Show simple item record

dc.contributor.authorIngram, N.
dc.contributor.authorMcVeigh, L.E.
dc.contributor.authorAbou-Saleh, R.H.
dc.contributor.authorMaynard, J.
dc.contributor.authorPeyman, S.A.
dc.contributor.authorMcLaughlan, J.R.
dc.contributor.authorFairclough, M.
dc.contributor.authorMarston, G.
dc.contributor.authorValleley, E.M.A.
dc.contributor.authorJimenez-Macias, J.L.
dc.contributor.authorCharalambous, A.
dc.contributor.authorTownley, W.
dc.contributor.authorHaddrick, M.
dc.contributor.authorWierzbicki, A.
dc.contributor.authorWright, A.
dc.contributor.authorVolpato, M.
dc.contributor.authorSimpson, P.B.
dc.contributor.authorTreanor, D.E.
dc.contributor.authorThomson, N.H.
dc.contributor.authorLoadman, Paul M.
dc.contributor.authorBushby, R.J.
dc.contributor.authorJohnson, B.R.G.
dc.contributor.authorJones, P.F.
dc.contributor.authorEvans, T.
dc.contributor.authorFreear, S.
dc.contributor.authorMarkham, A.F.
dc.contributor.authorEvans, S.D.
dc.contributor.authorColetta, P.L.
dc.date.accessioned2020-09-04T11:12:31Z
dc.date.available2020-09-04T11:12:31Z
dc.date.issued2020
dc.identifier.citationIngram N, McVeigh LE, Abou-Saleh RH et al (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. Accepted for Publication.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17999
dc.descriptionYesen_US
dc.description.abstractMost 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.en_US
dc.description.sponsorshipEPSRC funding (EP/I000623/1, EP/K023845/1 and EP/P023266/1) and the MRC for a Confidence in Concept award and MR/L01629X. L.E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://www.thno.org/toc/acceptmsen_US
dc.rights© 2020 Ivyspring International Publisher.. Reproduced in accordance with the publisher's self-archiving policy.en_US
dc.subjectMicrobubbleen_US
dc.subjectUltrasounden_US
dc.subjectVEGFR2en_US
dc.subjectNanoformulationen_US
dc.subjectColorectal canceren_US
dc.titleUltrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissuesen_US
dc.status.refereedYesen_US
dc.date.Accepted2020-08-14
dc.date.application2020-08
dc.typeArticleen_US
dc.type.versionAccepted manuscripten_US
refterms.dateFOA2020-09-04T11:13:41Z


Item file(s)

Thumbnail
Name:
Loadman_Theranostics.pdf
Size:
1.342Mb
Format:
PDF
Thumbnail
Name:
thMB paper Theranostics.docx
Size:
2.714Mb
Format:
Microsoft Word 2007
Description:
To keep suppressed

This item appears in the following Collection(s)

Show simple item record