Highlights in ultrasound-targeted microbubble destruction-mediated gene/drug delivery strategy for treatment of malignancies

Li, Hui; Zhang, Yao; Shu, Hong; Lv, Wenhao; Su, Chunhong; Nie, Fang

doi:10.1016/j.ijpharm.2021.121412

Cited by 31 publications

(25 citation statements)

References 140 publications

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“…Ultrasound has been widely used in clinical practice due to its outstanding advantages such as nonradiative, noninvasive, and cost-effective [ 24 , 25 ]. Besides, the development of nanostructured materials in therapeutic perspective has further attracted attention to the combined application of both these fronts [ 26 ]. However, it has been found that it is difficult for either passively or actively targeted drug-laden NPs to penetrate tumor tissues due to high interstitial fluid pressure and dense extracellular matrix obstruction.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells

Zou

Mao

et al. 2022

BioMed Research International

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Objectives. Preparation of a multifunctional drug-loaded phase-change nanoparticle (NP), pirfenidone perfluoropentane liposome NPs (PPL NPs), and combined with low-intensity focused ultrasound (LIFU) to influence epithelial mesenchymal transition (EMT) for hepatocellular carcinoma (HCC) by inhibiting the activity of activated Hepatic Stellate Cells (a-HSCs). Methods. PPL NPs were prepared by the thin film dispersion method. The appearance, particle size, zeta potential, encapsulation efficiency, drug loading rate, drug release in vitro, and stability of PPL NPs were tested. The role of a-HSCs in HCC metastasis was studied by CCK-8, colony formation assay, apoptosis, cellular uptake assay, wound healing assay, and Transwell assay. Western blot was used to detect the related protein expression levels. In vitro and vivo, the acoustic droplet vaporization (ADV) of PPL NPs was tested at different times and LIFU intensities. Biosafety of the PPL NPs was assessed by measuring nude mouse body weight and hematoxylin and eosin (H&E) staining. Results. The results showed that the PPL NPs had good biosafety, with an average particle size of 346.6 ± 62.21 nm and an average zeta potential of -15.23 mV. When the LIFU power is 2.4 W/cm2, it can improve the permeability of cells, further promote the uptake of drugs by cells, and improve the toxicity of drugs. In vitro experiments showed that PPL NPs could inhibit the proliferation of a-HSCs cells, thereby affecting the metastasis of HCC, and were related to the TGFβ-Smad2/3-Snail signaling pathway. Both in vivo and in vitro PPL NPs enhanced ultrasound imaging by LIFU-triggered ADV. Conclusion. The PPL NPs designed and prepared in this study combined with LIFU irradiation could significantly alter the EMT of HCC by inhibiting LX2. Clinically, PPL NPs will also be considered a promising contrast agent due to their ultrasound imaging capabilities.

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Section: Introductionmentioning

confidence: 99%

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells

Zou

Mao

et al. 2022

BioMed Research International

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“…By destroying the microvascular system, which provides nutrients and oxygen to the tumor, it also inhibits tumor growth. 33 Second, after NB explosion, ultrasound fixed-point irradiation drug-loaded NBs can form many transient and reversible pores on the surface of the cell membrane. By increasing the permeability of the cell membrane, the drug can accumulate in high concentrations in the tumor, thereby enhancing its therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

“…This significantly improves treatment efficiency and reduces systemic toxicity and drug side effects, rendering it the tumor-targeted therapy strategy with the most promising potential at present. [33][34][35] In this study, ultrasound NBs were used as drug delivery carriers. Based on the bridging effect between biotin-streptavidin, PD-L1 mAb/DOX-NBs were successfully prepared with a small and uniform particle size, high antibody connection rate, and good safety in vivo.…”

Section: Discussionmentioning

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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“…UTMD-mediated drug or gene delivery system has the following advantages: (1) safe; (2) non-invasive; (3) therapeutic effects of drug and microbubble delivered via US imaging and/or gene, integrating the diagnosis and treatment of target tissues; (4) Economic and practical; (5) strong targeted delivery ability; and (6) longer stay in the tumour site [ 26 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…US has long been medically used and is one of the most important diagnostic tools in clinical practice due to its non-invasiveness, radiological safety, low price and high repetitive nature [ 25 ]. UTMD technology is a recent and novel drug and gene delivery strategy, which can improve the efficiency of gene transfection in targeted tissues and drug delivery to organs [ 26 , 27 ]. Using US microvesicles to carry therapeutic genes or drugs, UTMD acts on the target tissue, generating shear stress in cells to form transient cell membrane pores, improving cell membrane permeability [ 28 ] and promoting the targeted release of genes or drugs.…”

Section: Introductionmentioning

confidence: 99%

Exploring the relationship between autophagy and Gefitinib resistance in NSCLC by silencing PDLIM5 using ultrasound-targeted microbubble destruction technology

Zhang

et al. 2022

Cancer Cell Int

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Background Ultrasound-targeted microbubble destruction (UTMD) technology is a new drug and gene delivery strategy. This study investigates novel ultrasound (US) sensitive siRNA-loaded nanobubbles (siRNA-NBs) to explore the relationship between PDLIM5 mediated autophagy and drug resistance development using epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). Methods US sensitive siRNA-NBs were designed to inhibit the expression of PDLIM5 in gefitinib-resistant human NSCLC PC9GR cells in vitro. The expression of autophagy-related proteins (P62 and LC3-II/I) and autophagosomes in PC9GR cells after PDLIM5 gene silencing were explored. Results US-sensitive PDLIM5-targeted siRNA-NBs were effectively delivered into PC9GR cells, inhibiting PDLIM5 expression, increasing LC3-II/I and p62 expressions and increasing autophagosomes in PC9GR cells in vitro. Conclusions Using UTMD, US-sensitive siRNA-NBs have the potential as an ideal delivery vector to mediate highly effective RNA interference for NSCLC cells. Furthermore, PDLIM5 plays a role in the autophagy-mediated resistance in gefitinib-resistant PC9GR cells.

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Highlights in ultrasound-targeted microbubble destruction-mediated gene/drug delivery strategy for treatment of malignancies

Cited by 31 publications

References 140 publications

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells

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

Exploring the relationship between autophagy and Gefitinib resistance in NSCLC by silencing PDLIM5 using ultrasound-targeted microbubble destruction technology

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