Photo-controlled co-delivery of verteporfin and acriflavine via platelets achieves potentiated glioblastoma-targeted photodynamic therapy

The potential of glioblastoma (GBM) photodynamic therapy (PDT) is limited by inadequate GBM drug delivery, and the development of resistance to PDT as a result of cellular damage response that critically involves the hypoxia-inducible factor-1α (HIF-1α) and yes-associated protein (YAP). Herein, addressing these challenges, we demonstrated a strategy of photo-controlled, targeted co-delivery of verteporfin (Vp), a photosensitizer and YAP inhibitor as well, and acriflavine (Af), a HIF-1α inhibitor via platelets for enhanced GBM PDT. Mouse platelets were separately loaded with Vp (Vp@Plt) and Af (Af@Plt) and the mixture thereof is termed Vp@Plt + Af@Plt. Alternatively, platelets were simultaneously loaded with Vp and Af to yield (Vp + Af)@Plt. First, both Vp@Plt + Af@Plt and (Vp + Af)@Plt were shown to achieve rapid and efficient laser-triggered, GBM-targeted delivery of Vp and Af, which led to markedly higher phototoxicity in the GBM cells (GBCs) and ultimately more potent GBM PDT than Vp@Plt in mice. Next, a mechanistic study revealed the induction of a mutually promotional interaction of HIF-1α and YAP in the GBCs in response to PDT-inflicted DNA damage. This interaction protected HIF-1α from degradation and meanwhile assisted in the nuclear translocation of YAP leading to increased nuclear presence of both HIF-1α and YAP and escalated DNA damage repair activity under their regulation. Both Af and Vp were found to block the PDT-induced HIF-1α-YAP interaction and thereby severely impaired DNA damage repair, eventually resulting in exacerbated cell death. In conclusion, Af and Vp can be adequately co-delivered in GBM via platelets in a photo-controlled manner to achieve efficacious GBM PDT through double blocking of the HIF-1α-YAP interaction in the GBCs.