Guo Xiaonan, Zhu Xiaoshuang, Liu Dakan, Gong Yubin, Sun Jing, Dong Changxian
Department of Hemangioma and Vascular Malformation, Henan Provincial People's Hospital, Zhengzhou, People's Republic of China.
Department of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
Int J Nanomedicine. 2017 Sep 18;12:6923-6936. doi: 10.2147/IJN.S137634. eCollection 2017.
To reduce the adverse effects and high frequency of administration of propranolol to treat infantile hemangioma, we first utilized propranolol-loaded liposomes-in-microsphere (PLIM) as a novel topical release system to realize sustained release of propranolol.
PLIM was developed from encapsulating propranolol-loaded liposomes (PLs) in microspheres made of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymers (PLGA-PEG-PLGA). The release profile of propranolol from PLIM was evaluated, and its biological activity was investigated in vitro using proliferation assays on hemangioma stem cells (HemSCs). Tumor inhibition was studied in nude mice bearing human subcutaneous infantile hemangioma.
The microspheres were of desired particle size (77.8 μm) and drug encapsulation efficiency (23.9%) and achieved sustained drug release for 40 days. PLIM exerted efficient inhibition of the proliferation of HemSCs and significantly reduced the expression of two angiogenesis factors (vascular endothelial growth factor-A [VEGF-A] and basic fibroblast growth factor [bFGF]) in HemSCs. Notably, the therapeutic effect of PLIM in hemangioma was superior to that of propranolol and PL in vivo, as reflected by significantly reduced hemangioma volume, weight, and microvessel density. The mean hemangioma weight of the PLIM-treated group was significantly lower than that of other groups (saline =0.28 g, propranolol =0.21 g, PL =0.13 g, PLIM =0.03 g; PLIM vs saline: <0.001, PLIM vs propranolol: <0.001, PLIM vs PL: <0.001). The mean microvessel density of the PLIM-treated group was significantly lower than that of other groups (saline =40 vessels/mm, propranolol =31 vessels/mm, PL =25 vessels/mm, PLIM =11 vessels/mm; PLIM vs saline: <0.001, PLIM vs propranolol: <0.01, PLIM vs PL: <0.05).
Our findings show that PLIM is a very promising approach to locally and efficiently deliver propranolol to the hemangioma site leading to a significant inhibition of infantile hemangioma.
为了减少普萘洛尔治疗婴儿血管瘤时的不良反应及高给药频率，我们首次将载普萘洛尔脂质体微球（PLIM）作为一种新型局部释放系统来实现普萘洛尔的持续释放。
通过将载普萘洛尔脂质体（PLs）包裹于由聚（乳酸-共-乙醇酸）-b-聚（乙二醇）-b-聚（乳酸-共-乙醇酸）共聚物（PLGA-PEG-PLGA）制成的微球中制备PLIM。评估了普萘洛尔从PLIM中的释放曲线，并使用血管瘤干细胞（HemSCs）增殖试验在体外研究了其生物活性。在荷人皮下婴儿血管瘤的裸鼠中研究了肿瘤抑制作用。
微球具有所需的粒径（约77.8μm）和药物包封效率（约23.9%），并实现了40天的药物持续释放。PLIM有效抑制了HemSCs的增殖，并显著降低了HemSCs中两种血管生成因子（血管内皮生长因子-A [VEGF-A]和碱性成纤维细胞生长因子 [bFGF]）的表达。值得注意的是，PLIM在血管瘤中的治疗效果在体内优于普萘洛尔和PL，这表现为血管瘤体积、重量和微血管密度显著降低。PLIM治疗组的平均血管瘤重量显著低于其他组（生理盐水组 =0.28 g，普萘洛尔组 =0.21 g，PL组 =0.13 g，PLIM组 =0.03 g；PLIM组与生理盐水组比较：<0.001，PLIM组与普萘洛尔组比较：<0.001，PLIM组与PL组比较：<0.001）。PLIM治疗组的平均微血管密度显著低于其他组（生理盐水组 =40个血管/mm，普萘洛尔组 =31个血管/mm，PL组 =25个血管/mm，PLIM组 =11个血管/mm；PLIM组与生理盐水组比较：<0.001，PLIM组与普萘洛尔组比较：<0.01，PLIM组与PL组比较：<0.05）。
我们的研究结果表明，PLIM是一种非常有前景的方法，可将普萘洛尔局部有效地递送至血管瘤部位，从而显著抑制婴儿血管瘤。
