In Vivo Fate of Macromolecular Prodrugs and Lung Targeting

The fate of macromolecular conjugates when administered by the systemic route is heavily dependent on the distribution and elimination properties of the prodrug. In addition, endothelial and epithelial membrane transport is of primary importance with regard to targeting and drug action. Distribution and elimination profiles are primarily determined by factors such as molecular size, charge, water solubility, and hydrophilic and lipophilic balance. Apart from the incorporation of specific targeting features into the conjugate (i.e., antibodies), such physiochemical factors can play an important role in tissue targeting. The administration of macromolecule-drug conjugates by inhalation has received relatively little attention, although some studies involving anticancer agents are available. If such conjugates are required to access the circulatory system, then initial diffusion or transport across the alveolar capillary membrane must take place. In addition, interaction will occur with other structures, such as the alveolar epithelial cells that face the air spaces, the capillary endothelial cells that are the major constituents of the pulmonary macrocirculation, and the phagocytic pulmonary intravascular macrophages.

The relationship between pulmonary sequestering of macromolecules and molecular weight or particle size is not clear. Hashida et al. [160] showed that distribution of C-dextran-mitomycin C conjugates was dependent on molecular weight when given intravenously in rats, conjugates of MW 10,000-500,000 being sequestered mainly by spleen, liver, and lymph nodes, with no significant accumulation in the lung, heart, or muscle. Interestingly, cationic dextran conjugates of MW 70,000 or less are immediately distributed to the kidney and excreted, indicating that the glomerular capillary membrane is impermeable to polycationic macromolecules in excess of MW 70,000. There have been numerous studies in dogs and rats that indicate that particles exceeding 7 mm are retained in the lung after intravascular administration [161]. However, other studies in ruminants have shown that liposomes, bacteria, and magnetic iron microaggregates are sequestered in the lung, even at particle sizes much smaller than 7 mm [162,163]. Studies [164] have suggested that particulate trapping in the pulmonary circulation may not be solely dependent on size but may also be determined by other factors, for example, the involvement of pulmonary intravascular macrophages (PIMs), because pulmonary sequestration is often associated with pulmonary hypertension and lung injury, conditions that increase the lung burden of pulmonary intravascular macrophages. Other studies [165] have shown that disruption of hepatic bacterial clearance mechanisms may also induce PIM formation in the lung; of importance in this connection, patients with impaired hepatic function often exhibit substantial pulmonary uptake of intravascular colloidal imaging agents that are normally localized in the liver, spleen, and bone marrow of healthy patients.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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