Abstract
Nano-formulations that are responsive to tumour-related and externally-applied stimuli can offer improved, site-specific antitumor effects, and can improve the efficacy of conventional therapeutic agents. Here, we describe the performance of a novel stimulus-responsive nanoparticulate platform for the targeted treatment of prostate cancer using sonodynamic therapy (SDT). The nanoparticles were prepared by self-assembly of poly(L-glutamic acid-L-tyrosine) co-polymer with hematoporphyrin. The nanoparticulate formulation was characterized with respect to particle size, morphology, surface charge and singlet oxygen production during ultrasound exposure. The response of the formulation to the presence of cathepsin B, a proteolytic enzyme that is overexpressed and secreted in the tumour microenvironment of many solid tumours, was assessed. Our results showed that digestion with cathepsin B led to nanoparticle size reduction. In the absence of ultrasound, the formulation exhibited greater toxicity at acidic pH than at physiological pH, using the human prostate cells lines LNCaP and PC3 as targets. Nanoparticle cellular uptake was enhanced at acidic pH – a condition that was also associated with greater cathepsin B production. Nanoparticles exhibited enhanced ultrasound-induced cytotoxicity against both prostate cancer cell lines. Subsequent proof-of-concept in vivo studies demonstrated that, when ectopic human xenograft LNCaP tumours in SCID mice were treated with SDT using the systemically-administered nanoparticulate formulation at a single dose, tumour volumes decreased by up to 64% within 24 h. No adverse effects were observed in the nanoparticle-treated mice and their body weight remained stable. The potential of this novel formulation to deliver safe and effective treatment of prostate cancer is discussed.
Highlights
Sonodynamic therapy (SDT) employs low-intensity ultrasound in combination with sensitizing agents, such as porphyrins, for the gener ation of cytotoxic reactive oxygen species (ROS) and the subsequent sitespecific ablation of tumours [1]
The PGATyr samples incubated in the absence of cathepsin B showed a smeared profile with molecular weights extending from 70 kDa to less than 10 kDa
In the presence of cathepsin B, the smeared profile shifted towards lower molecular weights, when samples were digested at pH 7.4 (Supplementary Data, Fig. S1a)
Summary
Sonodynamic therapy (SDT) employs low-intensity ultrasound in combination with sensitizing agents, such as porphyrins, for the gener ation of cytotoxic reactive oxygen species (ROS) and the subsequent sitespecific ablation of tumours [1]. Since many sonosensitisers are photosensitisers, it has been suggested that the production of ROS during SDT is due to photoexcitation of the sensitizer by sonoluminescence (Fig. 1a) The latter excites the sensitizing agent and this phenomenon results in the production of either cytotoxic singlet oxygen (1O2) by intersystem crossing and direct energy transfer (Type II reactions) or to the gener ation of other cytotoxic free radicals by electron transfer to other molecular species such as biological molecules (Type I reactions) [5]. Further highlighting the benefits of SDT, no cancer cell population has shown resistance to therapy-triggered ROS production or their cytotoxic effects [6] This is important, given the as yet unresolved issues of radiation and chemotherapy associated resistance
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