PLGA每週兩次，為期四週的全身性用藥治療，可以降低的α-平滑肌肌動蛋白表現量以及減少膠原蛋白的沉積，顯示出能有效的改善於四氯化碳誘導肝纖維化小鼠的纖維化肝臟。除此之外，包覆sorafenib之PLGA奈子粒子可以顯著的縮小異常微血管半徑，降低微血管密度，使纖維化肝臟的血管趨於正常化。總結來說，我們的研究結果顯示包覆sorafenib的PLGA奈子粒子對於肝纖維化的預防與治療的臨床潛力。

Sorafenib, a tyrosine kinase inhibitor, has been shown as a potential antifibrotic agent. However, a narrow therapeutic window limits its clinical use and therapeutic efficacy of sorafenib. Herein we have developed and designed a drug delivery system - nanoparticle (NP) formulations prepared from mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) as a vehicle to deliver sorafenib into fibrotic livers of CCl4-induced fibrosis mouse model. We characterized and compared pharmaceutical and biological properties of two different PLGA nanoparticles: PEG-PLGA (PEG-PLGA/PLGA = 10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA = 5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density, leading to vessel normalization in the fibrotic livers. In conclusion, our results support the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.

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