Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption

Abstract

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in breast cancer brain metastases at cellular resolution: doxorubicin, a nontargeted chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy, we demonstrate significant increases in the extravasation of both agents (sevenfold and twofold for doxorubicin and T-DM1, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 µm and 42 ± 7 vs. 12 ± 4 µm for doxorubicin and T-DM1, respectively) after the application of FUS compared with control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Experimental data demonstrate that FUS in combination with microbubbles enhances significantly the endothelial cell uptake of the small chemotherapeutic agent. Quantification with PBPK modeling reveals an increase in transmembrane transport by more than two orders of magnitude. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel wall pores with a narrow range of sizes (diameter, 10-50 nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of strategies to treat brain metastases.

Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

“…DOX is one of the most commonly used chemotherapy drugs for treatment of breast cancer. However, due to its limited ability to penetrate the BBB,22 DOX is not used for clinical management of BCBMs. We assessed LANPs for systemic delivery of DOX to the brain for BCBMs treatment.…”

Single‐Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics

“…This study presents an IVM‐based approach to simultaneously track (1) the pharmacokinetics and selective association of mAb with its putative targets in tumors, (2) heterogeneous target expression on cancer cells, and (3) infiltrating immune populations, all at the single‐cell level. This work builds on the growing development of IVM as a tool for studying drug pharmacology in cancer, and previous reports have used IVM to examine the behavior of cytotoxic chemotherapies , targeted kinase and poly‐ADP ribose polymerase inhibitors, nanoparticle‐encapsulated therapeutics , and anti‐PD1 immune checkpoint blockade mAb therapy . In several cases, mosaic xenograft models have been successfully used to test the impact of a particular protein on drug pharmacology, while holding other features of the TME relatively constant.…”

How to Make Anticancer Drugs Cross the Blood–Brain Barrier to Treat Brain Metastases

“…When excited by ultrasounds, microbubbles expand and exert a mechanical force on the endothelial cells of the BBB, leading to tight junction disruption [72] and also to increased activity of active transports [73] ( Figure 2B). Preclinical studies using ultrasound disruption for the delivery of anticancer drugs have recently been reviewed [74]. The use of focused ultrasounds can lead to an average 4-fold increase in the delivery of chemotherapeutic agents and a 3.5-fold increase in the delivery of monoclonal antibodies [74].…”

“…Preclinical studies using ultrasound disruption for the delivery of anticancer drugs have recently been reviewed [74]. The use of focused ultrasounds can lead to an average 4-fold increase in the delivery of chemotherapeutic agents and a 3.5-fold increase in the delivery of monoclonal antibodies [74].…”