First-in-Human Safety and Efficacy Study on Combination of High-Intensity Focused Ultrasound Sonication and Micellar Nanoparticle-Encapsulated Epirubicin, K-912; a Novel Sonodynamic Therapy for the Treatment of Refractory Abdominal Cancers

Yoshihiro Muragaki; Atsushi Sofuni; Jun Okamoto; Tohru Satoh; Hiroshi  Iseki; Soko Ikuta; Yasutsugu Asai; Shin Yoshizawa; Shin-ichiro Umemura; Takao Itoi

doi:10.51094/jxiv.1262

##article.authors##

Yoshihiro Muragaki Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
Atsushi Sofuni Department of Gastroenterology and Hepatology, Tokyo Medical University
Jun Okamoto Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
Tohru Satoh Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
Hiroshi Iseki Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
Soko Ikuta Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
Yasutsugu Asai Department of Gastroenterology and Hepatology, Tokyo Medical University
Shin Yoshizawa Communications Engineering, Tohoku University Graduate School of Engineering
Shin-ichiro Umemura Communications Engineering, Tohoku University Graduate School of Engineering
Takao Itoi Department of Gastroenterology and Hepatology, Tokyo Medical University

DOI:

https://doi.org/10.51094/jxiv.1262

キーワード:

3 3 design、 micellar nanoparticle-encapsulated epirubicin、 dose escalation、 high-intensity focused ultrasound、 pancreatic cancer、 sonodynamic therapy、 unresectable refractory tumor

抄録

Objective: Aims of this first-in-human clinical trial were to evaluate the safety and efficacy of sonodynamic therapy (SDT) using a newly developed triggered-pulse high-intensity focused ultrasound (HIFU) device, MS-2, and micellar nanoparticle-encapsulated epirubicin, K-912, in patients with unresectable refractory abdominal cancers.

Methods: This was a single center prospective exploratory clinical trial. The HIFU sonication power (75 and 150 W at 1 MHz) and K-912 dose (30 and 80 mg/m²) were increased incrementally (4 cohorts) according to 3+3 design. Each cohort consisted of three patients. K-912 was administered intravenously one day before HIFU treatment.

Results: A total of 12 patients with stage IV pancreatic cancer (n = 11) and cholangiocellular carcinoma (n = 1) completed the SDT. The mean sonication time and total number of sonication was 22.3 min and 17.4 shots, respectively. No adverse events of grade ≥3 were observed during the trial up to 30 days after HIFU treatment. No adverse events related to K-912 were noted. The HIFU sonication power and K-912 dose considered to be tolerable were 150 W and 80 mg/m², respectively. The rate of complete and partial tumor coagulative necrosis was 33.3% and 41.7%, respectively. The primary disease control rate was 66.7%. Pain was improved in 33.3% of patients.

Conclusions: This trial demonstrated that SDT using MS-2 and K-912 was safe and well tolerated in patients with advanced abdominal tumors and showed promising preliminary clinical activity.

利益相反に関する開示

The authors declare no conflicts of interest in association with the present study.

ダウンロード *前日までの集計結果を表示します

ダウンロード実績データは、公開の翌日以降に作成されます。

引用文献

Phenix CP, Togtema M, Pichardo S, Zehbe I, Curiel L. High intensity focused ultrasound technology, its scope and applications in therapy and drug delivery. J Pharm Pharm Sci. 2014;17(1):136-53.

Maloney E, Hwang JH. Emerging HIFU applications in cancer therapy. Int J Hyperthermia. 2015;31(3):302-9.

Gunderman A, Montayre R, Ranjan A, Chen Y. Review of Robot-Assisted HIFU Therapy. Sensors (Basel). 2023;23(7):3707.

De Maio A, Alfieri G, Mattone M, Ghanouni P, Napoli A. High-Intensity Focused Ultrasound Surgery for Tumor Ablation: A Review of Current Applications. Radiol Imaging Cancer. 2024;6(1):e230074.

Hipp E, Partanen A, Karczmar GS, Fan X. Safety limitations of MR-HIFU treatment near interfaces: a phantom validation. J Appl Clin Med Phys. 2012;13(2):3739.

Furusawa H, Namba K, Thomsen S, Akiyama F, Bendet A, Tanaka C, et al. Magnetic resonance-guided focused ultrasound surgery of breast cancer: reliability and effectiveness. J Am Coll Surg. 2006;203(1):54-63.

Li JJ, Xu GL, Gu MF, Luo GY, Rong Z, Wu PH, et al. Complications of high intensity focused ultrasound in patients with recurrent and metastatic abdominal tumors. World J Gastroenterol. 2007;13(19):2747-51.

Yumita N, Nishigaki R, Umemura K, Umemura S. Synergistic effect of ultrasound and hematoporphyrin on sarcoma 180. Jpn J Cancer Res. 1990;81(3):304-8.

Horise Y, Maeda M, Konishi Y, Okamoto J, Ikuta S, Okamoto Y, et al. Sonodynamic therapy with anticancer micelles and high-intensity focused ultrasound in treatment of canine cancer. Front Pharmacol. 2019;10:545.

Roovers S, Segers T, Lajoinie G, Deprez J, Versluis M, De Smedt SC, et al. The Role of ultrasound-driven microbubble dynamics in drug delivery: from microbubble fundamentals to clinical translation. Langmuir. 2019;35(31):10173-91.

Yasuda J, Yoshizawa S, Umemura S. Efficient generation of cavitation bubbles and reactive oxygen species using triggered high-intensity focused ultrasound sequence for sonodynamic treatment. Jpn J Appl Phys. 2016;55 (7S1):07KF24-1-5.

Lafond M, Yoshizawa S, Umemura S. Sonodynamic therapy: advances and challenges in clinical translation. J Ultrasound Med. 2019;38(3):567-80.

Yumita N, Nishigaki R, Umemura K, Umemura S. Hematoporphyrin as a sensitizer of cell-damaging effect of ultrasound. Jpn J Cancer Res. 1989;80(3):219-22.

Yoshizawa S, Takagi R, Umemura S. Enhancement of high-intensity focused ultrasound heating by short-pulse generated cavitation. Appl Sci. 2017;7(3):288.

Umemura S, Yumita N, Okano Y, Kaneuch M, Magario N, Ishizaki M et al. Sonodynamically-induced in vitro cell damage enhanced by adriamycin. Cancer Lett. 1997;121(2):195-201.

Yasuda J, Miyashita T, Taguchi K, Yoshizawa S, Umemura S. Quantitative assessment of reactive oxygen sonochemically generated by cavitation bubbles. Jpn J Appl Phys. 2015;54(7S1):07HF21.

Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed Engl. 2003;42(38):4640-3.

Bae Y, Nishiyama N, Fukushima S, Koyama H, Matsumura Y, Kataoka K. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem. 2005;16(1):122-30.

Cersosimo RJ, Hong WK. Epirubicin: a review of the pharmacology, clinical activity, and adverse effects of an adriamycin analogue. J Clin Oncol. 1986;4(3):425-39.

Harada M, Bobe I, Saito H, Shibata N, Tanaka R, Hayashi T, et al. Improved anti-tumor activity of stabilized anthracycline polymeric micelle formulation, NC-6300. Cancer Sci. 2011;102(1):192-9.

Takahashi A, Yamamoto Y, Yasunaga M, Koga Y, Kuroda J, Takigahira M, et al. NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin. Cancer Sci. 2013;104(7):920-5.

Mukai H, Kogawa T, Matsubara N, Naito Y, Sasaki M, Hosono A. A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors. Invest New Drugs. 2017;35(3):307-14.

Chawla SP, Goel S, Chow W, Braiteh F, Singh AS, Olson JEG et al. A Phase 1b dose escalation trial of NC-6300 (Nanoparticle Epirubicin) in patients with advanced solid tumors or advanced, metastatic, or unresectable soft-tissue sarcoma. Clin Cancer Res. 2020;26(16):4225-32.

Takemae K, Okamoto J, Horise Y, Masamune K, Muragaki Y. et al. Function of epirubicin-conjugated polymeric micelles in sonodynamic therapy. Front Pharmacol. 2019;10:546.

Maeda M, Muragaki Y, Okamoto J, Yoshizawa S, Abe N, Nakamoto H, et al. Sonodynamic Therapy Based on Combined Use of Low Dose Administration of Epirubicin-Incorporating Drug Delivery System and Focused Ultrasound. Ultrasound Med Biol. 2017;43(10):2295-301.

Sofuni A, Moriyasu F, Sano T, Itokawa F, Tsuchiya T, Kurihara T, et al. Safety trial of high-intensity focused ultrasound therapy for pancreatic cancer. World J Gastroenterol. 2014;20(28):9570-7.

Sehmbi AS, Froghi S, Oliveira de Andrade M, Saffari N, Fuller B, Quaglia A, et al. Systematic review of the role of high intensity focused ultrasound (HIFU) in treating malignant lesions of the hepatobiliary system. HPB (Oxford). 2021;23(2):187-96.

Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020;395 (10242):2008-20.

Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology. 2022;163(2):386-402.e1.