Prostate cancer is the second most common form of cancer in men with 1.28 million cases diagnosed worldwide in 2018 [1]. Since the introduction of prostate specific antigen (PSA) testing, the vast majority of cases are diagnosed early when the disease is localised to the prostate [2]. In this setting, the most common treatment options are radical prostatectomy or external beam radiotherapy (EBRT). EBRT is associated with excellent cure rates but biochemical recurrence still occurs in 10–30 % of patients [3], [4]. For patients with recurrent disease, androgen deprivation therapy (ADT) is often used as a salvage treatment but is associated with considerable genitourinary morbidities [5]. Indeed, prolonged ADT treatment also results in the development of androgen resistant prostate cancer [6].

Due to the success of EBRT and ADT in the treatment of prostate cancer, cytotoxic chemotherapy is generally only administered for patients with advanced disease. Initially the benefits of docetaxel were confined to metastatic castration resistant prostate cancer (mCRPC) however, results from the STAMPEDE and other trials have revealed that patients with high risk locally advanced or metastatic castration sensitive prostate cancer treated concurrently with ADT and docetaxel (DTX) chemotherapy, had a significantly improved overall survival compared to patients treated with ADT alone [7]. Unfortunately, this improvement in survival was accompanied by a 20 % increase in grade 3–5 adverse events highlighting the need for more targeted treatments that are better tolerated.

Photodynamic therapy (PDT) is a targeted therapy that has also been tested as a treatment for prostate cancer [8]. PDT involves the activation of an otherwise non-toxic sensitizer drug with light in the presence of molecular oxygen to produce cytotoxic levels of reactive oxygen species (ROS). However, the inability of light to penetrate deeply into human tissue has restricted the use of PDT to superficial lesions that are easily accessed by conventional light sources [9], [10]. Sonodynamic therapy (SDT) has emerged as an alternative to PDT and uses low-intensity ultrasound instead of light to activate the sensitizer [11]. SDT has the benefit that ultrasound is a widely used imaging modality and, unlike light, can penetrate tens of centimeters into soft tissue [12]. We have previously demonstrated that combining SDT with gemcitabine chemotherapy was more effective at controlling the growth of pancreatic tumours in murine models, than either SDT or gemcitabine treatment alone [13]. By using ultrasound responsive microbubbles to deliver the combination treatment, the improved efficacy was achieved using an 80-fold lower chemotherapy dose, meaning the treatment was also well tolerated. Microbubbles (MB) are micron-scale phospholipid, polymer, or protein stabilized gas-filled particles (1–10 µm) that have gained widespread clinical use as ultrasound contrast agents [13]. At the intensities used in diagnostic ultrasound applications, the MBs oscillate symmetrically in a process known as stable cavitation. At higher ultrasound intensities, but still well within levels considered safe for use in humans, the MBs undergo inertial cavitation and rupture, shedding their shell fragments at the site of MB destruction [14]. If drugs are attached to, or encapsulated within the MBs and the ultrasound stimulus is focused on the target of interest (i.e. a tumour), inertial cavitation can facilitate targeted drug delivery [15].

In this manuscript, we report the development of a single MB formulation carrying DTX and Rose Bengal (DTX-MB-RB) for the ultrasound targeted chemo-sonodynamic therapy treatment of prostate cancer. Treatment efficacy was determined in 3D spheroid and murine models of androgen sensitive and androgen resistant prostate cancer. To the best of our knowledge, this is the first report of UTMD mediated chemo-SDT for the treatment of prostate cancer.