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 doxorubicin-loaded C3F8 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.
Highlights
Ovarian cancer (OC) is the fifth leading cause of cancer deaths among women in the United States
Passive delivery strategies can mediate some of the clinical systemic chemotherapy problems, they suffer from several limitations such as poor drug distribution and penetration resulting in an insufficient level of drug accumulation at the target tumor
Plain NBs showed an average diameter of 280 ± 112 nm while 359 ± 95 and 296 ± 153 nm were observed in Dox.HCl-NBs and hydrophobic doxorubicinloaded C3F8 nanobubble (hDox-NB), respectively. hydrophobic Dox (hDox) loading significantly altered the size of NBs, resulting in 25% smaller size compared to Dox.HCl-NBs (Figure 1D)
Summary
Ovarian cancer (OC) is the fifth leading cause of cancer deaths among women in the United States. Passive delivery strategies can mediate some of the clinical systemic chemotherapy problems (such as severe cardiotoxicity associated with free doxorubicin), they suffer from several limitations such as poor drug distribution and penetration resulting in an insufficient level of drug accumulation at the target tumor. This remains a big challenge in cancer drug delivery. MBs can induce sonoporation of vasculature and cell membranes resulting in an increasing permeability, local drug release, and penetration (Martin and Dayton, 2013) Their effectiveness in vivo is limited as a blood pool agent due to their large size (1–10 μm) which does not allow extravasation beyond the vasculature. They cannot take advantage of passive delivery via the EPR effect for increased tumor specific delivery and efficient intratumoral penetration, which requires particles with diameter in the range of 400-800 nm (Greish, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
