Development of a Dual Drug-Loaded, Surfactant-Stabilized Contrast Agent Containing Oxygen

Abstract

Co-delivery of cancer therapeutics improves efficacy and encourages synergy, but delivery faces challenges, including multidrug resistance and spatiotemporal distribution of therapeutics. To address these, we added paclitaxel to previously developed acoustically labile, oxygen-core, surfactant-stabilized microbubbles encapsulating lonidamine, with the aim of developing an agent containing both a therapeutic gas and two drugs acting in combination. Upon comparison of unloaded, single-loaded, and dual-loaded microbubbles, size (~1.7 µm) and yield (~2 × 109 microbubbles/mL) (~1.7) were not statistically different, nor were acoustic properties (maximum in vitro enhancements roughly 18 dB, in vitro enhancements roughly 18 dB). Both drugs encapsulated above required doses calculated for head and neck squamous cell carcinoma, the cancer of choice. Interestingly, paclitaxel encapsulation efficiency increased from 1.66% to 3.48% when lonidamine was included. During preparation, the combination of single drug-loaded micelles gave higher encapsulation (µg drug/g microbubbles) than micelles loaded with either drug alone (lonidamine, 104.85 ± 22.87 vs. 87.54 ± 16.41), paclitaxel (187.35 ± 8.38 vs. 136.51 ± 30.66). In vivo intravenous microbubbles produced prompt ultrasound enhancement within tumors lasting 3–5 min, indicating penetration into tumor vasculature. The ability to locally destroy the microbubble within the tumor vasculature was confirmed using a series of higher intensity ultrasound pulses. This ability to locally destroy microbubbles shows therapeutic promise that warrants further investigation.

Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer

“…Following characterization with HPLC, LND encapsulation within the microbubble showed an average of 25.7 ± 1.5 µg/mL, with a total of 705.7 ± 80.8 µg LND encapsulated per batch. Though the encapsulation efficiency was low (1.71%), it was able to surpass the minimum required loading of 4.8 µg/mL based on the minimum effective LND dose in tissue [28,32]. The population and size distribution LND microbubbles have been previously reported, at an average of (2.7 ± 0.2) × 10 9 MB/mL [6].…”