The impact of enzymatic degradation on the uptake of differently sized therapeutic molecules

Anticancer Res. Nov-Dec 2008;28(6A):3557-66.

Abstract

Background: The extracellular matrix represents a major barrier for drug delivery. This work compares the effects of collagenase and hyaluronidase on tumour uptake and distribution of two differently sized therapeutic molecules, IgG and liposomal doxorubicin.

Materials and methods: The enzymes were injected i.v. prior to the therapeutic molecules, and uptake and distribution were studied by confocal laser scanning microscopy. The therapeutic molecules were colocalized with the vasculature and collagen network visualized by the second harmonic signal.

Results: Hyaluronidase increased the uptake of liposomal doxorubicin to a small extent, whereas collagenase had no effect. Collagenase increased, but hyaluronidase reduced the uptake of IgG. Neither of the enzymes induced changes in the collagen network measured by the second harmonic signal.

Conclusion: Degradation of the collagen network improves delivery of molecules with the size of IgG, whereas degradation of the gel of glycosaminoglycans has a higher impact on the distribution of small drugs such as doxorubicin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacokinetics*
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / enzymology
  • Bone Neoplasms / metabolism*
  • Cell Line, Tumor
  • Collagen / metabolism
  • Collagenases / pharmacology*
  • Doxorubicin / pharmacokinetics*
  • Drug Interactions
  • Extracellular Matrix / drug effects*
  • Extracellular Matrix / enzymology
  • Extracellular Matrix / metabolism
  • Female
  • Humans
  • Hyaluronoglucosaminidase / pharmacology*
  • Immunoglobulin G / immunology
  • Mice
  • Microscopy, Confocal
  • Osteosarcoma / drug therapy
  • Osteosarcoma / enzymology
  • Osteosarcoma / metabolism*
  • Skin / drug effects
  • Skin / enzymology
  • Skin / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Doxorubicin
  • Collagen
  • Hyaluronoglucosaminidase
  • Collagenases