Pulmonary Delivery of Extracellular Vesicle-Encapsulated Dinaciclib as an Effective Lung Cancer Therapy.

Abstract

Simple SummaryThe clinical outcomes of lung cancer remain poor. The targeted delivery of treatment and the implementation of a method to overcome drug resistance are essential for the improvement of cancer therapy. The aim of our study was to assess the treatment effectiveness of engineered extracellular vesicles (EV) carrying both dinaciclib, a potent CDK inhibitor, and the proapoptotic factor TRAIL for a combinatorial lung cancer therapy. We showed that the engineered complexed EV agent, EV-T-Dina, was stable both in vitro and in vivo. Importantly, EV-T-Dina can overcome the drug-resistance of lung cancer cells, and when nebulized and administered by the pulmonary route, it demonstrated high efficacy and satisfactory safety for the treatment of lung cancers. The underlying mechanism for the synergistic killing of cancer cells by dinaciclib and TRAIL was associated with the concomitant downregulation of the anti-apoptotic factors cFLIP, MCL-1, and Survivin. Thus, the aerosolized EV-T-Dina potentially constitutes a novel and effective therapy for lung cancers.The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the killing of cancer cells with the potent cyclin-dependent kinase (CDK) inhibitor Dinaciclib (Dina). However, both optimal drug formulations and delivery strategies are yet to be established to facilitate the clinical application of the combination of EV-T and Dina. We hypothesize that Dina can be encapsulated into EV-T to produce a complexed formulation, designated EV-T-Dina, which can be nebulized for pulmonary delivery to treat lung cancer with potentially improved efficacy and safety. The prepared EV-T-Dina shows good stability both in vitro and in vivo and is very efficient at killing two highly TRAIL-resistant cancer lines. The ability to overcome TRAIL resistance is associated with the concomitant downregulation of the expression of cFLIP, MCL-1, and Survivin by Dina. The EV-T-Dina solution is nebulized for inhalation, showing unique deposition in animal lungs and importantly it demonstrates a significant suppression of the growth of orthotopic A549 tumors without any detectable adverse side events. In conclusion, the aerosolized EV-T-Dina constitutes a novel therapy, which is highly effective and safe for the treatment of lung cancers.