Sundland Rachael M, Ballan Donia, Callier Kylie M, Ayemoba Joy, Bellary Aditi, Iwanicki Isabella J, Wu Lydia L, Larkins Tylar, Flores-Guzman Fernando, Gomez-Villa Jacky, Wyles Gracey, Feshitan Jameel, Kandel Jessica J, Sirsi Shashank R, Hernandez Sonia L
Department of Surgery, Section of Pediatric Surgery, The University of Chicago Medicine.
Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA.
Ultrasound Med Biol. 2025 Feb;51(2):348-357. doi: 10.1016/j.ultrasmedbio.2024.10.014. Epub 2024 Nov 23.
Despite aggressive therapy, approximately 50% of patients with neuroblastoma (NB) fail to respond, and survivors endure lifelong toxicities. Sonopermeation increases drug uptake via cell bilayer disruption through focused ultrasound and microbubbles (MBs)-gas-filled, sound sensitive lipid spheres. MB response to a given ultrasound pulse (cavitation) varies according to MB size. We asked whether size-sorted MBs (SSMB) 4 to 5 µm in diameter will more consistently and predictably enhance doxorubicin uptake, compared with polydisperse MBs (PMB, 0.5-10 µm in diameter), thereby increasing drug delivery to NB xenografts.
Human NB cells were implanted into the left kidney of nude mice and grown for 5 to 6 wk. Mice received sonopermeation alongside either PMB or SSMB at low (0.6 MPa) or high (2 MPa) negative pressures. Some mice also received different chemotherapy agents (doxorubicin, etoposide or cyclophosphamide). Circulating tumor cells were assessed by flow cytometry 1 h after treatment. Survival was assessed for up to 21 d, a subset of mice was euthanized 24 h after treatment for histological assessment of apoptosis, vascular lumen size and tight junctions.
Tumors treated with SSMB and high pressure showed synergy with liposomal doxorubicin (L-DOX) owing to increased vascular lumen and disruption of tight junctions, resulting in drug uptake, apoptosis, lack of tumor growth and increased survival. We found no difference in the numbers of circulating tumor cells.
Sonopermeation with SSMB at 2 MPa synergizes with L-DOX delivery, increasing apoptosis, perfusion and vascular permeability, suggesting that SSMB sonopermeation at high pressure is promising for NB-targeted treatment, especially in combination with L-DOX.
尽管采用了积极的治疗方法，但约50%的神经母细胞瘤（NB）患者无反应，且幸存者要承受终身毒性。超声透入通过聚焦超声和微泡（MBs）——充气的、对声音敏感的脂质球，破坏细胞双层膜来增加药物摄取。MB对给定超声脉冲的反应（空化）因MB大小而异。我们研究了直径4至5微米的大小分选微泡（SSMB）与多分散微泡（PMB，直径0.5 - 10微米）相比，是否能更一致且可预测地增强阿霉素摄取，从而增加药物向NB异种移植瘤的递送。
将人NB细胞植入裸鼠左肾，生长5至6周。小鼠在低（0.6兆帕）或高（2兆帕）负压下接受超声透入，同时给予PMB或SSMB。一些小鼠还接受不同的化疗药物（阿霉素、依托泊苷或环磷酰胺）。治疗后1小时通过流式细胞术评估循环肿瘤细胞。评估生存期长达21天，一部分小鼠在治疗后24小时安乐死，用于凋亡、血管腔大小和紧密连接的组织学评估。
用SSMB和高压治疗的肿瘤与脂质体阿霉素（L - DOX）显示出协同作用，这是由于血管腔增大和紧密连接破坏，导致药物摄取、凋亡、肿瘤生长停滞和生存期延长。我们发现循环肿瘤细胞数量没有差异。
2兆帕的SSMB超声透入与L - DOX递送协同作用，增加凋亡、灌注和血管通透性，表明高压下的SSMB超声透入对NB靶向治疗有前景，特别是与L - DOX联合使用时。
