Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer

Sun, Lihong; Zhang, Jinxia; Xu, Menghong; Zhang, Lulu; Tang, Qinglian; Chen, Jing; Gong, Ming; Sun, Shijie; Ge, Huiyu; Wang, Shumin; Liang, Xiaolong; Cui, Ligang

doi:10.1021/acsami.1c21924

Cited by 30 publications

(22 citation statements)

References 42 publications

(63 reference statements)

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“…Briefly, 0.6 mg DSPC and 0.2 mg DSPE-PEG2000-NHS (with molar ratio of about 9:1) were used to prepare the lipid nanoparticles, followed by incubation with 0.2 mg targeted peptide C12 for 1 hour at 30°C (molar ratio of DSPE-PEG2000-NHS/C12 peptide =1:2). Then, the formed targeted C12-lipid nanoparticles were dialyzed to remove unconnected peptide and used to prepare Gal-3-C12@lipo MBs by the same way of inflating and shaking (29).…”

Section: Synthesis Of Lipo Mbs and Gal-3-c12@lipo Mbsmentioning

confidence: 99%

Contrast-enhanced ultrasound combined targeted microbubbles for diagnosis of highly aggressive papillary thyroid carcinoma

Wang²,

Xi³

et al. 2023

Front. Endocrinol.

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BackgroundAccurate diagnosis of highly aggressive papillary thyroid cancer (PTC) may greatly help avoid overdiagnosis and overtreatment of PTC. However, there is still a lack of a convenient and accurate method. Targeted microbubbles, an emerging ultrasound contrast agent, have the potential to accurately diagnose highly aggressive PTC.PurposeTo design and prepare a targeted microbubble for specific contrast-enhanced ultrasound (CEUS) imaging of highly invasive PTC.MethodsUsing β-galactoside-binding protein galectin-3 (Gal-3) overexpressed on the surface of highly invasive PTC cells as a target, C12 polypeptide (ANTPCGPYTHDCPVKR) with high affinity and specificity for Gal-3 was coupled to the surface of lipid microbubbles to prepare targeted microbubbles (Gal-3-C12@lipo MBs). The targeted microbubbles were prepared by thin-film hydration method and mechanical shaking method. The morphology, diameter, concentration and stability of microbubbles were investigated by fluorescence microscopy and an AccuSizer. The biosafety of microbubbles was studied using BCPAP cells through CCK8 assay. Confocal laser scanning microscope and flow cytometry were applied to research the cellular uptake of microbubbles to investigate the targeting ability to highly aggressive PTC. Finally, the specific contrast-enhanced ultrasound imaging of microbubbles in highly invasive PTC was validated on the mice bearing subcutaneous BCPAP tumor model via a clinically ultrasound imaging system.ResultsGal-3-C12@lipo MBs were successfully prepared which showed a well-defined spherical morphology with an average diameter of 1.598 ± 0.848 μm. Gal-3-C12@lipo MBs showed good stability without rupture within 4 hours after preparation. At the cellular level, Gal-3-C12@lipo MBs exhibited favorable biosafety and superior targeting ability to BCPAP cells, with 2.8-fold higher cellular uptake than non-targeted lipid microbubbles (Lipo MBs). At the animal level, Gal-3-C12@lipo MBs significantly improved the quality of contrast-enhanced ultrasound imaging in highly invasive PTC, with an echo intensity of tumor significantly higher than that of Lipo MBs.ConclusionWe designed and fabricated a novel targeted microbubble for the specific ultrasound imaging diagnosis of highly aggressive PTC. The targeted microbubbles have good stability, superior biosafety and high targeting specificity, which can significantly improve the tumor signal-to-noise ratio of highly invasive PTC, and have the potential to facilitate and accurately diagnose highly invasive PTC.

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Section: Synthesis Of Lipo Mbs and Gal-3-c12@lipo Mbsmentioning

confidence: 99%

Contrast-enhanced ultrasound combined targeted microbubbles for diagnosis of highly aggressive papillary thyroid carcinoma

Wang²,

Xi³

et al. 2023

Front. Endocrinol.

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“…In addition, the approach was more targeted than epirubicin therapy alone and was associated with reduced cardiac toxicity in mice models. Sun et al (20) constructed an ultrasonic MB loaded with trastuzumab coupled with acoustic sensitizer nanoparticles. They found that the delivery and treatment efficiency with nanoparticles was improved with UTMD and successfully inhibited the proliferation of tumor cells, achieving a targeted combination of sonodynamic therapy and antibody therapy with nanoparticles for treating HER2positive gastric cancer (Figure 4).…”

Section: Utmd-mediated Antibody Immunotherapymentioning

confidence: 99%

Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy

et al. 2022

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Tumor immunotherapy has shown strong therapeutic potential for stimulating or reconstructing the immune system to control and kill tumor cells. It is a promising and effective anti-cancer treatment besides surgery, radiotherapy and chemotherapy. Presently, some immunotherapy methods have been approved for clinical application, and numerous others have demonstrated promising in vitro results and have entered clinical trial stages. Although immunotherapy has exhibited encouraging results in various cancer types, however, a large proportion of patients are limited from these benefits due to specific characteristics of the tumor microenvironment such as hypoxia, tumor vascular malformation and immune escape, and current limitations of immunotherapy such as off-target toxicity, insufficient drug penetration and accumulation and immune cell dysfunction. Ultrasound-target microbubble destruction (UTMD) treatment can help reduce immunotherapy-related adverse events. Using the ultrasonic cavitation effect of microstreaming, microjets and free radicals, UTMD can cause a series of changes in vascular endothelial cells, such as enhancing endothelial cells’ permeability, increasing intracellular calcium levels, regulating gene expression, and stimulating nitric oxide synthase activities. These effects have been shown to promote drug penetration, enhance blood perfusion, increase drug delivery and induce tumor cell death. UTMD, in combination with immunotherapy, has been used to treat melanoma, non-small cell lung cancer, bladder cancer, and ovarian cancer. In this review, we summarized the effects of UTMD on tumor angiogenesis and immune microenvironment, and discussed the application and progress of UTMD in tumor immunotherapy.

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“…International Journal of Nanomedicine 2022:17 3990 systemic toxicity and side effects, 25,26 and to evaluate synergistic antitumor mechanisms in the immune responses of ultrasound-mediated PD-L1 mAb/DOX-NBs on HCC xenografts.…”

Section: Dovepressmentioning

confidence: 99%

“…Thus, in this study, the method of ultrasound-triggered NBs drug delivery targeting was implemented to improve local drug concentrations and limit drug uptake by normal cells, thus significantly enhancing therapeutic effects and reducing systemic toxicity and side effects, 25 , 26 and to evaluate synergistic antitumor mechanisms in the immune responses of ultrasound-mediated PD-L1 mAb/DOX-NBs on HCC xenografts.…”

Section: Introductionmentioning

confidence: 99%

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Chen¹,

Luo²,

Liu³

et al. 2022

IJN

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Purpose Ultrasound nanobubbles (NBs) can kill tumor cells, mediated by their effects of cavitation and acoustic perforation through ultrasound, while as novel drug carriers, biomaterial-modified NBs release drugs at a target region. In this work, the ultrasound NBs bridged by biotin-streptavidin were prepared simultaneously to be loaded with both programmed death ligand 1 monoclonal antibody (PD-L1 mAb) and doxorubicin (DOX), which are immune checkpoint inhibitors (ICIs) and chemotherapeutic agents, to synergize immunotherapy and chemotherapy combined with sonodynamic therapy (SDT). Methods The PD-L1 mAb/DOX NBs, using bridging affinity biotin (BRAB) technology as a bridge, were prepared by thin-film hydration and mechanical oscillation for the targeted delivery of biotinylated PD-L1 mAb and DOX. Characterization and pharmacokinetic studies of PD-L1 mAb/DOX NBs were performed in vitro and in vivo. The antitumor effect of ultrasound-mediated PD-L1 mAb/DOX-NBs was studied in the subcutaneously transplanted tumor of the H22 hepatoma model, and the mechanism of synergistic tumor repression was investigated. Results The data of in vitro targeting experiments, contrast-enhanced ultrasound imaging (CEUS), in vivo imaging of the small animals imaging system (IVIS), and frozen sections showed that PD-L1 mAb/DOX-NBs have well-targeted aggregation in the tumor. By observing tumor inhibition rate, tissue cell apoptosis, and apoptosis-related gene and protein expression, the PD-L1 mAb/DOX-NBs group showed the best immunotherapy effects, and its tumor volume and mass inhibition rates were about 69.64% and 75.97%, respectively ( P < 0.01). Therefore, blocking the PD-1/PD-L1 pathway could improve immune cells’ tumor-killing ability. Antitumor immune cytokines were further enhanced when combined with DOX-induced tumor cell apoptosis and immunogenic cell death (ICD). Conclusion In summary, ultrasound-mediated PD-L1 mAb/DOX-NBs showed significant synergistic antitumor effects, providing a potential combined immunotherapy strategy for HCC.

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Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer

Cited by 30 publications

References 42 publications

Contrast-enhanced ultrasound combined targeted microbubbles for diagnosis of highly aggressive papillary thyroid carcinoma

Contrast-enhanced ultrasound combined targeted microbubbles for diagnosis of highly aggressive papillary thyroid carcinoma

Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

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