PMID- 32724463 OWN - NLM STAT- MEDLINE DCOM- 20210505 LR - 20240329 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 18 DP - 2020 TI - Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake in vivo. PG - 8143-8161 LID - 10.7150/thno.45903 [doi] AB - Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study. CI - (c) The author(s). FAU - Bellary, Aditi AU - Bellary A AD - Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA. FAU - Villarreal, Arelly AU - Villarreal A AD - Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA. FAU - Eslami, Rojin AU - Eslami R AD - Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA. FAU - Undseth, Quincy J AU - Undseth QJ AD - Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA. FAU - Lec, Bianca AU - Lec B AD - Department of Surgery, University of Chicago Medical School, Chicago, IL, USA. FAU - Defnet, Ann M AU - Defnet AM AD - Department of Surgery, University of Chicago Medical School, Chicago, IL, USA. FAU - Bagrodia, Naina AU - Bagrodia N AD - Department of Surgery, University of Chicago Medical School, Chicago, IL, USA. FAU - Kandel, Jessica J AU - Kandel JJ AD - Department of Surgery, University of Chicago Medical School, Chicago, IL, USA. FAU - Borden, Mark A AU - Borden MA AD - Biomedical Engineering, Mechanical Engineering, University of Colorado, Boulder, CO, USA. FAU - Shaikh, Sumbul AU - Shaikh S AD - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Chopra, Rajiv AU - Chopra R AD - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. AD - Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Laetsch, Theodore W AU - Laetsch TW AD - Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, USA. FAU - Delaney, Lauren J AU - Delaney LJ AD - Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA. FAU - Shaw, Colette M AU - Shaw CM AD - Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA. FAU - Eisenbrey, John R AU - Eisenbrey JR AD - Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA. FAU - Hernandez, Sonia L AU - Hernandez SL AD - Department of Surgery, University of Chicago Medical School, Chicago, IL, USA. FAU - Sirsi, Shashank R AU - Sirsi SR AD - Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA. AD - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. LA - eng GR - R01 CA199937/CA/NCI NIH HHS/United States GR - R01 CA235756/CA/NCI NIH HHS/United States GR - R01 CA238241/CA/NCI NIH HHS/United States GR - R21 EB015040/EB/NIBIB NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200709 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Contrast Media) RN - 0 (liposomal doxorubicin) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - 80168379AG (Doxorubicin) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Blood Volume Determination/instrumentation/methods MH - Capillary Permeability/radiation effects MH - Cell Line, Tumor MH - Contrast Media/administration & dosage MH - Doxorubicin/administration & dosage/*analogs & derivatives/pharmacokinetics MH - Drug Delivery Systems/methods MH - Feasibility Studies MH - Humans MH - Mice MH - *Microbubbles MH - Neuroblastoma/blood supply/diagnostic imaging/*drug therapy MH - Perfusion Imaging/*methods MH - Photoacoustic Techniques/instrumentation/methods MH - Polyethylene Glycols/administration & dosage/pharmacokinetics MH - Single-Case Studies as Topic MH - Ultrasonic Waves MH - Ultrasonography, Interventional/instrumentation/*methods MH - Xenograft Model Antitumor Assays PMC - PMC7381728 OTO - NOTNLM OT - Sonoporation OT - image-guided drug delivery. OT - neuroblastoma OT - quantitative contrast-enhanced ultrasound (qCEUS) OT - sonopermeabilization OT - sonopermeation COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/07/30 06:00 MHDA- 2021/05/06 06:00 PMCR- 2020/01/01 CRDT- 2020/07/30 06:00 PHST- 2020/03/11 00:00 [received] PHST- 2020/06/03 00:00 [accepted] PHST- 2020/07/30 06:00 [entrez] PHST- 2020/07/30 06:00 [pubmed] PHST- 2021/05/06 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p8143 [pii] AID - 10.7150/thno.45903 [doi] PST - epublish SO - Theranostics. 2020 Jul 9;10(18):8143-8161. doi: 10.7150/thno.45903. eCollection 2020.