Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer
| العنوان: | Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer |
|---|---|
| المؤلفون: | Anthony P. McHale, Marym Mohammad Hadi, Fabiola Sciscione, Nikolitsa Nomikou, Bala Ramesh, Mark Emberton, Heather Nesbitt, Shiv Patel, Alexander J. MacRobert, John F. Callan, Hamzah Masood |
| المصدر: | Journal of Controlled Release |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Pharmaceutical Science, 02 engineering and technology, Mice, SCID, Cathepsin B, Article, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, Mice, In vivo, Cell Line, Tumor, LNCaP, medicine, Tumor Microenvironment, Animals, Humans, Cytotoxicity, 030304 developmental biology, Hematoporphyrin, 0303 health sciences, Tumour microenvironment, Sonodynamic therapy, Proteolytic enzymes, Prostatic Neoplasms, Hydrogen-Ion Concentration, 021001 nanoscience & nanotechnology, medicine.disease, Sensitizer, chemistry, Cancer research, Nanoparticles, 0210 nano-technology |
| الوصف: | 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. Graphical abstract Unlabelled Image Highlights • Digestion by cathepsin B leads to nanoparticle size reduction. • The acidic pH facilitates improved cellular uptake of the nanoparticles. • Ultrasound–induced cytotoxic effects were elicited only for the nanoparticle-treated prostate cancer cells. • Sonodynamic treatment resulted in an average of 36% reduction in prostate tumour volume, within 24 h. |
| تدمد: | 1873-4995 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6bcdc8dbe2dfec92616b74e48f1b9679 https://pubmed.ncbi.nlm.nih.gov/33245955 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6bcdc8dbe2dfec92616b74e48f1b9679 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18734995 |
|---|