Recent Advances in Microbubble-Augmented Cancer Therapy

doi:10.37015/AUDT.2020.200055

Abstract

Abstract:

Contrast-enhanced ultrasound (CEUS) applications in cancer management have expanded over the past two decades. Through detection of vascularization and perfusion changes, CEUS provides a potentially reliable means of early prediction of response to different cancer therapies including systemic chemotherapy and locoregional therapies. Ultrasound-induced cavitation of contrast agents has a range of effects on the surrounding microenvironment. These effects can be manipulated to sensitize the tumors to radio- and chemotherapy, as well as achieve targeted delivery through drug-loaded contrast agents. Newer forms of drug carriers are being developed with improved drug-carrying capacity and tissue penetration. This review aims at providing a synopsis of the latest developments in CEUS’ use in oncologic therapy. While the majority of work described in this review is still in the pre-clinical phases, results have been encouraging and show potential translational benefit for cancer patients in the near future.

Key words: Contrast-enhanced ultrasound; Microbubble cavitation; Microbubble-augmented; Radiation enhancement; Ultrasound-stimulated microbubbles

Mohamed Tantawi, MD, Ji-Bin Liu, MD, John R Eisenbrey, PhD. Recent Advances in Microbubble-Augmented Cancer Therapy. Advanced Ultrasound in Diagnosis and Therapy, 2020, 4(3): 155-168.

References

[1]	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424.
[2]	Park JW, Hong K, Kirpotin DB, Colbern G, Shalaby R, Baselga J, et al. Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. Clin Cancer Res 2002; 8:1172-81.
[3]	Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53:615-27.
[4]	Goldberg BB, Liu JB, Forsberg F. Ultrasound contrast agents: a review. Ultrasound Med Biol 1994; 20:319-33.
[5]	Kooiman K, Roovers S, Langeveld SAG, Kleven RT, Dewitte H, O'Reilly MA, et al. Ultrasound-responsive cavitation nuclei for therapy and drug delivery.Ultrasound Med Biol 2020; 46:1296-325.
[6]	Fournier L, Bellucci A, Vano Y, Bouaboula M, Thibault C, Elaidi R, et al. Imaging response of antiangiogenic and immune-oncology drugs in metastatic renal cell carcinoma (mRCC): current status and future challenges. Kidney Cancer 2017; 1:107-14.
[7]	Lassau N, Bonastre J, Kind M, Vilgrain V, Lacroix J, Cuinet M, et al. Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study. Invest Radiol 2014; 49:794-800.
[8]	Hudson JM, Bailey C, Atri M, Stanisz G, Milot L, Williams R, et al. The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib. Eur Radiol 2018; 28:2281-90.
[9]	Frampas E, Lassau N, Zappa M, Vullierme MP, Koscielny S, Vilgrain V. Advanced hepatocellular carcinoma: early evaluation of response to targeted therapy and prognostic value of perfusion CT and dynamic contrast enhanced-ultrasound. preliminary results.Eur J Radiol 2013; 82:e205-11.
[10]	Lassau N, Koscielny S, Chami L, Chebil M, Benatsou B, Roche A, et al. Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification--preliminary results. Radiology 2011; 258:291-300.
[11]	Ueda N, Nagira H, Sannomiya N, Ikunishi S, Hattori Y, Kamida A, et al. Contrast-enhanced ultrasonography in evaluation of the therapeutic effect of chemotherapy for patients with liver metastases. Yonago Acta Med 2016; 59:255-61.
[12]	Schirin-Sokhan R, Winograd R, Roderburg C, Bubenzer J, do ó NC, Guggenberger D, et al. Response evaluation of chemotherapy in metastatic colorectal cancer by contrast enhanced ultrasound.World J Gastroenterol 2012; 18:541-5.
[13]	Amadori M, Barone D, Scarpi E, Oboldi D, Amadori E, Bandi G, et al. Dynamic contrast-enhanced ultrasonography (D-CEUS) for the early prediction of bevacizumab efficacy in patients with metastatic colorectal cancer. Eur Radiol 2018; 28:2969-78.
[14]	Kuorda H, Abe T, Fujiwara Y, Okamoto T, Yonezawa M, Sato H, et al. Change in arterial tumor perfusion is an early biomarker of lenvatinib efficacy in patients with unresectable hepatocellular carcinoma. World J Gastroenterol 2019; 25:2365-72.
[15]	Jia K, Li L, Wu XJ, Hao MJ, Xue HY. Contrast-enhanced ultrasound for evaluating the pathologic response of breast cancer to neoadjuvant chemotherapy: A meta-analysis. Medicine (Baltimore) 2019; 98:e14258.
[16]	Nam K, Eisenbrey JR, Stanczak M, Sridharan A, Berger AC, Avery T, et al. Monitoring neoadjuvant chemotherapy for breast cancer by using three-dimensional subharmonic aided pressure estimation and imaging with US contrast agents: preliminary experience. Radiology 2017; 285:53-62.
[17]	Mauri G, Porazzi E, Cova L, Restelli U, Tondolo T, Bonfanti M, et al. Intraprocedural contrast-enhanced ultrasound (CEUS) in liver percutaneous radiofrequency ablation: clinical impact and health technology assessment. Insights Imaging 2014; 5:209-16.
[18]	Liu Z, Wang X, Xing L, Pan Y, Huang S. The application comparison of contrast-enhanced ultrasound and contrast-enhanced computed tomography in radiofrequency ablation treatment for hepatocellular carcinoma. Cancer Biother Radiopharm 2019; 34:621-25.
[19]	Zhao X, Wang W, Zhang S, Liu J, Zhang F, Ji C, et al. Improved outcome of percutaneous radiofrequency ablation in renal cell carcinoma: a retrospective study of intraoperative contrast-enhanced ultrasonography in 73 patients. Abdom Imaging 2012; 37:885-91.
[20]	Shi W, He Y, Ding W, Gong S, Wang Y, Xiao J, et al. Contrast-enhanced ultrasonography used for post-treatment responses evaluation of radiofrequency ablations for hepatocellular carcinoma: a meta-analysis. Br J Radiol 2016; 89:20150973.
[21]	Xuan M, Zhou F, Ding Y, Zhu Q, Dong J, Zhou H, et al. Diagnostic accuracy of contrast-enhanced ultrasound in assessing the therapeutic response to radio frequency ablation for liver tumors: systematic review and meta-analysis. Surg Endosc 2018; 32:2067-75.
[22]	Cao J, Dong Y, Mao F, Wang W. Dynamic three-dimensional contrast-enhanced ultrasound to predict therapeutic response of radiofrequency ablation in hepatocellular carcinoma: preliminary findings. Biomed Res Int 2018; 2018: 6469703.
[23]	Stanczak M, Lyshchik A, Shaw CM, Forsberg F, Eisenbrey JR. Contrast-enhanced sonography and fusion technology for assessment of an embolized renal angiomyolipoma. J Ultrasound Med 2016; 35:2292-5.
[24]	Eisenbrey JR, Shaw CM, Lyshchik A, Machado P, Lallas CD, Trabulsi EJ, et al. Contrast-enhanced subharmonic and harmonic ultrasound of renal masses undergoing percutaneous cryoablation. Acad Radiol 2015; 22:820-6.
[25]	Calio BP, Lyshchik A, Li J, Stanczak M, Shaw CM, Adamo R, et al. Long term surveillance of renal cell carcinoma recurrence following ablation using 2D and 3D Contrast-enhanced ultrasound. Urology 2018; 121:189-96.
[26]	Guo F, Hu B, Chen L, Li J. Clinical application of contrast-enhanced ultrasound after percutaneous renal tumor ablation. Br J Radiol 2019; 92:20190183.
[27]	Olson MC, Abel EJ, Mankowski Gettle L. Contrast-enhanced ultrasound in renal imaging and intervention. Curr Urol Rep 2019; 20:73.
[28]	Guo F, Hu B, Chen L, Li J. Clinical application of contrast-enhanced ultrasound after percutaneous renal tumor ablation. Br J Radiol 2019; 92:20190183.
[29]	Kono Y, Lucidarme O, Choi SH, Rose SC, Hassanein TI, Alpert E, et al. Contrast-enhanced ultrasound as a predictor of treatment efficacy within 2 weeks after transarterial chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2007; 18:57-65.
[30]	Gummadi S, Eisenbrey JR, Lyshchik A. Contrast-enhanced ultrasonography in interventional oncology. Abdom Radiol (NY) 2018; 43:3166-75.
[31]	Shaw CM, Eisenbrey JR, Lyshchik A, O'Kane PL, Merton DA, Machado P, et al.Contrast-enhanced ultrasound evaluation of residual blood flow to hepatocellular carcinoma after treatment with transarterial chemoembolization using drug-eluting beads: a prospective study. J Ultrasound Med 2015; 34:859-67.
[32]	Zhong J, Su Z, Zhang Y, Zhang H, Lin P, Tang X, et al. Contrast-enhanced ultrasonography versus contrast-enhanced computed tomography for assessment of residual tumor from hepatocellular carcinoma treated with transarterial chemoembolization: a meta-analysis. J Ultrasound Med 2018; 37:1881-90.
[33]	Yang Y, Li Q, Guo X, Tu J, Zhang D. Mechanisms underlying sonoporation: Interaction between microbubbles and cells. Ultrason Sonochem 2020; 67:105096.
[34]	Qin P, Han T, Yu ACH, Xu L. Mechanistic understanding the bioeffects of ultrasound-driven microbubbles to enhance macromolecule delivery. J Control Release 2018; 272:169-81.
[35]	Meijering BD, Juffermans LJ, van Wamel A, Henning RH, Zuhorn IS, Emmer M, et al. Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation.Circ Res 2009; 104:679-87.
[36]	Jain A, Tiwari A, Verma A, Jain SK. Ultrasound-based triggered drug delivery to tumors. Drug Deliv Transl Res 2018; 8:150-64.
[37]	Czarnota GJ. Ultrasound-stimulated microbubble enhancement of radiation response. Biol Chem 2015; 396:645-57.
[38]	Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300:1155-9.
[39]	Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003; 22:5897-906.
[40]	Al-Mahrouki AA, Karshafian R, Giles A, Czarnota GJ. Bioeffects of ultrasound-stimulated microbubbles on endothelial cells: gene expression changes associated with radiation enhancement in vitro. Ultrasound Med Biol 2012; 38:1958-69.
[41]	Nofiele JT, Karshafian R, Furukawa M, Al Mahrouki A, Giles A, Wong S, et al. Ultrasound-activated microbubble cancer therapy: ceramide production leading to enhanced radiation effect in vitro. Technol Cancer Res Treat 2013; 12:53-60.
[42]	[ Czarnota GJ, Karshafian R, Burns PN, Wong S, Al Mahrouki A, Lee JW, et al. Tumor radiation response enhancement by acoustical stimulation of the vasculature. Proc Natl Acad Sci U S A 2012; 109:E2033-41.
[43]	Al-Mahrouki AA, Iradji S, Tran WT, Czarnota GJ. Cellular characterization of ultrasound-stimulated microbubble radiation enhancement in a prostate cancer xenograft model. Dis Model Mech 2014; 7:363-72.
[44]	Tran WT, Iradji S, Sofroni E, Giles A, Eddy D, Czarnota GJ. Microbubble and ultrasound radioenhancement of bladder cancer. Br J Cancer 2012; 107:469-76.
[45]	Lai P, Tarapacki C, Tran WT, El Kaffas A, Lee J, Hupple C, et al. Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo. Oncoscience 2016; 3:98-108.
[46]	Daecher A, Stanczak M, Liu JB, Zhang J, Du S, Forsberg F, et al. Localized microbubble cavitation-based antivascular therapy for improving HCC treatment response to radiotherapy. Cancer Lett 2017; 411:100-05.
[47]	Escoffre JM, Piron J, Novell A, Bouakaz A. Doxorubicin delivery into tumor cells with ultrasound and microbubbles. Mol Pharm 2011; 8:799-806.
[48]	Lee NG, Berry JL, Lee TC, Wang AT, Honowitz S, Murphree AL, et al. Sonoporation enhances chemotherapeutic efficacy in retinoblastoma cells in vitr. Invest Ophthalmol Vis Sci 2011; 52:3868-73.
[49]	Sorace AG, Warram JM, Umphrey H, Hoyt K. Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer. J Drug Target 2012; 20:43-54.
[50]	Heath CH, Sorace A, Knowles J, Rosenthal E, Hoyt K. Microbubble therapy enhances anti-tumor properties of cisplatin and cetuximab in vitro and in vivo. Otolaryngol Head Neck Surg 2012; 146:938-45.
[51]	Sasaki N, Kudo N, Nakamura K, Lim SY, Murakami M, Kumara WR, et al. Ultrasound image-guided therapy enhances antitumor effect of cisplatin. J Med Ultrason (2001) 2014; 41:11-21.
[52]	Escoffre JM, Novell A, Serrière S, Lecomte T, Bouakaz A. Irinotecan delivery by microbubble-assisted ultrasound: in vitro validation and a pilot preclinical study. Mol Pharm 2013; 10:2667-75.
[53]	Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW, et al. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 2010; 255:415-25.
[54]	Goertz DE, Todorova M, Mortazavi O, Agache V, Chen B, Karshafian R, et al. Antitumor effects of combining docetaxel (taxotere) with the antivascular action of ultrasound stimulated microbubbles. PLoS One 2012; 7:e52307.
[55]	Zhao YZ, Dai DD, Lu CT, Lv HF, Zhang Y, Li X, et al. Using acoustic cavitation to enhance chemotherapy of DOX liposomes: experiment in vitro and in vivo. Drug Dev Ind Pharm 2012; 38:1090-8.
[56]	Park EJ, Zhang YZ, Vykhodtseva N, McDannold N. Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model.J Control Release 2012; 163:277-84.
[57]	Kotopoulis S, Delalande A, Popa M, Mamaeva V, Dimcevski G, Gilja OH, et al. Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer xenograft. Mol Imaging Biol 2014; 16:53-62.
[58]	Xiao N, Liu J, Liao L, Sun J, Jin W, Shu X. Improved delivery of doxorubicin by altering the tumor microenvironment using ultrasound combined with microbubbles and chemotherapy. J buon 2019; 24:844-52.
[59]	Kotopoulis S, Dimcevski G, Gilja OH, Hoem D, Postema M. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: a clinical case study. Med Phys 2013; 40:072902.
[60]	Dimcevski G, Kotopoulis S, Bj?nes T, Hoem D, Schj?tt J, Gjertsen BT, et al. A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. J Control Release 2016; 243:172-81.
[61]	Castle J, Kotopoulis S, Forsberg F. Sonoporation for augmenting chemotherapy of pancreatic ductal adenocarcinoma. Methods Mol Biol 2020; 2059: 191-205.
[62]	Wang Y, Li Y, Yan K, Shen L, Yang W, Gong J, et al. Clinical study of ultrasound and microbubbles for enhancing chemotherapeutic sensitivity of malignant tumors in digestive system. Chin J Cancer Res 2018; 30:553-63.
[63]	Yousefian B, Firoozabadi SM, Mokhtari-Dizaji M. Sonochemotherapy of breast adenocarcinoma: an experimental in vivo model. J Ultrasound 2015; 18:165-71.
[64]	Burke CW, Alexander Et, Timbie K, Kilbanov AL, Price RJ. Ultrasound-activated agents comprised of 5FU-bearing nanoparticles bonded to microbubbles inhibit solid tumor growth and improve survival. Mol Ther 2014; 22:321-28.
[65]	Snipstad S, Berg S, M?rch Y, Bj?rk?y A, Sulheim E, Hansen R, et al. Ultrasound improves the delivery and therapeutic effect of nanoparticle-stabilized microbubbles in breast cancer xenografts. Ultrasound Med Biol 2017; 43:2651-69.
[66]	Sirsi SR, Borden MA. State-of-the-art materials for ultrasound-triggered drug delivery. Adv Drug Deliv Rev 2014; 72:3-14.
[67]	Ibsen S, Schutt CE, Esener S. Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment. Drug Des Devel Ther 2013; 7:375-88.
[68]	Kwan JJ, Myers R, Coviello CM, Graham SM, Shah AR, Stride E, et al. Ultrasound-propelled nanocups for drug delivery. Small 2015; 11:5305-14.
[69]	Cao Y, Chen Y, Yu T, Guo Y, Liu F, Yao Y, et al. Drug release from phase-changeable nanodroplets triggered by low-intensity focused ultrasound. Theranostics 2018; 8:1327-39.
[70]	Stride E, Segers T, Lajoinie G, Cherkaoui S, Bettinger T, Versluis M, et al. Microbubble agents: new directions. Ultrasound Med Biol 2020; 46:1326-43.
[71]	Luo W, Wen G, Yang L, Tang J, Wang J, Wang J, et al. Dual-targeted and pH-sensitive doxorubicin prodrug-microbubble complex with ultrasound for tumor treatment. Theranostics 2017; 7:452-65.
[72]	Xing L, Shi Q, Zheng K, Shen M, Ma J, Li F, et al. Ultrasound-mediated microbubble destruction (UMMD) facilitates the delivery of CA19-9 targeted and paclitaxel loaded mPEG-PLGA-PLL nanoparticles in pancreatic cancer. Theranostics 2016; 6:1573-87.
[73]	Jablonowski LJ, Cochran MC, Eisenbrey JR, Teraphongphom NT, Wheatley MA. Shell effects on acoustic performance of a drug-delivery system activated by ultrasound. J Biomed Mater Res A 2017; 105:3189-96.
[74]	McEwan C, Kamila S, Owen J, Nesbitt H, Callan B, Borden M, et al. Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.Biomaterials 2016; 80:20-32.
[75]	Nesbitt H, Sheng Y, Kamila S, Logan K, Thomas K, Callan B, et al. Gemcitabine loaded microbubbles for targeted chemo-sonodynamic therapy of pancreatic cancer. J Control Release 2018; 279:8-16.
[76]	Kotopoulis S, Stigen E, Popa M, Safont MM, Healey A, Kv?le S, et al. Sonoporation with acoustic cluster therapy (ACT?) induces transient tumour volume reduction in a subcutaneous xenograft model of pancreatic ductal adenocarcinoma. J Control Release 2017; 245:70-80.
[77]	Wischhusen JC, Chowdhury SM, Lee T, Wang H, Bachawal S, Devulapally R, et al. Ultrasound-mediated delivery of miRNA-122 and anti-miRNA-21 therapeutically immunomodulates murine hepatocellular carcinoma in vivo. J Control Release 2020; 321:272-84.
[78]	Bai M, Shen M, Teng Y, Sun Y, Li F, Zhang X, et al. Enhanced therapeutic effect of Adriamycin on multidrug resistant breast cancer by the ABCG2-siRNA loaded polymeric nanoparticles assisted with ultrasound. Oncotarget 2015; 6:43779-90.
[79]	Zhang B, Chen M, Zhang Y, Chen W, Zhang L, Chen L. An ultrasonic nanobubble-mediated PNP/fludarabine suicide gene system: A new approach for the treatment of hepatocellular carcinoma. PLoS One 2018; 13:e0196686.
[80]	Kopechek JA, Carson AR, McTiernan CF, Chen X, Hasjim B, Lavery L, et al. Ultrasound targeted microbubble destruction-mediated delivery of a transcription factor decoy inhibits STAT3 signaling and tumor growth.Theranostics 2015; 5:1378-87.
[81]	Ren ST, Shen S, He XY, Liao YR, Sun PF, Wang B, et al. The effect of docetaxel-loaded micro-bubbles combined with low-frequency ultrasound in H22 hepatocellular carcinoma-bearing mice. Ultrasound Med Biol 2016; 42:549-60.
[82]	Eisenbrey JR, Burstein OM, Kambhampati R, Forsberg F, Liu JB, Wheatley MA. Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery. J Control Release 2010; 143:38-44.
[83]	Cochran MC, Eisenbrey JR, Soulen MC, Schultz SM, Ouma RO, White SB, et al. Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model. Acad Radiol 2011; 18:1341-8.
[84]	Teraphongphom N, Chhour P, Eisenbrey JR, Naha PC, Witschey WR, Opasanont B, et al. Nanoparticle loaded polymeric microbubbles as contrast agents for multimodal imaging. Langmuir 2015; 31:11858-67.
[85]	Gong Y, Wang Z, Dong G, Sun Y, Wang X, Rong Y, et al. Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits. Drug Deliv 2016; 23:2280-89.
[86]	Chen K, Zhang L. Effect of drug-loaded microbubbles combined with ultrasound on the apoptosis of cancer cells and the expression of Bax and Bcl-2 in a rabbit VX2 liver tumor model. Biosci Rep 2019; 39:
[87]	Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits.Radiology 2001; 220:640-6.
[88]	Treat LH, McDannold N, Zhang Y, Vykhodtseva N, Hynynen K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma.Ultrasound Med Biol 2012; 38:1716-25.
[89]	Ting CY, Fan CH, Liu HL, Huang CY, Hsieh HY, Yen TC, et al. Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 2012; 33:704-12.
[90]	Fan CH, Ting CY, Liu HL, Huang CY, Hsieh HY, Yen TC, et al. Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials 2013; 34:2142-55.
[91]	Yan F, Li L, Deng Z, Jin Q, Chen J, Yang W, et al. Paclitaxel-liposome-microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers. J Control Release 2013; 166:246-55.
[92]	Logan K, Foglietta F, Nesbitt H, Sheng Y, McKaig T, Kamila S, et al. Targeted chemo-sonodynamic therapy treatment of breast tumours using ultrasound responsive microbubbles loaded with paclitaxel, doxorubicin and Rose Bengal.Eur J Pharm Biopharm 2019; 139:224-31.
[93]	Tinkov S, Coester C, Serba S, Geis NA, Katus HA, Winter G, et al. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization. J Control Release 2010; 148:368-72.
[94]	Kuo TT, Wang CH, Wang JY, Chiou HJ, Fan CH, Yeh CK. Concurrent osteosarcoma theranostic strategy using contrast-enhanced ultrasound and drug-loaded bubbles. Pharmaceutics 2019; 11:
[95]	Pu C, Chang S, Sun J, Zhu S, Liu H, Zhu Y, et al. Ultrasound-mediated destruction of LHRHa-targeted and paclitaxel-loaded lipid microbubbles for the treatment of intraperitoneal ovarian cancer xenografts. Mol Pharm 2014; 11:49-58.
[96]	Cavalli R, Soster M, Argenziano M. Nanobubbles: a promising efficient tool for therapeutic delivery. Ther Deliv 2016; 7:117-38.
[97]	Maeda H. Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 2012; 164:138-44.
[98]	Meng M, Gao J, Wu C, Zhou X, Zang X, Lin X, et al. Doxorubicin nanobubble for combining ultrasonography and targeted chemotherapy of rabbit with VX2 liver tumor. Tumour Biol 2016; 37:8673-80.
[99]	Wu M, Wang Y, Wang Y, Zhang M, Luo Y, Tang J, et al. Paclitaxel-loaded and A10-3.2 aptamer-targeted poly(lactide-co-glycolic acid) nanobubbles for ultrasound imaging and therapy of prostate cancer.Int J Nanomedicine 2017; 12:5313-30.
[100]	Lea-Banks H, O'Reilly MA, Hynynen K.Ultrasound-responsive droplets for therapy: A review. J Control Release 2019; 293:144-54.
[101]	Liu J, Xu F, Huang J, Xu J, Liu Y, Yao Y, et al. Low-intensity focused ultrasound (LIFU)-activated nanodroplets as a theranostic agent for noninvasive cancer molecular imaging and drug delivery. Biomater Sci 2018; 6:2838-49.
[102]	Bush N, Healey A, Shah A, Box G, Kirkin V, Eccles S, et al. Theranostic attributes of acoustic cluster therapy and its use for enhancing the effectiveness of liposomal doxorubicin treatment of human triple negative breast cancer in mice. Front Pharmacol 2020; 11:75.
[103]	Fix SM, Borden MA, Dayton PA. Therapeutic gas delivery via microbubbles and liposomes. J Control Release 2015; 209:139-49.
[104]	Fix SM, Papadopoulou V, Velds H, Kasoji SK, Rivera JN, Borden MA, et al. Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model - A preliminary study. PLoS One 2018; 13:e0195667.
[105]	Eisenbrey JR, Albala L, Kramer MR, Daroshefski N, Brown D, Liu JB, et al. Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue. Int J Pharm 2015; 478:361-67.
[106]	Eisenbrey JR, Shraim R, Liu JB, Li J, Stanczak M, Oeffinger B, et al. Sensitization of hypoxic tumors to radiation therapy using ultrasound-sensitive oxygen microbubbles. Int J Radiat Oncol Biol Phys 2018; 101:88-96.
[107]	Delaney LJ, Ciraku L, Oeffinger BE, Wessner CE, Liu JB, Li J, et al. Breast cancer brain metastasis response to radiation after microbubble oxygen delivery in a murine model. J Ultrasound Med 2019; 38:3221-28.