Shin Dae Hwan, Lee Sang-Jin, Kim Jung Seok, Ryu Jae-Ha, Kim Jin-Seok
J Biomed Nanotechnol. 2015 Nov;11(11):1989-2002. doi: 10.1166/jbn.2015.2146.
Glioblastoma stem cells have been shown to confer chemoresistance and radioresistance, leading to angiogenesis and the recurrence of tumors in glioblastoma multiforme. Combination therapy targeting glioblastoma stem cells and anti-angiogenesis has been a focus of treatment strategies because of the enhanced efficacy achieved by dual inhibition of tumor proliferation and nutrient delivery. In this study, glioblastoma stem cells and glioblastoma stem cell-induced angiogenesis in glioblastoma multiforme were challenged by combined treatment with anti-CD133 monoclonal antibody conjugated liposomes encapsulating gemcitabine and bevacizumab. Both liposomal encapsulation and conjugation of an anti-CD133 antibody significantly enhanced the cytotoxicity of gemcitabine toward glioblastoma stem cells in vitro. Moreover, combined treatment with this gemcitabine formulation and bevacizumab significantly inhibited tube formation, migration, and proliferation of endothelial cells in vitro. The antitumor efficacy of immunoliposomal gemcitabine and bevacizumab combination therapy in a xenograft model was significantly greater than that of monotherapy, presumably reflecting the enhanced effects on glioblastoma stem cells themselves and glioblastoma stem cell-induced angiogenesis caused by synergistic interactions between the two drugs. Moreover, combination therapy prolonged the mean survival time of xenografted mice. Taken altogether, our results suggest that combined therapy with immunoliposomal gemcitabine and bevacizumab shows promise for the treatment of glioblastoma multiforme.
胶质母细胞瘤干细胞已被证明具有化学抗性和放射抗性，导致多形性胶质母细胞瘤中出现血管生成和肿瘤复发。由于双重抑制肿瘤增殖和营养供应可提高疗效，针对胶质母细胞瘤干细胞和抗血管生成的联合治疗一直是治疗策略的重点。在本研究中，通过将包裹吉西他滨和贝伐单抗的抗CD133单克隆抗体共轭脂质体联合治疗，对多形性胶质母细胞瘤中的胶质母细胞瘤干细胞和胶质母细胞瘤干细胞诱导的血管生成进行了挑战。脂质体包裹和抗CD133抗体的共轭均显著增强了吉西他滨在体外对胶质母细胞瘤干细胞的细胞毒性。此外，这种吉西他滨制剂与贝伐单抗联合治疗在体外显著抑制了内皮细胞的管形成、迁移和增殖。免疫脂质体吉西他滨和贝伐单抗联合治疗在异种移植模型中的抗肿瘤疗效显著高于单一疗法，这可能反映了对胶质母细胞瘤干细胞本身以及两种药物之间协同相互作用引起的胶质母细胞瘤干细胞诱导的血管生成的增强作用。此外，联合治疗延长了异种移植小鼠的平均生存时间。综上所述，我们的结果表明，免疫脂质体吉西他滨和贝伐单抗联合治疗有望用于多形性胶质母细胞瘤的治疗。
