Abstract
BackgroundPhotodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers.ResultsThe as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment.ConclusionsThis study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment.Graphical
Highlights
Photodynamic therapy (PDT) is an evolving and promising therapeutic modality for its non-invasiveness, high selectivity, and low systemic toxicity compared to traditional chemotherapy and radiotherapy
Synthesis and characterization of 3BP@poly(lactic-co-glycolic acid) (PLGA)‐IR780 3BP@PLGA-IR780 was prepared via a double-emulsion in absence of light, with hydrophilic 3BP encapsulated inside the core and lipophilic IR780 in the lipid bilayer
Typical scanning electron microscopic (SEM) and transmission electron microscopic (TEM) images showed that the as-prepared 3BP@PLGA-IR780 and 3BP@PLGA nanoplatforms presented a spherical structure (Fig. 1a, b, Additional file 1: Fig. S1a and S1b)
Summary
Photodynamic therapy (PDT) is an evolving and promising therapeutic modality for its non-invasiveness, high selectivity, and low systemic toxicity compared to traditional chemotherapy and radiotherapy. These hypoxic cells are reported to be more resistant to ROS than aerobic cells as well [11, 12] To solve this problem, some strategies have been designed to alleviate hypoxia in tumor environment, many of which are developed to directly deliver oxygen molecules (O2) or hydrogen peroxide catalysts to tumor tissues with nanocarriers [10, 13, 14]. There remains insufficiencies, such as limited oxygen loading capacity, pre-mature oxygen release and low oxygen production effciency [15] Bearing these in mind, aiming at the reduction of oxygen consumption is an insightful bypass to discourage tumor hypoxia. Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. A multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers
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