The effect of transferrin-targeted, resveratrol-loaded liposomes on neurosphere cultures of glioblastoma: Implications for targeting tumor-initiating cells.

Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor-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 tumor relapse. Resveratrol, (RES) has shown chemopreventive effects in all the major stages of cancer including initiation, promotion and progression, but poor physico-chemical 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 tumor cells and TICs in GBMs. Since both these sub-populations of cells are known to over-express transferrin receptors, we developed transferrin-targeted RES-L (Tf-RES-L) to enhance tumor-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.