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Ultrasound-guided intratumoral administration of collagenase-2 improved liposome drug accumulation in solid tumor xenografts

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Abstract

Purpose

To investigate the effect of intratumoral administration of collagenase-2 on liposomal drug accumulation and diffusion in solid tumor xenografts.

Methods

Correlation between tumor interstitial fluid pressure (IFP) and tumor physiological properties (size and vessel fraction by B-mode and Doppler ultrasound, respectively) was determined. IFP response to intravenous or intratumoral collagenase-2 (0.1%) treatment was compared with intratumoral deactivated collagenase-2. To evaluate drug accumulation and diffusion, technetium-99 m-(99mTc)-liposomal doxorubicin (Doxil™) was intravenously injected after collagenase-2 (0.1 and 0.5%, respectively) treatment, and planar scintigraphic images acquired and percentage of the injected dose per gram tissue calculated. Subsequently, tumors were subjected to autoradiography and histopathology.

Results

IFP in two-week-old head and neck squamous cell carcinoma xenografts was 18 ± 3.7 mmHg and not correlated to the tumor size but had reverse correlation with the vessel fraction (r = −0.91, P < 0.01). Intravenous and intratumoral collagenase-2 use reduced IFP by a maximum of 35–40%. Compared to the control, the low IFP level achieved through intratumoral route remained for a long period (24 vs. 2 h, P < 0.05). SPECT images and autoradiography showed significantly higher 99mTc-Doxil™ accumulation in tumors with intratumoral collagenase-2 treatment, confirmed by %ID/g in tumors (P < 0.05), and pathological findings showed extensive distribution of Doxil™ in tumors.

Conclusions

Intratumoral injection of collagenase-2 could effectively reduce IFP in HNSCC xenografts for a longer period than using intravenous approach, which allowed for more efficient accumulation and homogeneous diffusion of the Doxil™ within the tumor interstitium.

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Acknowledgments

Microscopic images were generated in the Core Optical Imaging Facility, which is supported by UTHSCSA, NIH-NCI P30 CA54174 (San Antonio Cancer Institute), NIH-NIA P30 AG013319 (Nathan Shock Center), and (NIH-NIA P01AG19316). Pilot Grant from Radiology Department, The University of Texas Health Science Center at San Antonio.

Conflict of interest statement

None.

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Authors and Affiliations

  1. Department of Radiology, Fudan University Huadong Hospital, 221 W. Yan’an Road, Shanghai, 200040, China

    Xiangpeng Zheng

  2. Department of Radiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA

    Xiangpeng Zheng, Beth A. Goins, Cristina Santoyo, Ande Bao & Gary D. Fullerton

  3. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA

    Ivan L. Cameron

  4. The Core-Optical Imaging Facility, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA

    Victoria C. Frohlich

Authors
  1. Xiangpeng Zheng
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  2. Beth A. Goins
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  3. Ivan L. Cameron
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  4. Cristina Santoyo
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  5. Ande Bao
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  6. Victoria C. Frohlich
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  7. Gary D. Fullerton
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Correspondence to Xiangpeng Zheng.

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Zheng, X., Goins, B.A., Cameron, I.L. et al. Ultrasound-guided intratumoral administration of collagenase-2 improved liposome drug accumulation in solid tumor xenografts. Cancer Chemother Pharmacol 67, 173–182 (2011). https://doi.org/10.1007/s00280-010-1305-1

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  • DOI: https://doi.org/10.1007/s00280-010-1305-1

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