Increasing Doxorubicin Loading in Lipid-Shelled Perfluoropropane Nanobubbles via a Simple Deprotonation Strategy

Abstract

Drug delivery to solid tumors using echogenic nanobubbles (NBs) and ultrasound (US) has recently gained significant interest. The approach combines attributes of nanomedicine and the enhanced permeation and retention (EPR) effect with the documented benefits of ultrasound to improve tumor drug distribution and treatment outcomes. However, optimized drug loading strategies, the drug-carrying capacity of NBs and their drug delivery efficiency have not been explored in depth and remain unclear. Here, we report for the first time on the development of a novel deprotonated hydrophobic doxorubicinloaded C 3 F 8 nanobubble (hDox-NB) for more effective US-mediated drug delivery. In this study, the size distribution and yield of hDox-NBs were measured via resonant mass measurement, while their drug-loading capacity was determined using a centrifugal filter technique. In vitro acoustic properties including contrast-imaging enhancement, initial echogenic signal, and decay were assessed and compared to doxorubicin hydrochloride loaded-NBs (Dox.HCl-NBs). In addition, in vitro therapeutic efficacy of hDox-NBs was evaluated by cytotoxicity assay in human ovarian cancer cells (OVCAR-3). The results showed that the hDox-NBs were small (300.7 ± 4.6 nm), and the drug loading content was significantly enhanced (2 fold higher) compared to Dox.HCl-NBs. Unexpectedly, the in vitro acoustic performance was also improved by inclusion of hDox into NBs. hDox-NB showed higher initial US signal and a reduced signal decay rate compared to Dox.HCl-NBs. Furthermore, hDox-NBs combined with higher intensity US exhibited an excellent therapeutic efficacy in human ovarian cancer cells as shown in a reduction in cell viability. These results suggest that hDox-NBs could be considered as a promising theranostic agent to achieve a more effective noninvasive US-mediated drug delivery for cancer treatment.

An Advanced In Situ Magnetic Resonance Imaging and Ultrasonic Theranostics Nanocomposite Platform: Crossing the Blood–Brain Barrier and Improving the Suppression of Glioblastoma Using Iron-Platinum Nanoparticles in Nanobubbles

“…In Figure S9a, ultrasonic treatment was performed at 20, 100, and 180 s. After each treatment, a stronger Dox absorption peak was obtained, confirming that the drug was released because of the bubble burst. 45 Additionally, to evaluate the amount of DOX, we use the UV−vis spectrometer to measure the spectrum of DOX (Figure S9b). The encapsulation efficiency and loading capacity of Dox in the NBs had been quantified with a specific absorption wavelength of DOX at 480 nm.…”

Stimuli-responsive nanobubbles for biomedical applications

“…Similar results were also obtained by other groups. 263,264 In order to further improve the cellular uptake of anticancer drugs and achieve an enhanced chemotherapeutic effect, Li et al developed Dox conjugated with cell-permeable peptides (CPP), which were entrapped in shelled NBs. 265 Under ultrasound stimulation, CPP-Dox was released from NBs and penetrated into cancer cells.…”

Ultrasound and Nanomedicine for Cancer-Targeted Drug Delivery: Screening, Cellular Mechanisms and Therapeutic Opportunities

“…Even though DOX is not easily released when encapsulated in nanobubbles, it can also reduce the toxicity to normal cells and be effective in inhibiting tumor growth at specific locations. Currently available packaging materials include poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol), superhydrophobic mesoporous silica [120], lipid shell-stabilized perfluoropropane (C 3 F 8 ) gas [121], and glycine/poly(ethylene glycol) (PEG)/RGD-modified poly(methacrylic acid), which are able to improve ultrasonic imaging by 1.47 times. A relationship has been found between cancer-associated fibroblasts (CAF) and the development of drug resistance in cancer cells.…”