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

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-((99m)Tc)-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 (99m)Tc-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.

• Authors: Xiangpeng Zheng, Beth A Goins, Ivan L Cameron, Cristina Santoyo, Ande Bao, Victoria C Frohlich, Gary D Fullerton
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 1 Pg. 173-82 (Jan 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20306263 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Liposomes
• Radiopharmaceuticals
• Doxorubicin
• Sodium Pertechnetate Tc 99m
• Matrix Metalloproteinase 8

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacokinetics)
• Autoradiography
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, pharmacokinetics)
• Extracellular Fluid (drug effects, metabolism)
• Female
• Head and Neck Neoplasms (drug therapy, veterinary)
• Liposomes
• Matrix Metalloproteinase 8 (administration & dosage, pharmacology)
• Radionuclide Imaging (methods)
• Radiopharmaceuticals (chemistry)
• Rats
• Rats, Nude
• Sodium Pertechnetate Tc 99m (chemistry)
• Tomography, Emission-Computed, Single-Photon
• Ultrasonography, Doppler (methods)
• Xenograft Model Antitumor Assays