Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissues
| Autor: | Sally A. Peyman, Malcolm Haddrick, William Townley, Michael Fairclough, Elizabeth M. A. Valleley, Nicola Ingram, Antonia Wierzbicki, Richard J. Bushby, Radwa H. Abou-Saleh, Stephen D. Evans, Pamela F. Jones, Gemma Marston, Darren Treanor, Milene Volpato, Antonia Charalambous, Juliana Maynard, Neil H. Thomson, Laura E. McVeigh, J. Anthony Evans, Jorge L Jimenez-Macias, A Wright, P. Louise Coletta, Peter B Simpson, Benjamin R. G. Johnson, Steven Freear, Alexander F. Markham, James R. McLaughlan, Paul M. Loadman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Drug
Biodistribution media_common.quotation_subject Biological Availability Medicine (miscellaneous) Antineoplastic Agents colorectal cancer 02 engineering and technology Pharmacology Irinotecan Microbubble 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine Therapeutic index Cell Line Tumor medicine Humans Tissue Distribution Pharmacology Toxicology and Pharmaceutics (miscellaneous) media_common Liposome Microbubbles ultrasound business.industry nanoformulation Microfluidic Analytical Techniques 021001 nanoscience & nanotechnology Combined Modality Therapy Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays VEGFR2 Ultrasonic Waves Positron-Emission Tomography 030220 oncology & carcinogenesis Pharmacodynamics Drug delivery Female Colorectal Neoplasms 0210 nano-technology business Research Paper medicine.drug |
| Zdroj: | Fairclough, M 2020, ' Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissues ', Theranostics, vol. 10, no. 4 . https://doi.org/10.7150/thno.49670 Ingram, N, McVeigh, L E, Abou-Saleh, R H, Maynard, J, Peyman, S A, McLaughlan, J R, Fairclough, M, Marston, G, Valleley, E M A, Jimenez-Macias, J L, Charalambous, A, Townley, W, Haddrick, M, Wierzbicki, A, Wright, A, Volpato, M, Simpson, P B, Treanor, D E, Thomson, N H, Loadman, P M, Bushby, R J, Johnson, B R G, Jones, P F, Evans, J A, Freear, S, Markham, A F, Evans, S D & Coletta, P L 2020, ' Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumor drug accumulation and limiting bioavailability and toxicity in normal tissues ', Theranostics, vol. 10, no. 24, pp. 10973-10992 . https://doi.org/10.7150/thno.49670 Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2-targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues. |
| Databáze: | OpenAIRE |
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