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.
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: Jessica F Liu; Ziyang Lan; Carolina Ferrari; Joel M Stein; Elizabeth Higbee-Dempsey; Lesan Yan; Ahmad Amirshaghaghi; Zhiliang Cheng; David Issadore; Andrew Tsourkas Journal: ACS Nano Date: 2019-12-23 Impact factor: 15.881
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Authors: Oliver K Appelbe; Qingbei Zhang; Charles A Pelizzari; Ralph R Weichselbaum; Stephen J Kron Journal: Mol Pharm Date: 2016-09-01 Impact factor: 4.939