Ultrasound‐Triggered Delivery of Anticancer Therapeutics from MRI‐Visible Multilayer Microcapsules

Abstract

Although imaging‐guided drug delivery represents a noninvasive alternative to both surgical resection and systemic methods, it has seen limited clinical use due to the potential toxicity and fast clearance of currently available imaging agents. Herein, we introduce theranostic biocompatible microcapsules as efficient contrast‐enhanced imaging agents that combine magnetic resonance imaging (MRI) with ultrasound‐triggered drug release for real‐time tracking and targeted delivery in vivo. The 3‐μm diameter capsules are assembled via layer‐by‐layer deposition of the natural polyphenol tannic acid and poly(N‐vinylpyrrolidone) with 4 nm iron oxide nanoparticles incorporated in the capsule wall. The nanoparticle‐modified capsules exhibit excellent T1 and T2 MRI contrast in a clinical 3T MRI scanner. Loaded with the anticancer drug doxorubicin, these capsules circulate in the blood stream for at least 48 h, which is a remarkable improvement compared to nonencapsulated nanoparticles. The application of focused ultrasound results in targeted drug release with a 16‐fold increase in doxorubicin localization in tumors compared to off‐target organs in a mouse model of breast cancer. Owing to the active contrast, long circulation, customizable size, shape, composition, and precise delivery of high payload concentrations, these materials present a powerful and safe platform for imaging‐guided precision drug delivery.

Preparation and Application of Iron Oxide Nanoclusters

“…Figure 9b shows MRI images of mice before and 2 h post-injection with BSA ultrasmall iron oxide nanoclusters, where the brain and kidney regions were significantly brightened, suggesting the nanoclusters remained in the blood stream even 2 h after injection. Similarly, ultrasmall iron oxide nanoparticles sandwiched between polymer layers of layer-by-layer assembled microcapsules showed not only increased blood circulation time, but also served as great drug nanocarriers for ultrasound-triggered drug release [27]. Figure 9c shows MRI images of a control mouse and a mouse 48 h post-injection, where the bright region near the heart suggested the long blood circulation time of these nanoparticle-loaded capsules.…”

“…Figure 5 shows representative TEM images of iron oxide nanoclusters that were produced with different matrices, where the polymer shells can be clearly seen (Figure 5a), but the silica and protein encapsulation formed matrix-iron oxide composite materials (Figure 5b,c). The matrix-assisted method has several distinctive advantages: first, drug molecules can be simultaneously encapsulated into the nanoclusters during the aggregation process, creating magnetic resonance imaging (MRI)-visible drug delivery vehicles; second, biocompatibility and water solubility can be easily achieved based on the choices of the matrices; and finally, by tuning the nanocluster sizes, other functionality can be achieved, such as ultrasound response [27].…”

“…Compared to drug release triggered by photothermal stimulation, magnetic fields have better tissue penetration. In addition, the localization of iron oxide nanoparticles inside the shells decreased the permeability of microcapsules, preventing premature drug release before applying external stimuli [27].…”

Current Advances of Hollow Capsules as Controlled Drug Delivery Systems

“…A similar approach modification to fabricate ultrasound sensitive capsule for drug delivery was adopted by Alford, et al. with a slight modification . In this work, the authors suggested that the incorporation of two layers of Fe 2 O 3 nanoparticles could enhance not only the MR contrast imaging but also the released profile of encapsulated DOX upon the application of ultrasound treatment .…”

“…with a slight modification . In this work, the authors suggested that the incorporation of two layers of Fe 2 O 3 nanoparticles could enhance not only the MR contrast imaging but also the released profile of encapsulated DOX upon the application of ultrasound treatment . Besides that, the high hydrophilicity of the outer layer poly(N‐vinylpyrrolidone) could hinder the adhesion of protein, resulting to longer circulation of capsules in the bloodstream.…”