Ultrasound responsive self-assembled micelles loaded with hypocrellin for cancer sonodynamic therapy

Abstract

Nanoparticles have been demonstrated to be effective in targeted drug delivery to tumor due to the enhanced permeability and retention (EPR) effect. However, the inhomogeneous distribution of the nanoparticles in the tumor and the slow release of the drug make the therapeutic effect unsatisfied. Here, we present reactive oxygen species (ROS)-responsive micelles comprising poly (ethylene glycol)-poly(propylene sulfide) (PEG-PPS) for targeted delivery and in situ release of drug. Upon the irradiation of ultrasound, the loaded sonosensitizer hypocrellin (HC) will generate ROS to trigger the disassembly of the micelles and meanwhile realize sonodynamic therapy (SDT) effect of cancer. The in vivo experiment indicates that the HC loaded PEG-PPS are biocompatible and much more efficacious than an equivalent amount of free HC in inhibiting the growth of cancer.

Introduction

Significant progress has been made in developing nano drug delivery systems due to the remarkable superiorities including prolonged circulation time, improved accumulation via enhanced permeability and retention (EPR) effect, and reduced adverse effects (Chen et al., 2017, Maeda and Matsumura, 2011). Despite these advantages, the nano drug delivery systems also demonstrate the shortcomings: slow drug release, inefficient tumor cell uptake, and uneven distribution intratumor distribution due to the poor penetration ability. Smart nanocarriers, which can realize on-demand drug release in response to various stimuli, including light (Guo and You, 2017), temperature, redox (Huo et al., 2014, Waleka et al., 2020, Mackiewicz et al., 2015), pH (Liu et al., 2010, Xie et al., 2014), and multiple stimuli (Mackiewicz et al., 2019), demonstrate great potential in improving the therapeutic efficiency.

Reactive oxygen species (ROS), which are common biochemicals in the human body (Trachootham et al., 2009, Peter, 2005), have been reported as stimuli for drug release. The ROS, such as H₂O₂, ClO⁻, hydroxyl radicals, and peroxynitrite, can trigger thioether groups to undergo a phase transition from hydrophobic to hydrophilic, presenting a strategy for ROS sensitive micelles construction (Mahmoud et al., 2011, Geven et al., 2021). ROS can also be applied for the treatment of diseases. Therapies based on ROS have been extensively studied recently, such as photodynamic therapy (PDT) (Huang, 2005), sonodynamic therapy (SDT) (Chen et al., 2017, Shen et al., 2015), and other oxygen independent strategies. SDT employs the ultrasound to activate the sonosensitizer to generate ROS (Shibaguchi et al., 2011), including super oxide anion (O²⁻), hydroxyl radicals (OH), and singlet oxygen, showing a broad applicability for various diseases due to the good penetration of ultrasound (Pan et al., 2018, Yan et al., 2020). The sonosensitizers used in SDT are usually low-toxic and are poisonous only when irradiated by ultrasound (Xin et al., 2016, Shen et al., 2014). Hence, the SDT can reduce the side effect efficiently.

In this study, we synthesized the ROS-responsive block copolymer with poly (ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) as a hydrophilic and hydrophobic parts, respectively. Micelles loaded with sonosensitizer hypocrellin (HC) could be formed by the self-assembly of the amphiphilic PEG-PPS polymer. Upon the irradiation of ultrasound, ROS was generated by the loaded HC to trigger the disassembly of micelles due to the oxidation of PPS, resulting in the burst release of HC and homogeneous dispersion in tumor. The ROS generated in SDT can also destroy the cancer cells to enhance the anti-tumor effect (Scheme 1).