Multi-Focused Acoustic Radiation Force Impulse Modulation of Murine Hepatic Xenografts Enhances Nanoscale DOX@Lip Delivery and Therapeutic Effect.

PURPOSE

To investigate whether multi-focused acoustic radiation force impulse (MF-ARFI) applied to murine xenograft liver tumors prior to intravenous administration of doxorubicin-loaded PEGylated liposomes (DOX@Lip) can enhance drug delivery efficiency through modulating the enhanced permeation and retention effect of the tumor, reduce side effects, and improve antitumor effect.

MATERIALS AND METHODS

DOX@Lip and tumor-mimetic matrices were synthesized and characterized. Huh-7 cells and DOX@Lip were exposed to MF-ARFI and observed. MF-ARFI was applied to both tumor-mimetic matrices and saline with DOX@Lip to assess displacement effects. Subsequently, murine xenograft models were established and underwent MF-ARFI preconditioning before DOX@Lip injection. Tumor volume dynamics and body weight changes were longitudinally monitored. Terminal assessments included histopathology (H&E), apoptosis (TUNEL), and molecular profiling (BCL-2 and BAX by Western blot) of tumors and major organs.

RESULTS

There was no significant difference in the live/dead cell staining results between the Huh7 cells with and without MF-ARFI. There was no significant difference in cell apoptosis rates of Huh7 cells between DOX@Lip and DOX@Lip+MF-ARFI. MF-ARFI exposure induced measurable displacement of DOX@Lip in both tumor-mimetic matrices and saline. Mice receiving combined DOX@Lip and MF-ARFI treatment exhibited significantly attenuated tumor growth (p<0.05) and slight weight loss, which were significantly different from DOX and DOX+MF-ARFI treatments. Cardiac histopathology revealed no significant differences in myocardial toxicity between DOX@Lip and DOX@Lip+MF-ARFI groups relative to PBS controls. Conversely, tumors from the DOX@Lip+MF-ARFI group demonstrated distinct histopathological alterations compared to other groups. TUNEL staining results indicated a relatively higher level of cell apoptosis in mice treated with DOX@Lip+MF-ARFI. Molecular analyses showed MF-ARFI pretreatment significantly reduced BCL-2 expression (p<0.05) while elevating the BAX/BCL-2 ratio versus DOX@Lip monotherapy.

CONCLUSION

Preconditioning xenograft tumors with MF-ARFI prior to DOX@Lip administration faciliates DOX@Lip delivery and significantly enhances antitumor effect while reducing cardiotoxicity. This combinatorial strategy demonstrates translational potential for optimizing liposomal chemotherapeutic delivery and effect.