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Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts.

Eikenes L, Tari M, Tufto I, Bruland OS, de Lange Davies C - Br. J. Cancer (2005)

Bottom Line: Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner.Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase.Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, The Norwegian University of Science and Technology, Høgskoleringen 5, 7491 Trondheim, Norway. live.eikenes@phys.ntnu.no

ABSTRACT
Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

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Distribution of liposomal doxorubicin in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (A) or liposomal doxorubicin combined with hyaluronidase (1500 U) (B). Representative images of doxorubicin (green) relative to capillaries (red) are presented from the rim to the centre of the tumour sections.
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fig6: Distribution of liposomal doxorubicin in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (A) or liposomal doxorubicin combined with hyaluronidase (1500 U) (B). Representative images of doxorubicin (green) relative to capillaries (red) are presented from the rim to the centre of the tumour sections.

Mentions: The distribution of doxorubicin in the periphery and central parts of the tumour was compared by imaging tumour sections along a radial track from the periphery to the centre of the section. In untreated tumours, liposomal doxorubicin was mainly located in the periphery of the tumour. The drug was found up to 450 μm from the rim of the tumour. In tumours only treated with liposomal doxorubicin, hardly any doxorubicin fluorescence was detected in the central part of the tumours (Figure 6A). Hyaluronidase improved the distribution of doxorubicin considerably, although doxorubicin was still rather heterogeneously distributed. Hyaluronidase allocated doxorubicin further away from the vessels in the periphery, and doxorubicin was located around vessels in the central part of the section where no doxorubicin was observed in tumours given liposomal doxorubicin alone (Figure 6B).


Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts.

Eikenes L, Tari M, Tufto I, Bruland OS, de Lange Davies C - Br. J. Cancer (2005)

Distribution of liposomal doxorubicin in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (A) or liposomal doxorubicin combined with hyaluronidase (1500 U) (B). Representative images of doxorubicin (green) relative to capillaries (red) are presented from the rim to the centre of the tumour sections.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361478&req=5

fig6: Distribution of liposomal doxorubicin in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (A) or liposomal doxorubicin combined with hyaluronidase (1500 U) (B). Representative images of doxorubicin (green) relative to capillaries (red) are presented from the rim to the centre of the tumour sections.
Mentions: The distribution of doxorubicin in the periphery and central parts of the tumour was compared by imaging tumour sections along a radial track from the periphery to the centre of the section. In untreated tumours, liposomal doxorubicin was mainly located in the periphery of the tumour. The drug was found up to 450 μm from the rim of the tumour. In tumours only treated with liposomal doxorubicin, hardly any doxorubicin fluorescence was detected in the central part of the tumours (Figure 6A). Hyaluronidase improved the distribution of doxorubicin considerably, although doxorubicin was still rather heterogeneously distributed. Hyaluronidase allocated doxorubicin further away from the vessels in the periphery, and doxorubicin was located around vessels in the central part of the section where no doxorubicin was observed in tumours given liposomal doxorubicin alone (Figure 6B).

Bottom Line: Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner.Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase.Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, The Norwegian University of Science and Technology, Høgskoleringen 5, 7491 Trondheim, Norway. live.eikenes@phys.ntnu.no

ABSTRACT
Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

Show MeSH
Related in: MedlinePlus