a Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine , Northeastern University , Boston , MA , USA.
J Drug Target. 2019 Jun-Jul;27(5-6):601-613. doi: 10.1080/1061186X.2018.1550647. Epub 2018 Dec 4.
Glioblastomas (GBMs) are known to harbour subsets of cells known as tumour-initiating cells (TICs), which are responsible for the maintenance, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on rapidly dividing cells, sparing the TICs and result in tumour relapse. Resveratrol (RES) has shown chemopreventive effects in all the major stages of cancer including initiation, promotion and progression, but poor physicochemical and pharmacokinetic properties limit its use as a free drug. Hence we developed a liposomal formulation of RES (RES-L) to eradicate both the bulk tumour cells and TICs in GBMs. Since both these subpopulations of cells are known to over-express transferrin receptors, we developed transferrin-targeted RES-L (Tf-RES-L) to enhance tumour-specific delivery. We studied the effects of RES on neurospheres (NS) used as an in vitro model to study TICs derived from GBM cell lines. Free RES and RES formulations inhibited the anchorage-independent growth of GBM neurospheres. The NS-derived cells expressed TfRs and the Tf-targeted liposomes showed a significantly higher association with NS versus the non-targeted liposomes. Finally an increased activation of caspases 3/7 was seen when NS were treated with RES formulations. Together, these studies advocate for further investigations with RES-L and the use Tf to target the TIC populations.
胶质母细胞瘤（GBM）已知含有称为肿瘤起始细胞（TIC）的细胞亚群，这些细胞负责 GBM 的维持、侵袭和复发。传统的化疗药物作用于快速分裂的细胞，而 TIC 则得以幸免，导致肿瘤复发。白藜芦醇（RES）在癌症的所有主要阶段（包括起始、促进和进展）都表现出化学预防作用，但较差的物理化学和药代动力学特性限制了其作为游离药物的应用。因此，我们开发了 RES 的脂质体制剂（RES-L），以根除 GBM 中的大量肿瘤细胞和 TIC。由于这两种细胞亚群都已知过度表达转铁蛋白受体，因此我们开发了转铁蛋白靶向 RES-L（Tf-RES-L）以增强肿瘤特异性递送。我们研究了 RES 对神经球（NS）的影响，神经球被用作研究源自 GBM 细胞系的 TIC 的体外模型。游离 RES 和 RES 制剂抑制了 GBM 神经球的无锚定生长。NS 衍生的细胞表达 TfRs，并且与非靶向脂质体相比，靶向 Tf 的脂质体与 NS 具有更高的相关性。最后，当 NS 用 RES 制剂处理时，观察到 caspase 3/7 的激活增加。总之，这些研究提倡对 RES-L 进行进一步研究，并使用 Tf 来靶向 TIC 群体。
