Spatial and temporal profile of cisplatin delivery by ultrasound-assisted intravesical chemotherapy in a bladder cancer model

Abstract

Non-muscle invasive bladder cancer is one of the most common tumors of the urinary tract. Despite the current multimodal therapy, recurrence and progression of disease have been challenging problems. We hereby introduced a new approach, ultrasound-assisted intravesical chemotherapy, intravesical instillation of chemotherapeutic agents and microbubbles followed by ultrasound exposure. We investigated the feasibility of the treatment for non-muscle invasive bladder cancer. In order to evaluate intracellular delivery and cytotoxic effect as a function to the thickness, we performed all experiments using a bladder cancer mimicking 3D culture model. Ultrasound-triggered microbubble cavitation increased both the intracellular platinum concentration and the cytotoxic effect of cisplatin at the thickness of 70 and 122 μm of the culture model. The duration of enhanced cytotoxic effect of cisplatin by ultrasound-triggered microbubble cavitation was approximately 1 hr. Based on the distance and duration of delivery, we further tested the feasibility of repetition of the treatment. Triple treatment increased the effective distance by 1.6-fold. Our results clearly showed spatial and temporal profile of delivery by ultrasound-triggered microbubble cavitation in a tumor-mimicking structure. Furthermore, we demonstrated that the increase in intracellular concentration results in the enhancement of the cytotoxic effect in a structure with the certain thickness. Repetition of ultrasound exposure would be treatment of choice in future clinical application. Our results suggest ultrasound-triggered microbubble cavitation can be repeatable and is promising for the local control of non-muscle invasive bladder cancer.

Insonation of Systemically Delivered Cisplatin-Loaded Microbubbles Significantly Attenuates Nephrotoxicity of Chemotherapy in Experimental Models of Head and Neck Cancer

“…This combination gave significantly better outcomes than Group II treated with CDDP alone ( p < 0.0001) or Group V with CDDP-MBs plus ultrasound ( p < 0.0001), indicating that CDDP combined with USMB can additively enhance in vivo uptake of CDDP into head and neck cancer cells. These data are not only consistent with our in vitro observations ( Figure 2 E), but are also supported by other recent studies [ 4 , 5 , 7 ].…”

“…In our current study, although the loading efficiency of CDDP onto the CDDP-MBs was limited to about 10%, the ultrasound-mediated destruction of these CDDP-MBs with an inert gas core preserved the effective cytotoxicity of CDDP without concerns about additional modifications or incorporation of other agents. Moreover, previous studies that evaluated the efficacy of CDDP aided by USMB were mostly focused on using the USMB to increase tumor uptake of CDDP by co-administration of MBs and CDDP [ 4 , 5 , 7 , 30 , 31 ]. To the best of our knowledge, this is the first study to prepare gas-filled and CDDP-carrying MBs for the application of USMB in cancer chemotherapy ( Figure 6 ).…”

“…Similarly, hematologic adverse effect and nephrotoxicity can result in life-threatening sepsis and renal failure. Thus, ongoing research is increasingly aimed at developing new strategies to maximize the cisplatin concentration in tumors while minimizing the cisplatin levels in normal tissues [ 4 , 5 , 6 , 7 , 8 ].…”

Ultrasound-Mediated Drug Delivery With a Clinical Ultrasound System: In Vitro Evaluation

“…In particular, hydrophilic drugs such as bleomycin and cisplatin, that have difficulties crossing the cell membrane, may benefit from local USMB therapy, leading to increased delivery of such drugs in vitro ( Iwanaga et al, 2007 ; Watanabe et al, 2008 ; Maeda et al, 2009 ; Heath et al, 2012 ; Sasaki et al, 2012 ; Lamanauskas et al, 2013 ; Sato et al, 2014 ; Sato et al, 2015 ; Lammertink et al, 2016 ; Tamosiunas et al, 2016 ; Hirabayashi et al, 2017 ; Sasaki et al, 2017 ; Chen et al, 2018 ; Fekri et al, 2019 ) and increased anti-tumor response in vivo ( Iwanaga et al, 2007 ; Watanabe et al, 2008 ; Heath et al, 2012 ; Sato et al, 2014 ; Sato et al, 2015 ; Hirabayashi et al, 2017 ; Chen et al, 2018 ). The first clinical trials using the combination of chemotherapy and USMB have been conducted.…”

Hyaluronic Acid Modified Au@SiO2@Au Nanoparticles for Photothermal Therapy of Genitourinary Tumors

“…However, the problem of resection is a high recurrence rate due to the incomplete removal of cancer cells [ 8 , 9 ]. Additionally, radical resection leads to trauma, high surgical risk, and siginificant changes in urination, which is a huge burden for the patient [ 10 ]. Therefore, identifying noninvasive or minimally invasive treatment methods to remove cancer cells and preserving patient organs is warranted.…”