Monoclonal antibody delivery to intraperitoneal tumors in rats: effects of route of administration and intraperitoneal solution osmolality.
Monoclonal antibody (MAb) transport in peritoneal tissue is dominated by convection, which is dependent on the net driving force of i.p. hydrostatic and osmotic pressure. To test the hypothesis that the i.p. osmolality has significant effects on IgG delivery to the tumor during the acute period after injection, solid tumors (FEMX-II) were transplanted into the anterior abdominal wall of nude rats. The wall is subject to well-defined pressure forces from the solution in the cavity. MAb 96.5, which specifically binds to FEMX-II cells, was simultaneously injected i.v. (111In-MAb 96.5 in Krebs Ringer solution) and i.p. (125I-MAb 96.5 in dialysis solution). Intraperitoneal hydrostatic pressure was held constant, and the osmolality of the i.p. solution was varied between isotonic and hypertonic (with the addition of 4% mannitol to an isotonic salt solution) in order to vary the direction of net convection. Plasma and peritoneal concentrations of both isotopes were measured at intervals over 200 min, and tissue concentration profiles in tumor and adjacent normal tissue were determined by dual-label quantitative autoradiography at 200 min. After i.v. administration, profiles were relatively flat and little affected by i.p. osmolality. After i.p. injection, profiles demonstrated steep concentration decreases from the peritoneal surface into the tissue for several hundred microns. Despite the change from the condition of water absorption from the cavity into the body (isotonic solution) to one of net volume gain by the cavity (hypertonic solution), tumor profiles were affected by i.p. osmolality only near the surface. Specific binding properties of the tumor were determined for the tumors studied and were consistent with high surface concentrations relative to normal tissue. Variation of the i.p. solution osmolality by changes in concentration of small molecules exerts only minor effects on the short-term MAb delivery from either systemic or regional administration to a target tumor in the anterior abdominal wall in the rat.
Flessner
M F
MF
Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892.
Dedrick
R L
RL
D000009:Abdominal Muscles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism*; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D007552:Isotonic Solutions / Q000737:chemistry; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy; D009994:Osmolar Concentration; D009995:Osmosis / Q000502:physiology; D010529:Peritoneal Cavity; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000628:therapy; D051381:Rats; D011923:Rats, Nude; D000077331:Ringer's Solution; D012996:Solutions / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007552:Isotonic Solutions; D012996:Solutions; D000077331:Ringer's Solution