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Abstract
Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of ‘platelets with ultrasound-triggered release property’, which takes advantage of 1) the platelets’ ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.
Author contributions statement
Conception and design: MYW and XC; Methodology: MYW, HZX, TFL and SYC; Analysis and interpretation of the data: KL, QZ and LZ; The drafting of the paper: MYW and XC; Revising it critically for intellectual content: MYW, JCC and XC; Experimental planning, data interpretation and manuscript review: JCC and XC; The final approval of the version to be published: ALL. All authors agree to be accountable for all aspects of the work.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Disclosure statement
No potential conflict of interest was reported by the authors.
Ethical approval statement
Animal handling and experimental procedures were in line with protocols approved by the Ethics Committee of Experimental Animal Welfare of Zhongnan Hospital of Wuhan University (Approval Document No.: ZN2021233). To validate the in vitro results, we replicated intracranial glioblastoma grafts of U87-MG cells in mice. Female Balb/c nude mice at 4–5 weeks of age (15-20 g) were obtained from Hunan SJA Laboratory Animal CO., LTD (Hunan, China) and were fed on standard diets and water at a temperature of 18–25 °C and 60–65% humidity before experiments. Intracranial glioblastoma models were established in mice under nembutal anesthesia. The ARRIVE criteria were followed in all animal experiments. Human platelets (Plt) were isolated from Peripheral venous blood in healthy volunteers with informed consent and the collection of blood samples conforms to the agreement approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (Approval Document No.: Kelun [2022042K]).