Active targeting nano-scale bubbles enhanced ultrasound cavitation chemotherapy in Y receptor-overexpressed breast cancer.
Qian Xuechen,Wang Yinjie,Xu Youfeng,Ma Ling,Xue Nianyu,Jiang Zhenqi,Cao Yi,Akakuru Ozioma Udochukwu,Li Juan,Zhang Shengmin,Wu Aiguo
Journal of materials chemistry. B
Ultrasound cavitation therapy has attracted much attention in recent years because the cavitation of microbubbles can be leveraged to boost the infiltration of chemotherapeutic drugs into cancer tissues. For breast cancer therapy, most of the previously reported microbubbles lack specific targeting capacity and permeability. In this study, we have successfully fabricated Y receptor ligand (NPY)-modified bubbles, and examined their therapeutic efficacies as size-dependent functions with or without NPY targeting. To achieve this, four types of micro-scale bubbles (MBs or MBs-NPY) and nano-scale bubbles (NBs or NBs-NPY) were comprehensively evaluated. In vivo results indicated that the NBs-NPY group with doxorubicin (DOX) under ultrasound irradiation showed a high tumor suppression effect and a prolonged survival time. Furthermore, the NBs-NPY with DOX group exhibited minimal damage to mouse vital organs, which points to the considerable tolerance of the proposed nanosystem for efficacious breast cancer therapy. In summary, these findings suggest that the developed NPY-targeted NBs could have a broad application prospect in ultrasound cavitation chemotherapy of Y receptor-overexpressed breast cancer.
10.1039/d0tb00556h
SonoVue vs. Sonazoid™ vs. Optison™: Which Bubble Is Best for Low-Intensity Sonoporation of Pancreatic Ductal Adenocarcinoma?
Kotopoulis Spiros,Popa Mihaela,Mayoral Safont Mireia,Murvold Elisa,Haugse Ragnhild,Langer Anika,Dimcevski Georg,Lam Christina,Bjånes Tormod,Gilja Odd Helge,Cormack Emmet Mc
Pharmaceutics
The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial research in this field, it is currently not known which of these microbubbles result in the greatest enhancement of therapy within the applied conditions. Three microbubble formulations-SonoVue, Sonazoid™, and Optison™-were physiochemically and acoustically characterized. The microbubble response to the ultrasound pulses used in vivo was simulated via a Rayleigh-Plesset type equation. The three formulations were compared in vitro for permeabilization efficacy in three different pancreatic cancer cell lines, and in vivo, using an orthotopic pancreatic cancer (PDAC) murine model. The mice were treated using one of the three formulations exposed to ultrasound from a GE Logiq E9 and C1-5 ultrasound transducer. Characterisation of the microbubbles showed a rapid degradation in concentration, shape, and/or size for both SonoVue and Optison™ within 30 min of reconstitution/opening. Sonazoid™ showed no degradation after 1 h. Attenuation measurements indicated that SonoVue was the softest bubble followed by Sonazoid™ then Optison™. Sonazoid™ emitted nonlinear ultrasound at the lowest MIs followed by Optison™, then SonoVue. Simulations indicated that SonoVue would be the most effective bubble using the evaluated ultrasound conditions. This was verified in the pre-clinical PDAC model demonstrated by improved survival and largest tumor growth inhibition. In vitro results indicated that the best microbubble formulation depends on the ultrasound parameters and concentration used, with SonoVue being best at lower intensities and Sonazoid™ at higher intensities.
10.3390/pharmaceutics14010098
Target tumor therapy in human gastric cancer cells through the combination of docetaxel-loaded cationic lipid microbubbles and ultrasound-triggered microbubble destruction.
Functional & integrative genomics
It is well accepted that ultrasound-induced microbubble (USMB) cavitation is a promising method for drug delivery. Ultrasound-targeted destruction of cytotoxic drug-loaded lipid microbubbles (LMs) is used to promote the treatment of cancer. This study aimed to investigate the antitumor effects from a combination of docetaxel-loaded cationic lipid microbubbles (DLLM) and ultrasound (US)-triggered microbubble destruction (UTMD) on gastric cancer (GC). It was found that the functional dose of DOC in this study was 1 × 10 mol/L. We found that DLLM combined with the UTMD group showed greater growth inhibition of the cultured human gastric cancer cells (HGCCs) when compared with the other five groups by arresting the G/M phase in the cell cycle. However, DLLM combined with UTMD showed a higher inhibition rate of tumor growth than DLLM combined with UTMD and that of the RC/CMV-p16 combined with UTMD in vitro and in vivo experiments. DLLM combined with UTMD significantly suppressed proliferation and promoted the apoptosis of HGCCs with more cells arrested in the G/M phase. In addition, DLLM combined with UTMD suppressed the proliferation and induced apoptosis by arresting cells in the G/M phase, which led to a great inhibition of GC progression. Thus, our results indicated that the combination of DLLM and UTMD might represent a novel and promising approach to chemotherapy for GC.
10.1007/s10142-022-00952-7
Inhibitory effect of 5-FU loaded ultrasound microbubbles on tumor growth and angiogenesis.
He Yang,Zhang Yue,Qin Hai-Ying,Gu Dong-Yue,Lu Xiao,Hu Jin-Xi,Ye Wei-Liang,He Guang-Bin
Bioorganic & medicinal chemistry letters
The anti-neovascularization treatment is one of the effective strategies for tumor molecular target therapy. At present, the target and effect of the anti-neovascularization treatment is limited, and it is urgent to establish a new vascular targeting strategy to effectively treat tumors. In this work, we used high intensity focused ultrasound (HIFU) combined with targeted microbubbles to establish a molecular targeted ultrasound response microbubble for neovascular cells. Furthermore, the effects of drug loaded microbubbles on neovascularization and tumor cells were studied. The tumor vascular targeted and ultrasound-responsive microbubbles of 5-FU@DLL4-MBs were prepared by the thin-film dispersion method. The size and zeta potential of 5-FU@DLL4-MBs was about 1248 nm and -9.1 mV. 5-FU@DLL4-MBs released 5-FU showed an ultrasound-responsive manner, and had better vascular-targeting ability. Furthermore, the 5-FU@DLL4-MBs showed the strongest cytotoxic effect on HUVECs or HepG-2 cells and can be effectively internalized into the HUVECs cells. Thus, 5-FU@DLL4-MBs combined with HIFU can be considered as a potential method for antitumor angiogenesis in the future.
10.1016/j.bmcl.2020.127534
Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer xenograft.
Kotopoulis Spiros,Delalande Anthony,Popa Mihaela,Mamaeva Veronika,Dimcevski Georg,Gilja Odd Helge,Postema Michiel,Gjertsen Bjørn Tore,McCormack Emmet
Molecular imaging and biology
PURPOSE:Adenocarcinoma of the pancreas remains one of the most lethal human cancers. The high mortality rates associated with this form of cancer are subsequent to late-stage clinical presentation and diagnosis, when surgery is rarely possible and of modest chemotherapeutic impact. Survival rates following diagnosis with advanced pancreatic cancer are very low; typical mortality rates of 50% are expected within 3 months of diagnosis. However, adjuvant chemotherapy improves the prognosis of patients even after palliative surgery, and successful newer neoadjuvant chemotherapeutical modalities have recently been reported. For patients whose tumours appear unresectable, chemotherapy remains the only option. During the past two decades, the nucleoside analogue gemcitabine has become the first-line chemotherapy for pancreatic adenocarcinoma. In this study, we aim to increase the delivery of gemcitabine to pancreatic tumours by exploring the effect of sonoporation for localised drug delivery of gemcitabine in an orthotopic xenograft mouse model of pancreatic cancer. EXPERIMENTAL DESIGN:An orthotopic xenograft mouse model of luciferase expressing MIA PaCa-2 cells was developed, exhibiting disease development similar to human pancreatic adenocarcinoma. Subsequently, two groups of mice were treated with gemcitabine alone and gemcitabine combined with sonoporation; saline-treated mice were used as a control group. A custom-made focused ultrasound transducer using clinically safe acoustic conditions in combination with SonoVue® ultrasound contrast agent was used to induce sonoporation in the localised region of the primary tumour only. Whole-body disease development was measured using bioluminescence imaging, and primary tumour development was measured using 3D ultrasound. RESULTS:Following just two treatments combining sonoporation and gemcitabine, primary tumour volumes were significantly lower than control groups. Additional therapy dramatically inhibited primary tumour growth throughout the course of the disease, with median survival increases of up to 10% demonstrated in comparison to the control groups. CONCLUSION:Combined sonoporation and gemcitabine therapy significantly impedes primary tumour development in an orthotopic xenograft model of human pancreatic cancer, suggesting additional clinical benefits for patients treated with gemcitabine in combination with sonoporation.
10.1007/s11307-013-0672-5
A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction.
Gao Jinhui,Logan Keiran A,Nesbitt Heather,Callan Bridgeen,McKaig Thomas,Taylor Mark,Love Mark,McHale Anthony P,Griffith Darren M,Callan John F
Journal of controlled release : official journal of the Controlled Release Society
FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.
10.1016/j.jconrel.2021.08.050
UTMD inhibits pancreatic cancer growth and metastasis by inducing macrophage polarization and vessel normalization.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Pancreatic cancer (PaCa) is a hypovascular type of tumor and is not very responsive to conventional chemotherapy due to the problem of low drug accumulation. Recent advancements in ultrasound targeted microbubble destruction (UTMD) have improved drug delivery into target tissues. UTMD operates via microbubble interaction with vascular endothelial cells; however, the molecular mechanism and interrelationship in the PaCa microenvironment remain enigmatic. Tumor-associated macrophages (TAMs) have different phenotypes and regulate tumorigenesis. Using a PaCa orthotopic model, we established that UTMD improved chemotherapy by redirecting TAM polarization from M2 macrophages to tumor-inhibiting M1 macrophages, remodeling vessel normalization, and inducing anti-tumor immune responses. Tumor vascular maturity and function were also improved, and an insignificant change in vascular density resulting in enhanced blood perfusion and inhibited tumor growth and metastasis were observed. Therefore, this research unveils the crucial role of TAM polarization on UTMD-induced tumor vessel normalization and inhibition of tumor progression. These findings offer a novel insight into UTMD-mediated drug delivery for anti-tumor and anti-angiogenic treatment.
10.1016/j.biopha.2023.114322
A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer.
Dimcevski Georg,Kotopoulis Spiros,Bjånes Tormod,Hoem Dag,Schjøtt Jan,Gjertsen Bjørn Tore,Biermann Martin,Molven Anders,Sorbye Halfdan,McCormack Emmet,Postema Michiel,Gilja Odd Helge
Journal of controlled release : official journal of the Controlled Release Society
BACKGROUND:The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival. METHODS:Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5min. SonoVue® was injected intravenously (0.5ml followed by 5ml saline every 3.5min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy. RESULTS:The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n=10) tolerated an increased number of gemcitabine cycles compared with historical controls (n=63 patients; average of 8.3±6.0cycles, versus 13.8±5.6cycles, p=0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n=10) was also increased from 8.9months to 17.6months (p=0.011). CONCLUSIONS:It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.
10.1016/j.jconrel.2016.10.007
Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model.
Yu Mi Hye,Lee Jae Young,Kim Hae Ri,Kim Bo Ram,Park Eun-Joo,Kim Hoe Suk,Han Joon Koo,Choi Byung Ihn
Korean journal of radiology
OBJECTIVE:To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. MATERIALS AND METHODS:A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. RESULTS:The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. CONCLUSION:High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.
10.3348/kjr.2016.17.5.779
Selecting the optimal parameters for sonoporation of pancreatic cancer in a pre-clinical model.
Schultz Christopher W,Ruiz de Garibay Gorka,Langer Anika,Liu Ji-Bin,Dhir Teena,Leitch Calum,Wessner Corinne E,Mayoral Mireia,Zhang Bo,Popa Mihaela,Huang Chunwang,Kotopoulis Spiros,Luo Xianghong,Zhen Yanhua,Niu Sihua,Torkzaban Mehnoosh,Wallace Kirk,Eisenbrey John R,Brody Jonathan R,McCormack Emmet,Forsberg Flemming
Cancer biology & therapy
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the modern world, in part due to poor delivery of chemotherapeutics. Sonoporation can be used to enhance the efficacy of standard of care therapies for PDAC. Using xenograft models of PDAC we investigate sonoporation using four ifferent ultrasound contrast agents (UCAs) and two ultrasound regimens to identify the ideal parameters to increase therapeutic efficacy. MIA-PaCa2 xenografts in over 175 immunodeficient mice were treated with gemcitabine and paclitaxel and subjected to low or high power ultrasound (60 and 200 mW/cm respectively) in conjunction with one of four different UCAs. The UCAs investigated were Definity®, SonoVue®, Optison™ or Sonazoid™. Tumor volumes, vascularity, hemoglobin, and oxygenation were measured and compared to controls. High power treatment in conjunction with Sonazoid sonoporation led to significantly smaller tumors when started early (tumors ~50mm; = .0105), while no UCAs significantly increased efficacy in the low power cohort. This trend was also found in larger tumors (~250mm) where all four UCA agents significantly increased therapeutic efficacy in the high power group ( < .01), while only Definity and SonoVue increased efficacy in the low power cohort ( < .03). Overall, the higher power ultrasound treatment modality was more consistently effective at decreasing tumor volume and increasing vascularity characteristics. In conclusion, Sonazoid was the most consistently effective UCA at decreasing tumor volume and increasing vascularity. Thus, we are pursuing a larger phase II clinical trial to validate the increased efficacy of sonoporation in conjunction with chemotherapy in PDAC patients.
10.1080/15384047.2021.1881026
Low-Intensity Focused Ultrasound Produces Immune Response in Pancreatic Cancer.
Ultrasound in medicine & biology
Pancreatic adenocarcinoma is an aggressive malignancy with limited therapeutic treatments available and a 5-y survival less than 10%. Pancreatic cancers have been found to be immunogenically "cold" with a largely immunosuppressive tumor microenvironment. There is emerging evidence that focused ultrasound can induce changes in the tumor microenvironment and have a constructive impact on the effect of immunotherapy. However, the immune cells and timing involved in these effects remain unclear, which is essential to determining how to combine immunotherapy with ultrasound for treatment of pancreatic adenocarcinoma. We used low-intensity focused ultrasound and microbubbles (LoFU + MBs), which can mechanically disrupt cellular membranes and vascular endothelia, to treat subcutaneous pancreatic tumors in C57BL/6 mice. To evaluate the immune cell landscape and expression and/or localization of damage-associated molecular patterns (DAMPs) as a response to ultrasound, we performed flow cytometry and histology on tumors and draining lymph nodes 2 and 15 d post-treatment. We repeated this study on larger tumors and with multiple treatments to determine whether similar or greater effects could be achieved. Two days after treatment, draining lymph nodes exhibited a significant increase in activated antigen presenting cells, such as macrophages, as well as expansion of CD8 T cells and CD4 T cells. LoFU + MB treatment caused localized damage and facilitated the translocation of DAMP signals, as reflected by an increase in the cytoplasmic index for high-mobility-group box 1 (HMGB1) at 2 d. Tumors treated with LoFU + MBs exhibited a significant decrease in growth 15 d after treatment, indicating a tumor response that has the potential for additive effects. Our studies indicate that focused ultrasound treatments can cause tumoral damage and changes in macrophages and T cells 2 d post-treatment. The majority of these effects subsided after 15 d with only a single treatment, illustrating the need for additional treatment types and/or combination with immunotherapy. However, when larger tumors were treated, the effects seen at 2 d were diminished, even with an additional treatment. These results provide a working platform for further rational design of focused ultrasound and immunotherapy combinations in poorly immunogenic cancers.
10.1016/j.ultrasmedbio.2022.06.017
Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial.
European radiology
OBJECTIVES:Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB. METHODS:Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events. RESULTS:Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups. CONCLUSIONS:The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events. TRIAL REGISTRATION:ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events. KEY POINTS:• This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.
10.1007/s00330-023-10210-4
Characteristic Blood-Perfusion Reduction of Walker 256 Tumor Induced by Diagnostic Ultrasound and Microbubbles.
Li Ningshan,Liao Yiyi,Tang Jiawei
Ultrasound in medicine & biology
Tumor angiogenesis is characterized by a defective, leaky and fragile microvascular construction, and microbubble-enhanced ultrasound (MEUS) with high-pressure amplitude is capable of disrupting tumor microvasculature and arresting blood perfusion. In this study, we tried to investigate whether the blood perfusion of a malignant tumor can be characteristically interrupted by combining microbubbles and diagnostic ultrasound (US). Twenty-nine Sprague-Dawley (SD) rats with subcutaneous Walker 256 tumors and seven healthy SD rats were included. Fifteen tumors were treated by MEUS, which combined constant microbubble injection and 20 episodes of irradiation by diagnostic US (i.e., acoustic radiation force impulse [ARFI] imaging). The other 14 tumors were treated by ARFI or sham US only. Seven skeleton muscles from healthy SD rats were also treated with MEUS, serving as the control. Contrast-enhanced ultrasound (CEUS) was performed before and after all treatments. The blood perfusion of the tumor MEUS group showed a significant drop immediately after treatment, followed by a quick, incomplete perfusion recovery within 10-20 min. The visual perfusion scoring result was consistent with the quantitative analysis by CEUS peak intensity. However, there were no significant perfusion changes in the tumor control groups or the muscle control group. Histologic examination found severe microvascular disruption and hemorrhage in the MEUS-treated tumors but not in the control groups. Therefore, the treatment combining diagnostic US and microbubbles can specifically decrease or interrupt the blood perfusion of Walker 256 tumors, which could be a potential new imaging method for diagnosing malignant tumors.
10.1016/j.ultrasmedbio.2020.07.009
Augmentation of tumour perfusion by ultrasound and microbubbles: A preclinical study.
Ultrasonics
BACKGROUND:Hypoperfusion and the resulting hypoxia in solid tumours are critical causes of treatment resistance. Ultrasound-stimulated microbubbles (USMB) enhance tumour perfusion in a mechanism named the "sononeoperfusion" effect, which may relieve tumour hypoperfusion and hypoxia. The aim of this study was to determine the optimal mechanical index (MI) and therapeutic ultrasound exposure time for the sononeoperfusion effect and preliminarily explore the mechanism of sononeoperfusion and its effect on tumours. METHODS:A total of 155 mice bearing MC38 tumours were included in this study. A modified diagnostic ultrasound and microbubbles (Zhifuxian) was used for USMB treatment. Tumour perfusion was evaluated by contrast-enhanced ultrasound (CEUS) and Hoechst 33342. The therapeutic pulse was operated with MIs of 0.1 to 0.5. The ultrasound exposure time was set from 150 s to 600 s. Endothelial nitric oxide synthase (eNOS) inhibition and NO, ATP, and phospho-eNOS (p-eNOS) detection were performed to explore the mechanisms of sononeoperfusion. Hypoxia-inducible factor-1α (HIF-1α) and tumour oxygen partial pressure (pO) represent hypoxic tumour conditions. RESULTS:Tumour perfusion was increased after USMB treatment at MIs of 0.1-0.4 and ultrasound exposure times of 150 s to 600 s, with optimal augmentation achieved at an MI of 0.3 and ultrasound exposure time of 450 s. The mean fluorescence intensity of Hoechst 33342 after USMB treatment was stronger than that of the control group. Biochemical assays showed a significant increase in ATP, p-eNOS and NO after USMB treatment. PO in tumour tissue increased significantly after USMB treatment and was maintained for more than 20 min. CONCLUSIONS:The best sononeoperfusion effect was obtained with an MI of 0.3 and an ultrasound exposure time of 450 s. The effect is most likely related to NO and ATP increases. The sononeoperfusion effect might be a novel way to ameliorate tumour hypoperfusion and hypoxia.
10.1016/j.ultras.2023.107219
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
International journal of pharmaceutics
Ultrasound is one of the safest and most advanced medical imaging technologies that is widely used in clinical practice. Ultrasound microbubbles, traditionally used for contrast-enhanced imaging, are increasingly applied in Ultrasound-targeted Microbubble Destruction (UTMD) technology which enhances tissue and cell membrane permeability through cavitation and sonoporation, to result in a promising therapeutic gene/drug delivery strategy. Here, we review recent developments in the application of UTMD-mediated gene and drug delivery in the diagnosis and treatment of tumors, including the concept, mechanism of action, clinical application status, and advantages of UTMD. Furthermore, the future perspectives that should be paid more attention to in this field are prospected.
10.1016/j.ijpharm.2021.121412
Application of Ultrasound Combined with Microbubbles for Cancer Therapy.
International journal of molecular sciences
At present, cancer is one of the leading causes of death worldwide. Treatment failure remains one of the prime hurdles in cancer treatment due to the metastatic nature of cancer. Techniques have been developed to hinder the growth of tumours or at least to stop the metastasis process. In recent years, ultrasound therapy combined with microbubbles has gained immense success in cancer treatment. Ultrasound-stimulated microbubbles (USMB) combined with other cancer treatments including radiation therapy, chemotherapy or immunotherapy has demonstrated potential improved outcomes in various in vitro and in vivo studies. Studies have shown that low dose radiation administered with USMB can have similar effects as high dose radiation therapy. In addition, the use of USMB in conjunction with radiotherapy or chemotherapy can minimize the toxicity of high dose radiation or chemotherapeutic drugs, respectively. In this review, we discuss the biophysical properties of USMB treatment and its applicability in cancer therapy. In particular, we highlight important preclinical and early clinical findings that demonstrate the antitumour effect combining USMB and other cancer treatment modalities (radiotherapy and chemotherapy). Our review mainly focuses on the tumour vascular effects mediated by USMB and these cancer therapies. We also discuss several current limitations, in addition to ongoing and future efforts for applying USMB in cancer treatment.
10.3390/ijms23084393
Ultrasound in tumor immunotherapy: Current status and future developments.
Ho Yi-Ju,Li Ju-Pi,Fan Ching-Hsiang,Liu Hao-Li,Yeh Chih-Kuang
Journal of controlled release : official journal of the Controlled Release Society
Immunotherapy has considerable potential in eliminating cancers by activating the host's own immune system, while the thermal and mechanical effects of ultrasound have various applications in tumor therapy. Hyperthermia, ablation, histotripsy, and microbubble stable/inertial cavitation can alter the tumor microenvironment to enhance immunoactivation to inhibit tumor growth. Microbubble cavitation can increase vessel permeability and thereby improve the delivery of immune cells, cytokines, antigens, and antibodies to tumors. Violent microbubble cavitation can disrupt tumor cells and efficiently expose them to numerous antigens so as to promote the maturity of antigen-presenting cells and subsequent adaptive immune-cell activation. This review provides an overview and compares the mechanisms of ultrasound-induced immune modulation for peripheral and brain tumor therapy, even degenerative brain diseases therapy. The possibility of reversing tumors to an immunoactive microenvironment by utilizing the cavitation of microbubbles loaded with therapeutic gases is also proposed as another potential pathway for immunotherapy. Finally, we disuss the challenges and opportunities of ultrasound in immunotherapy for future development.
10.1016/j.jconrel.2020.04.023
Enhanced Vascular Permeability by Microbubbles and Ultrasound in Drug Delivery.
Omata Daiki,Munakata Lisa,Maruyama Kazuo,Suzuki Ryo
Biological & pharmaceutical bulletin
Ultrasound and microbubbles, an ultrasound contrast agent, have recently increased attention to developing novel drug delivery systems. Ultrasound exposure can induce mechanical effects derived from microbubbles behaviors such as an expansion, contraction, and collapse depending on ultrasound conditions. These mechanical effects induce several biological effects, including enhancement of vascular permeability. For drug delivery, one promising approach is enhancing vascular permeability using ultrasound and microbubbles, resulting in improved drug transport to targeted tissues. This approach is applied to several tissues and drugs to cure diseases. This review describes the enhancement of vascular permeability by ultrasound and microbubbles and its therapeutic application, including our recent study. We also discuss the current situation of the field and its potential future perspectives.
10.1248/bpb.b21-00453
Ultrasound and Microbubbles Increase the Uptake of Platinum in Murine Orthotopic Pancreatic Tumors.
Ultrasound in medicine & biology
OBJECTIVE:Currently available cytotoxic treatments have limited effect on pancreatic ductal adenocarcinoma (PDAC) because desmoplastic stroma limits drug delivery. Efforts have been made to overcome these barriers by drug targeting the tumor microenvironment. Results so far are promising, but without clinical impact. Our aim was to investigate whether ultrasound and microbubbles could improve the uptake and therapeutic response of conventional chemotherapy. METHODS:Orthotopic pancreatic tumors growing in mice were treated with commercially available FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin and calcium folinate) and SonoVue microbubbles combined with focused ultrasound. Tumor uptake of platinum (Pt) was measured by inductively coupled plasma mass spectroscopy (ICP-MS), and tumor volumes were measured by ultrasound imaging. DISCUSSION:Uptake of Pt, the active ingredient of oxaliplatin, was significantly increased after ultrasound treatment of orthotopic PDAC tumors. Multiple injections with FOLFIRONOX increased the amount of Pt in tumors. However, the enhanced accumulation did not improve therapeutic response. Increased uptake of Pt confirms that ultrasound and microbubbles have potential in clinical practice with existing drugs. CONCLUSION:The lack of therapeutic response, despite increased uptake in tumor tissue, emphasizes the importance of studying how to overcome stromal barriers.
10.1016/j.ultrasmedbio.2023.01.014