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

被引：49

作者：

Ingram, Nicola ^{[1
]}

McVeigh, Laura E. ^{[1
]}

Abou-Saleh, Radwa H. ^{[2
,3
]}

Maynard, Juliana ^{[4
]}

Peyman, Sally A. ^{[2
]}

McLaughlan, James R. ^{[5
]}

Fairclough, Michael ^{[6
]}

Marston, Gemma ^{[1
]}

Valleley, Elizabeth M. A. ^{[1
]}

Jimenez-Macias, Jorge L. ^{[1
]}

Charalambous, Antonia ^{[1
]}

Townley, William ^{[4
]}

Haddrick, Malcolm ^{[4
]}

Wierzbicki, Antonia ^{[7
]}

Wright, Alexander ^{[1
]}

Volpato, Milene ^{[1
]}

Simpson, Peter B. ^{[4
]}

Treanor, Darren E. ^{[1
]}

Thomson, Neil H. ^{[8
]}

Loadman, Paul M. ^{[7
]}

Bushby, Richard J. ^{[2
,9
]}

Johnson, Benjamin R. G. ^{[2
]}

Jones, Pamela F. ^{[1
]}

Evans, J. Anthony ^{[1
]}

Freear, Steven ^{[5
]}

Markham, Alexander F. ^{[1
]}

Evans, Stephen D. ^{[2
]}

Coletta, P. Louise ^{[1
]}

机构：

[1] St James Univ Hosp, Leeds Inst Med Res, Wellcome Trust Brenner Bldg, Leeds LS9 7TF, W Yorkshire, England

[2] Univ Leeds, Sch Phys & Astron, Mol & Nanoscale Phys Grp, Leeds LS2 9JT, W Yorkshire, England

[3] Mansoura Univ, Fac Sci, Dept Phys, Mansoura, Egypt

[4] Med Discovery Catapult, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[5] Univ Leeds, Fac Elect & Elect Engn, Leeds LS2 9JT, W Yorkshire, England

[6] Univ Manchester, Wolfson Mol Imaging Ctr, Palatine Rd, Manchester M20 3LI, Lancs, England

[7] Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England

[8] St James Univ Hosp, Sch Dent, Wellcome Trust Brenner Bldg, Leeds LS9 7TF, W Yorkshire, England

[9] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire, England

来源：

THERANOSTICS | 2020年 / 10卷 / 24期

基金：

英国工程与自然科学研究理事会;

关键词：

Microbubble; ultrasound; VEGFR2; nanoformulation; colorectal cancer; LIPOSOME-LOADED MICROBUBBLES; FOCUSED ULTRASOUND; CONTRAST AGENT; TARGETED MICROBUBBLES; IN-VITRO; CANCER; DELIVERY; IRINOTECAN; PHARMACOLOGY; DOXORUBICIN;

D O I：

10.7150/thno.49670

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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, Zr-89 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. Zr-89 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.

引用

页码：10973 / 10992

页数：20