Pegylated liposomal doxorubicin (
PLD) is a representative nanomedicine that has improved
tumor selectivity and safety profile. However, the therapeutic superiority of
PLD over conventional
doxorubicin has been reported to be insignificant in clinical medicine. Combination treatment with
microbubbles and ultrasound (US) is a promising strategy for enhancing the antitumor effects of chemotherapeutics by improving
drug delivery. Recently, several preclinical studies have shown the
drug delivery potential of
lipid bubbles (LBs), newly developed monolayer
microbubbles, in combination with low-intensity US (LIUS). This study aimed to elucidate whether the combined use of LBs and LIUS enhanced the intratumoral accumulation and antitumor effect of
PLD in syngeneic mouse
tumor models. Contrast-enhanced US imaging using LBs showed a significant decrease in contrast enhancement after LIUS, indicating that LIUS exposure induced the destruction of LBs in the
tumor tissue. A quantitative evaluation revealed that the combined use of LBs and LIUS improved the intratumoral accumulation of
PLD. Furthermore,
tumor growth was inhibited by combined treatment with
PLD, LBs, and LIUS. Therefore, the combined use of LBs and LIUS enhanced the antitumor effect of
PLD by increasing its accumulation in the
tumor tissue. In conclusion, the present study provides important evidence that the combination of LBs and LIUS is an effective method for enhancing the intratumoral delivery and antitumor effect of
PLD in vivo.