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

Abstract

The use of cisplatin (CDDP), the most common chemotherapy drug for head and neck cancer, is limited by its undesirable side effects, especially nephrotoxicity. We investigated ultrasound microbubbles (USMB) as a tool to increase the local intra-tumoral CDDP level while decreasing systemic CDDP cytotoxicity. We allowed CDDP to interact with human serum albumin and then sonicated the resulting CDDP‒albumin complex to generate CDDP-loaded MBs (CDDP-MBs). We then established a head-and-neck tumor-bearing mouse model by implanting FaDu-fLuc/GFP cells into severe combined immunodeficiency mice and used IVIS® bioluminescence imaging to determine the tumor xenograft formation and size. Twice weekly (until Day 33), we administered CDDP only, CDDP + MBs + US, CDDP-MBs, or CDDP-MBs + US intravenously by tail-vein injection. The US treatment was administered at the tumor site immediately after injection. The in vivo systemic distribution of CDDP indicated that the kidney was the most vulnerable organ, followed by the liver, and then the inner ear. However, CDDP uptake into the kidney and liver was significantly decreased in both the CDDP-MBs and CDDP-MBs + US groups, suggesting that MB binding significantly reduced the systemic toxicity of CDDP. The CDDP-MBs + US treatment reduced the tumor size as effectively as conventional CDDP-only chemotherapy. Therefore, the combination of CDDP-MBs with ultrasound is effective and significantly attenuates CDDP-associated nephrotoxicity, indicating a promising clinical potential for this approach.

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

“…Optimization of US parameters for USMB cavitation by agarose phantoms. The sonication effects on MBs in vitro were evaluated by high-frequency US imaging using a commercial animal US imaging system (Prospect, S-Sharp Corporation) in tissue-mimicking agarose phantoms, as described previously (41). Briefly, a 2% agarose square-column phantom (10 × 20 × 20 mm 3 ) was constructed with a 2 × 2 × 20 mm 3 chamber at its center to load 400 μL of 1.4 × 10 7 MBs/mL, followed by sonication through the tympanic membrane (which simulated transcanal USMB cavitation in the middle ear cavity) or through the skull bone (which mimicked transcranial US sonication).…”

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

“…Deparaffinized slides were incubated with 3% hydrogen peroxidase in methanol for 10 min to block endogenous peroxidase activity and then washed with PBS. As described in our previous report (Chen et al, 2018), the tissue sections were permeabilized first, blocked for 30 min at room temperature with the supplied blocking buffer, and then incubated with the TUNEL reaction mixture for 60 min at 37°C in a humidified atmosphere in the dark. After PBS Tween-20 (PBST) washing, the tissues were stained with Converter-POD for an additional 30 min and washed with PBST.…”

“…The distortion product otoacoustic emissions (DPOAEs) were measured at the center frequencies (FCs) of 8, 16, 20, 24, and 32 kHz with a Real-time Signal Processing System (Tucker-Davis Technologies), as reported previously (Chen et al, 2018). Briefly, two simultaneous continuous pure tones, F1 and F2 were calculated using the FC to yield a frequency of primary 1 (Tone 1) and primary 2 (Tone 2).…”

Middle‐ear dexamethasone delivery via ultrasound microbubbles attenuates noise‐induced hearing loss

“…Upon exposure to US, MBs can exhibit several physical phenomena, including oscillation, cavitation, or sonoporation, which cause transient and reversible changes in the membrane permeability of surrounding cells. For this reason, MBs are now being intensively investigated for use in US‐mediated gene and drug delivery …”

“…For this reason, MBs are now being intensively investigated for use in US-mediated gene and drug delivery. 15,16 Here, we used US-aided MBs (US-MBs) to deliver synthetic glucocorticoid dexamethasone (DEX) into the inner ear of an NIHL guinea pig model to determine the effectiveness of this approach over the spontaneous absorption at the RWM following an IT injection. We examined the delivered concentration of DEX and its effects on hearing threshold shifts, hair cell loss, and inflammation.…”