Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption

Abstract

Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2͞ c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system. brain tumor ͉ microbubble A dvances in tumor cell biology have led to the availability of new types of anticancer chemotherapeutic agents that are superior to the conventional agents in that they can precisely target the signal-transduction system unique to malignant tumor cells, thereby lowering the toxic effects of anticancer agents on normal cells. Herceptin (trastuzumab; Genentech) is a humanized mAb that targets human epidermal growth factor receptor 2 (HER2͞c-erbB2) expressed in breast cancer cells. It has been used to treat breast cancer patients, and it has succeeded remarkably in controlling local and distal breast cancer lesions (1). Although breast cancer often metastasizes to the brain (2), Herceptin could only be used to treat extracranial lesions because there is currently no efficient method to deliver it to the CNS. The increased use of Herceptin to treat breast cancer patients has resulted in a higher incidence of brain metastasis from primary lesions (3, 4). When Herceptin was used as a first-line therapy in breast cancer patients, metastatic extracranial lesions responded to the agent in 71% of the patients who continued to develop metastatic lesions in the brain (3).The CNS is protected from the entry of foreign substances by the almost impenetrable blood-brain barrier (BBB) (5, 6), which hampers the delivery of potentially effective diagnostic or therapeutic agents and complicates the treatment of CNS diseases, including malignant brain diseases such as metastatic brain tumors. Because antibody-based agents with a molecular size of Ϸ150 kDa are easily blocked by the BBB, their delivery to the CNS requires the temporary suspension of the physiological role of the BBB to bar larger molecules from the CNS.Current advances in acoustic technology have made ultrasound a modality with therapeutic as well as diagnostic applicability. Focused ultrasound techniques facilitate the concentration of acoustic energy o...

Focused Ultrasound‐Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging‐Guided Brain Tumor Treatment

“…The first obstacle is the selectively permeable BBB, which hampers the transport and diffusion of large molecules (>500 Da) from the vasculature into the brain, thus reducing the effects of chemotherapeutic agents against the malignant brain tumors 11. Recently, focused ultrasound (FUS) combined with microbubbles (MB), has been increasingly recognized as a noninvasive strategy to induce transient, reversible, and local BBB disruption 12. The biosafety and effectiveness have also been demonstrated by numerous preclinical studies 13.…”

Use of Ultrasound Pulses Combined with Definity for Targeted Blood-Brain Barrier Disruption: A Feasibility Study

“…These studies have shown that the BBB disruption (BBBD) lasts for a few hours (Hynynen et al 2001;Hynynen et al 2005;Hynynen et al 2006) and can be reliably applied with negligible damage to the brain parenchyma (Hynynen et al 2001;Hynynen et al 2005;McDannold et al 2005;Hynynen et al 2006), at least when compared to invasive techniques. Studies have also shown that the BBBD can be performed using low ultrasound frequencies (0.26 MHz and 0.69 MHz) suitable for trans-cranial application with a focused beam Hynynen et al 2006), and that delivery of chemotherapy (Treat et al 2005) and antibodies can be achieved (Kinoshita et al 2006b;Kinoshita et al 2006a). …”

Current status and future potential of MRI‐guided focused ultrasound surgery

“…However, MRI contrast agents could be useful for monitoring. Studies investigating the delivery of chemotherapy agents (76) and antibodies (77,78) have found an association between the amount of agent delivered to the brain with the amount of contrast enhancement (Fig. 7).…”

“…It can also be applied at frequencies suitable for a transcranial application (73,75). The focal, anatomically selective opening acts as a virtual needle that can be noninvasively used for any selected target, such as noninvasive targeted drug delivery (76,77). Examples of MRI showing focal BBB opening in a rabbit brain are shown in Fig.…”