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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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Doxorubicin fluorescence intensity profile in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (○) or combined with hyaluronidase (1500 U) (•). Each symbol is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. The increase in the doxorubicin uptake in the hyaluronidase-treated tumours is significant throughout the whole tumour (P<0.05).
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fig7: Doxorubicin fluorescence intensity profile in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (○) or combined with hyaluronidase (1500 U) (•). Each symbol is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. The increase in the doxorubicin uptake in the hyaluronidase-treated tumours is significant throughout the whole tumour (P<0.05).

Mentions: To obtain more quantitative data of doxorubicin distribution and uptake, the doxorubicin fluorescence intensity was quantified by estimating the average pixel intensity per image (Figure 7), and by estimating the fluorescence pixel area per image (data not shown). Both measurements gave similar results. The measurements were made along two perpendicular radial tracks on 10 sections per tumour in three tumours. The uptake of doxorubicin in the periphery was six to nine times higher than that in the other parts of the tumours when liposomal doxorubicin was given alone, and two to six times higher in the periphery of tumours treated with hyaluronidase (Figure 7). Hyaluronidase increased the uptake of doxorubicin two to eight times throughout the whole tumour, and in the central parts of the tumour hyaluronidase increased the uptake of doxorubicin approximately four times (Figure 7). An ANOVA comparing tumours treated with hyaluronidase and tumours given liposomal doxorubicin alone showed that the increase was significant throughout the whole tumour (P<0.05).


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)

Doxorubicin fluorescence intensity profile in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (○) or combined with hyaluronidase (1500 U) (•). Each symbol is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. The increase in the doxorubicin uptake in the hyaluronidase-treated tumours is significant throughout the whole tumour (P<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2361478&req=5

fig7: Doxorubicin fluorescence intensity profile in osteosarcoma xenografts treated with liposomal doxorubicin alone (16 mg kg− 1) (○) or combined with hyaluronidase (1500 U) (•). Each symbol is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. The increase in the doxorubicin uptake in the hyaluronidase-treated tumours is significant throughout the whole tumour (P<0.05).
Mentions: To obtain more quantitative data of doxorubicin distribution and uptake, the doxorubicin fluorescence intensity was quantified by estimating the average pixel intensity per image (Figure 7), and by estimating the fluorescence pixel area per image (data not shown). Both measurements gave similar results. The measurements were made along two perpendicular radial tracks on 10 sections per tumour in three tumours. The uptake of doxorubicin in the periphery was six to nine times higher than that in the other parts of the tumours when liposomal doxorubicin was given alone, and two to six times higher in the periphery of tumours treated with hyaluronidase (Figure 7). Hyaluronidase increased the uptake of doxorubicin two to eight times throughout the whole tumour, and in the central parts of the tumour hyaluronidase increased the uptake of doxorubicin approximately four times (Figure 7). An ANOVA comparing tumours treated with hyaluronidase and tumours given liposomal doxorubicin alone showed that the increase was significant throughout the whole tumour (P<0.05).

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