Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

Abstract

Purpose Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. Materials and Methods CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. Results A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups ( P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay ( P < .05; R 2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

“…This significantly improves treatment efficiency and reduces systemic toxicity and drug side effects, rendering it the tumor-targeted therapy strategy with the most promising potential at present. [33][34][35] In this study, ultrasound NBs were used as drug delivery carriers. Based on the bridging effect between biotin-streptavidin, PD-L1 mAb/DOX-NBs were successfully prepared with a small and uniform particle size, high antibody connection rate, and good safety in vivo.…”

Barrier-breaking effects of ultrasonic cavitation for drug delivery and biomarker release

“… MRI-guided focused ultrasound enhanced doxorubicin delivery by 4-fold compared to controls and significantly suppressed the volumetric tumor growth rate (24.4 ± 10.9%). Ruan (2021) [131] Gemcitabine Murine bladder tumor model (RT112 cells) Microbubble: diameter data not given Conc. : 3 × 10 8 /mL Freq.…”

“…For chemotherapy alone, cavitation selectively and efficiently enhanced the accumulation (4–8-folds) of drugs (paclitaxel, doxorubicin, gemcitabine, etoposide, and hydroxychloroquine) in tumor regions to improve the therapeutic efficiency [12] , [13] , [129] , [130] , [131] , [132] . Idbaih et al reported a first-in-man clinical trial in patients with recurrent glioblastoma of the cavitation-enhanced trans -BBB delivery of a chemotherapeutic drug (carboplatin).…”

Ultrasound-Enabled Therapeutic Delivery and Regenerative Medicine: Physical and Biological Perspectives

“…US-mediated drug delivery methods hardly exacerbate the acute intestinal toxicity using the crypt assay in contrast to conventional chemoradiation. 93 In another gemcitabine delivery study, in vitro and in vivo RT112 bladder cancer cell line and murine orthotopic muscle-invasive bladder cancer model was tested. No significant increase in drug uptake was observed due to the US when compared to drug control of Drug+MBs.…”

“…Another study used US+MBs for targeted gemcitabine delivery to minimize normal-tissue toxicity in a mouse orthotopic MIBC model. US-mediated drug delivery methods hardly exacerbate the acute intestinal toxicity using the crypt assay in contrast to conventional chemoradiation . In another gemcitabine delivery study, in vitro and in vivo RT112 bladder cancer cell line and murine orthotopic muscle-invasive bladder cancer model was tested.…”