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


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.


CONCLUSIONS
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.
Erikson
Arne
A
Department of Physics, Norwegian University of Science and Technology, H-gskoleringen 5, 7491 Trondheim.
Tufto
Ingunn
I
Bjønnum
Anne Berit
AB
Bruland
Øyvind S
ØS
Davies
Catharina de Lange
Cde L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005109:Extracellular Matrix / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D018613:Microscopy, Confocal; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D004317:Doxorubicin; D003094:Collagen; D006821:Hyaluronoglucosaminidase; D017364:Collagenases