Nanoparticle-based drug delivery systems for controllable photodynamic cancer therapy

Abstract

Compared with the traditional treatment, photodynamic therapy (PDT) in the treatment of malignant tumors has the advantages of less damage to normal tissues, quick therapeutic effect, and ability to repeat treatments to the same site. However, most of the traditional photosensitizers (PSs) have severe skin photosensitization, poor tumor targeting, and low therapeutic effect in hypoxic tumor environment, which limit the application of PDT. Nanoparticle-based drug delivery systems can improve the targeting of PSs and release drugs with controllable photoactivity at predetermined locations, so as to achieve desired therapeutic effects with minimal side-effects. The present review summarizes the current nanoparticle platforms for PDT, and offers the description of different strategies including tumor-targeted delivery, controlled-release of PSs and the triggered photoactivity to achieve controllable PDT by nanoparticle-based drug delivery systems. The challenges and prospects for further development of intelligent PSs for PDT are also discussed.

Introduction

Traditional cancer therapies such as surgery, chemotherapy, and radiotherapy are unable to achieve satisfactory results on metastasis disease (Liu et al., 2019b; Min et al., 2005). Several complementary anti-cancer therapies, including gene therapy, hormonal therapy, and photodynamic therapy (PDT), have been used alone or in combination with traditional methods to improve therapeutic effects and alleviate side-effects (Sedighi et al., 2019). Among these therapies, PDT is a relatively new treatment modality with irreplaceable unique advantages for no matter the primary or metastatic malignant tumors (Dolmans et al., 2003).

PDT as a minimally invasive or non-invasive treatment, has been widely used in various types of cancer and other diseases. PDT can be applied repeatedly with low cumulative toxicity and no drug resistance. The anti-cancer effects of PDT could be summarized to three main mechanisms: the generation of reactive oxygen species (ROS), destruction of tumor-related blood vessels, and the activation of the immune response against cancer cells (Dolmans et al., 2003). Although PDT has many advantages, there are still some challenges in the wide application of PDT. One challenge is the long-enduring photoactivities of photosensitizers (PSs) which could cause severe skin photosensitization. The patients should stay in dark for several weeks after treatments. In addition, the lack of tumor selectivity of PSs might lead to high normal tissue accumulation and the consequent local and systemic toxic side-effects. The hypoxic tumor microenvironment is a very common characteristic of solid tumors. Due to the severe oxygen dependence, the therapeutic efficacy of PDT in hypoxic solid tumor is limited (Dolmans et al., 2003; Li et al., 2018c).

Nanotechnology which focused on studying the properties and the applications of materials with structure size in the range of 1-100 nm has been widely used in various fields. In biomedical research fields, nanotechnology has been used to design and development of drug delivery systems (DDSs). Nanotechnology-based drug delivery systems (NDDSs) offer many potential advantages in cancer treatment, such as improving targeting of the therapeutic drugs, protecting drugs from degradation during in vivo transport, controlled drug release at specific sites or cells in response to specific signals, and thus improving the therapeutic efficacy while minimizing side effects (Gao et al., 2014; Ortiz et al., 2017; Singh and Mitragotri, 2019). PSs entrapped in NDDSs could be passively target tumor tissues, or actively target specific cancer cells or even cellular organelles to improve the distribution of PSs in the tumor (Gao et al., 2014). The NDDSs could be designed to be responsive to light, heat, ultrasound and other physical signals, or be responsive to the special physiological characteristics of tumor and the surrounding microenvironment, so as to realize controlled-release of PSs at specific sites to increase the therapeutic effects of PDT and minimize the phototoxicity of PSs. By delicate design, the photodynamic activities of some PSs could be quenched inside the NDDS and be recovered in response to the stimulations, which could further minimize the toxicity and side-effects of PSs. Some NDDS could improve the anoxic environment of solid tumors by increasing the oxygen supply in tumor tissues, thus further enhancing the therapeutic effect of PDT.

The present review summarizes the current nanoparticle platforms for PDT, and offers the description of different strategies to achieve controllable PDT by NDDSs. We focused on three strategies including the tumor-targeted drug delivery, controlled-release of PSs and the triggered photoactivity of PSs by NDDSs. The potential challenges and prospects for further development of intelligent PSs for PDT are also discussed.