TY - JOUR
T1 - Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer
AU - Hadi, Marym Mohammad
AU - Nesbitt, Heather
AU - Masood, Hamzah
AU - Sciscione, Fabiola
AU - Patel, Shiv
AU - Ramesh, Bala S
AU - Emberton, Mark
AU - Callan, J
AU - MacRobert, Alexander
AU - McHale, Anthony P.
AU - Nomikou, Nikolitsa
N1 - Funding Information:
The work was supported by the Engineering and Physical Sciences Research Council UK (Grant Ref: EP/P020828/1 ), and the UCL Therapeutic Acceleration Support fund (sponsored by MRC / Wellcome Trust / UCLH , GOSH , and Moorfields BRC).
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/10
Y1 - 2021/1/10
N2 - 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.
AB - 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.
KW - Sonodynamic therapy
KW - Nanoparticles
KW - Sensitizer
KW - Prostate cancer
KW - Cathepsin B
KW - Tumour microenvironment
UR - https://pure.ulster.ac.uk/en/publications/investigating-the-performance-of-a-novel-ph-and-cathepsin-b-sensi
UR - https://www.sciencedirect.com/science/article/pii/S0168365920306908
UR - http://www.scopus.com/inward/record.url?scp=85097238531&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2020.11.040
DO - 10.1016/j.jconrel.2020.11.040
M3 - Article
C2 - 33245955
VL - 329
SP - 76
EP - 86
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -