Sonoporation enhances liposome accumulation and penetration in tumors with low EPR

JOURNAL OF CONTROLLED RELEASE

卷:231

Article; Proceedings Paper

Theek, Benjamin^1,2  Baues, Maike^1,2  Ojha, Tarun^1,2  Moeckel, Diana^1,2  Veettil, Seena Koyadan³  Steitz, Julia³  van Bloois, Louis⁴  Storm, Gert^4,5  Kiessling, Fabian^1,2  Lammers, Twan^1,2,4,5 

[1] Rhein Westfal TH Aachen, Univ Clin, Dept Expt Mol Imaging, Aachen, Germany

[2] Rhein Westfal TH Aachen, Helmholtz Inst Biomed Engn, Aachen, Germany

[3] Rhein Westfal TH Aachen, Univ Clin, Inst Lab Anim Sci, Aachen, Germany

[4] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, Utrecht, Netherlands

[5] Univ Twente, MIRA Inst Biomed Technol & Tech Med, Dept Targeted Therapeut, POB 217, NL-7500 AE Enschede, Netherlands

关键词: Sonoporation;    Microbubbles;    Ultrasound;    EPR;    Liposomes;   

DOI  :  10.1016/j.jconrel.2016.02.021

来源: Elsevier

【 摘 要 】

The Enhanced Permeability and Retention (EPR) effect is a highly variable phenomenon. To enhance EPR-mediated passive drug targeting to tumors, several different pharmacological and physical strategies have been evaluated over the years, including e.g. TNF alpha-treatment, vascular normalization, hyperthermia and radiotherapy. Here, we systematically investigated the impact of sonoporation, i.e. the combination of ultrasound (US) andmicrobubbles (MB), on the tumor accumulation and penetration of liposomes. Two different MB formulations were employed, and their ability to enhance liposome accumulation and penetration was evaluated in two different tumor models, which are both characterized by relatively low levels of EPR (i.e. highly cellular A431 epidermoid xenografts and highly stromal BxPC-3 pancreatic carcinoma xenografts). The liposomes were labeled with two different fluorophores, enabling in vivo computed tomography/fluorescence molecular tomography (CT-FMT) and ex vivo two-photon laser scanning microscopy (TPLSM). In both models, in spite of relatively high inter-and intra-individual variability, a trend towards improved liposome accumulation and penetration was observed. In treated tumors, liposome concentrations were up to twice as high as in untreated tumors, and sonoporation enhanced the ability of liposomes to extravasate out of the blood vessels into the tumor interstitium. These findings indicate that sonoporation may be a useful strategy for improving drug targeting to tumors with low EPR. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

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