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Cited by 221Proteoglycans and glycosaminoglycans researchNanoparticle-Based Drug DeliveryUltrasound and Hyperthermia Applications

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

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Eikenes, L, Tari, M, Tufto, I, Bruland, Ø S, de Lange Davies, C·2005·British Journal of Cancer
DOI 10.1038/sj.bjc.6602626PMC PMC2361478
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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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Crossref · 10.1038/sj.bjc.6602626

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Figures

Figure 1 Maximum reduction (%) in IFP 1 h after intratumoral injection of PBS (n=5), 150 U (n=6), 500 U (n=5), 1500 U (n=6) and 3000 U (n=6) hyaluronidase in o.t. tumours. Each value is the mean of n tumours, the bars represent s.e. *Data significantly different from untreated controls.
Figure 1 Maximum reduction (%) in IFP 1 h after intratumoral injection of PBS (n=5), 150 U (n=6), 500 U (n=5), 1500 U (n=6) and 3000 U (n=6) hyaluronidase in o.t. tumours. Each value is the mean of n tumours, the bars represent s.e. *Data significantly different from untreated controls.CC BY · PubMed Central
Figure 2 Interstitial fluid pressure response as a function of time after intratumoral injection of 150 U () (n=4), 500 U (Δ) (n=5), 1500 U (∇)(n=4) and 3000 U (□) (n=6) hyaluronidase in o.t. tumours. Interstitial fluid pressure is normalised to IFP before the injection. Each curve is the mean of n measurements.
Figure 2 Interstitial fluid pressure response as a function of time after intratumoral injection of 150 U () (n=4), 500 U (Δ) (n=5), 1500 U (∇)(n=4) and 3000 U (□) (n=6) hyaluronidase in o.t. tumours. Interstitial fluid pressure is normalised to IFP before the injection. Each curve is the mean of n measurements.CC BY · PubMed Central
Figure 3 Maximum reduction in IFP after intratumoral injection of hyaluronidase as a function of tumour volume. Each symbol represents one measurement, the solid line represents linear regression analysis and was found to be significant for all doses except 150 U.
Figure 3 Maximum reduction in IFP after intratumoral injection of hyaluronidase as a function of tumour volume. Each symbol represents one measurement, the solid line represents linear regression analysis and was found to be significant for all doses except 150 U.CC BY · PubMed Central
Figure 4 Normalised pressure after (A) intratumoral and (B) i.v. injection of 1500 U hyaluronidase in s.c. tumours. Microvascular pressure (•) was not measured continuously, and the data are based on different time intervals for n=5 (intratumoral injection) and n=7 (i.v. injection) mice. The bars represent s.e. at some time points. The IFP (○) graph is the mean of n=2 measurements.
Figure 4 Normalised pressure after (A) intratumoral and (B) i.v. injection of 1500 U hyaluronidase in s.c. tumours. Microvascular pressure (•) was not measured continuously, and the data are based on different time intervals for n=5 (intratumoral injection) and n=7 (i.v. injection) mice. The bars represent s.e. at some time points. The IFP (○) graph is the mean of n=2 measurements.CC BY · PubMed Central
Figure 5 Tumour tissue hyaluronan (blue) in o.t. osteosarcoma xenografts relative to capillaries (red) and tumour cells (green) treated with PBS (A) and hyaluronidase (1500 U) (B, C).
Figure 5 Tumour tissue hyaluronan (blue) in o.t. osteosarcoma xenografts relative to capillaries (red) and tumour cells (green) treated with PBS (A) and hyaluronidase (1500 U) (B, C).CC BY · PubMed Central
Figure 6 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.
Figure 6 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.CC BY · PubMed Central
Figure 7 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).
Figure 7 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).CC BY · PubMed Central
Figure 8 Number of images as a function of fluorescence intensity for osteosarcoma xenografts given liposomal doxorubicin alone (16 mg kg− 1) (□) or combined with hyaluronidase (1500 U) (▪). Each value is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. *Data significantly different from Caelyx™ alone.
Figure 8 Number of images as a function of fluorescence intensity for osteosarcoma xenografts given liposomal doxorubicin alone (16 mg kg− 1) (□) or combined with hyaluronidase (1500 U) (▪). Each value is the mean of 5–20 images per section and 10 sections per tumour in three tumours. Bars represent s.e. *Data significantly different from Caelyx™ alone.CC BY · PubMed Central
Figure 9 Intracellular distribution of doxorubicin (green) (A), DNA (red) (B) and colocalisation of doxorubicin and DNA (C) in osteosarcoma xenografts given liposomal doxorubicin alone (16 mg kg− 1). Bar=20 μm.
Figure 9 Intracellular distribution of doxorubicin (green) (A), DNA (red) (B) and colocalisation of doxorubicin and DNA (C) in osteosarcoma xenografts given liposomal doxorubicin alone (16 mg kg− 1). Bar=20 μm.CC BY · PubMed Central

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Metadata

Authors
Eikenes, L., Tari, M., Tufto, I., Bruland, Ø. S., & de Lange Davies, C.
Affiliations
  • Norwegian University of Science and Technology (NO)
  • University of Oslo (NO)
Corresponding author
Eikenes, L
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2005-06-07
Volume
93
Issue
1
Pages
81-88
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/sj.bjc.6602626
PMC
PMC2361478
OpenAlex
W1985957186
Cited by
221
References
41
Citations by year
2026: 7 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 19 · 2021: 13 · 2020: 17 · 2019: 13 · 2018: 15 · 2017: 11 · 2016: 14 · 2015: 11 · 2014: 16 · 2013: 10 · 2012: 12
FWCI
2.04
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Kreftforeningen
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
hyaluronidase, liposomal doxorubicin, pegylated liposomal doxorubicin, osteosarcoma, interstitial fluid pressure, extracellular matrix degradation, microvascular pressure, tumor xenografts, drug delivery enhancement
MeSH terms
Animals, Antibiotics, Antineoplastic, Doxorubicin, Female, Humans, Hyaluronoglucosaminidase, Liposomes, Mice, Inbred BALB C, Osteosarcoma, Transplantation, Heterologous, Microscopy, Confocal, Mice

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