Enhanced binding of modified pentosan polysulfate and heparin to bladder--a strategy for improved treatment of interstitial cystitis.
OBJECTIVE
To attach galactosyl residues to pentosan polysulfate (PPS) and heparin so that these drugs will bind to the endogenous lectins in the bladder. The increased binding may improve their efficacy for treating interstitial cystitis.


METHODS
The anionic polysaccharides, PPS, and heparin were modified by attachment of lactose. The covalent modification was by chemical linking of lactose derivatives or by beta-lactosyl transfer reaction from p-nitrophenyl beta-lactoside using the transglycosylation activity of Trichoderma reesei cellulase enzymes. The unmodified and modified PPS and heparin, as well as various mucin glycoproteins, were radiolabeled or biotinylated and examined for their ability to bind to rabbit and human bladder.


RESULTS
Both biotinylated and radiolabeled PPS and heparin bound very weakly or not at all to human and rabbit bladders. In contrast, the PPS and heparin modified by attachment of lactose, as well as the asialo mucin glycoproteins, bound strongly to human and rabbit bladders. This binding is apparently mediated by the interaction of the endogenous bladder galactins and the non-reducing galactose terminals in the lactose attached to the anionic polysaccharides or the asialoglycoproteins.


CONCLUSIONS
Lactose-pentosan sulfate and lactose-heparin bind more avidly to the bladder epithelium than the unmodified molecules. Thus, they may be more effective for interstitial cystitis than the parent drugs. Other possible applications of this approach include modification of intravesical chemotherapeutic agents for bladder cancer, or intravesically placed antibiotics, to improve their adherence and retention in the bladder.
Muthusamy
Arivalagan
A
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Erickson
Deborah R
DR
Sheykhnazari
Mostafa
M
Bhavanandan
Veer P
VP
D000818:Animals; D018856:Cystitis, Interstitial / Q000188:drug therapy*; D015195:Drug Design; D006493:Heparin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D010426:Pentosan Sulfuric Polyester / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011817:Rabbits; D001743:Urinary Bladder / Q000378:metabolism*
D010426:Pentosan Sulfuric Polyester; D006493:Heparin