Tumor Targeted Multifunctional Magnetic Nanobubbles for MR/US Dual Imaging and Focused Ultrasound Triggered Drug Delivery.

Zhen Jin,Shaohui Zheng,Heyun Tang,Wu Ren,Shang Jin,Wenshuai Jiang,Min Jiao,Jinlong Chang,Peipei Dou

doi:10.3389/fbioe.2020.586874

Abstract

The development of multifunctional nanoplatforms that are safe and have multiple therapeutic functions integrated with dual- or multi-imaging modality is one of the most urgent medical requirements for active cancer therapy. In our study, we prepared multifunctional magnetic nanobubbles (MF-MNBs) by co-encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin into polylactideco–glycolide–polyethylene glycol–folate (PLGA-PEG-FA) polymer-based nanobubbles for tumor-targeted ultrasound (US)/magnetic resonance (MR) imaging and focused ultrasound (FUS)-triggered drug delivery. Hydrophobic SPIONs were successfully embedded into MF-MNBs by a typical double emulsion process. The MF-MNBs were highly dispersed with well-defined spherical morphology and an average diameter of 208.4 ± 12.58 nm. The potential of MF-MNB as a dual-modal contrast agent for US and MR imaging was investigated via in vitro study, and the MF-MNB exhibits promising US/MR contrast ability. Moreover, tumor targeting ability was further enhanced by folate conjugation and assessed through in vitro cell test. Furthermore, FUS, as a non-invasive and remote-control technique, was adopted to trigger the release of doxorubicin from MF-MNB and generate the sonoporation effect to enhance drug release and cellular uptake of MF-MNBs. The 4T1 cell viability was significantly decreased by FA ligand-receptor-mediated targeting and FUS sonication. In addition, the developed MF-MNB also exhibits enhanced accumulation in tumor site by FA ligand-receptor-mediated tumor targeting, in which the accumulation of MF-MNB was further enhanced by FUS sonication. Hence, we believe that the MF-MNB could be a promising drug nanocarrier for US/MR-guided anticancer drug delivery to improve cancer treatment efficacy.

Highlights

Cancer has been one of the leading causes of death in the world according to world cancer statistics (Zeng et al, 2019)
The results demonstrated that the release rate of DOX with focused ultrasound (FUS) sonication was significantly enhanced when compared with that without FUS sonication, and approximately 92% of DOX was released in 2 days, while the multifunctional magnetic nanobubbles (MF-MNBs) without FUS sonication was less than 69% of the encapsulated DOX released
An almost threefold faster drug release time and 22% increased DOX release from MF-MNB in 2 days were achieved by FUS triggering

Summary

Introduction

Cancer has been one of the leading causes of death in the world according to world cancer statistics (Zeng et al, 2019). Cancer treatment mainly includes chemotherapy, radiotherapy, and clinical surgery. These therapeutic approaches can significantly inhibit cancer growth, they could be accompanied by severe side effects, such as systemic toxicity, recurrence, or physiologic dysfunction (Kievit and Zhang, 2011). Nanocarrier accumulation in solid tumor is generally based on the enhanced permeability and retention (EPR) effect, called passive targeting (Maeda, 2010). Extensive efforts have been devoted to develop multifunctional nanocarriers that combine therapeutic and diagnostic capabilities in a single probe to achieve imaging-guided cancer therapy (Kalidoss et al, 2019; Wang et al, 2020), which enables one to monitor the distribution and accumulation of nanocarriers and evaluate the treatment efficiency during and after therapy

Methods

Results

Discussion

Conclusion