Assessing Therapeutic Nanoparticle Accumulation in Tumors Using Nanobubble-Based Contrast-Enhanced Ultrasound Imaging

Michaela B Cooley; Dana Wegierak; Reshani Perera; Eric Abenojar; Pinunta Nittayacharn; Felipe M Berg; Youjoung Kim; Michael C Kolios; Agata A Exner

doi:10.1021/acsnano.4c11805

Assessing Therapeutic Nanoparticle Accumulation in Tumors Using Nanobubble-Based Contrast-Enhanced Ultrasound Imaging

ACS Nano. 2024 Nov 20. doi: 10.1021/acsnano.4c11805. Online ahead of print.

Authors

Michaela B Cooley¹, Dana Wegierak¹, Reshani Perera², Eric Abenojar², Pinunta Nittayacharn^{2

3}, Felipe M Berg^{1

4}, Youjoung Kim¹, Michael C Kolios^{5

6}, Agata A Exner^{1

2}

Affiliations

¹ Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, United States.
² Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106, United States.
³ Department of Biomedical Engineering, Faculty of Engineering, Mahidol University, Phutthamonthon, Nakhon Pathom 73170, Thailand.
⁴ Hospital Israelita Albert Einstein, São Paulo, São Paulo 05652-900, Brazil.
⁵ Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada.
⁶ Institute for Biomedical Engineering, Science and Technology (iBEST), A Partnership between St. Michael's Hospital, A Site of Unity Health Toronto and Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada.

PMID: 39566912
DOI: 10.1021/acsnano.4c11805

Abstract

This study explores the challenges associated with nanoparticle-based drug delivery to the tumor parenchyma, focusing on the widely utilized enhanced permeability and retention effect (EPR). While EPR has been a key strategy, its inconsistent clinical success lacks clear mechanistic understanding and is hindered by limited tools for studying relevant phenomena. This work introduces an approach that employs multiparametric dynamic contrast-enhanced ultrasound (CEUS) with a nanoscale contrast agent for noninvasive, real-time examination of tumor microenvironment characteristics. We demonstrate that CEUS imaging can: (1) evaluate tumor microenvironment features, (2) be used to help predict the distribution of doxorubicin-loaded liposomes in the tumor parenchyma, and (3) be used to predict nanotherapeutic efficacy. CEUS using nanobubbles (NBs) was carried out in two tumor types of high (LS174T) and low (U87) vascular permeability. LS174T tumors consistently showed significantly different time intensity curve (TIC) parameters, including area under the rising curve (AUC_R, 2.7×) and time to peak intensity (TTP, 1.9×) compared to U87 tumors. Crucially, a recently developed decorrelation time (DT) parameter specific to NB CEUS dynamics successfully predicted the distribution of doxorubicin-loaded liposomes within the tumor parenchyma (r = 0.86 ± 0.13). AUC_R, TTP, and DT were used to correlate imaging findings to nanotherapeutic response with 100% accuracy in SKOV-3 tumors. These findings suggest that NB-CEUS parameters can effectively discern tumor vascular permeability, serving as a biomarker for identifying tumor characteristics and predicting the responsiveness to nanoparticle-based therapies. The observed differences between LS174T and U87 tumors and the accurate prediction of nanotherapeutic efficacy in SKOV-3 tumors indicate the potential utility of this method in predicting treatment efficacy and evaluating EPR in diseases characterized by pathologically permeable vasculature. Ultimately, this research contributes valuable insights into refining drug delivery strategies and assessing the broader applicability of EPR-based approaches.

Keywords: EPR; companion nanoparticles; nanobubbles; oncology; tumors; ultrasound; ultrasound contrast agents.