No abstract

The huge molecular radius of immunoglobulins would seem to be a major drawback for the targeting of solid tumors, because of slow extravasation into tumor interstitium and along plasma half-life. The permeability of normal continuous capillary endothelia to intravascular solutes of different molecular sizes has been determined in animals, mainly for macromolecules, and different sources give data consistent with the graph in Fig. 1 (1-3). The position of whole antibodies (IgG, mol wt 150 kDa and effective molecular radius 5.5 nm) is well to the right of albumen (66 kDa and 3.5 nm), and they are therefore very slowly extravasated in normal tissues. A F(ab')2 fragment (100 kDa, 5.06 nm) should not extravasate much faster than the intact molecule on this basis and a monomeric Fab' fragment (50 kDa, 3.48 nm) still has quite a high molecular radius (4), so a much smaller molecule would be necessary to equilibrate very quickly with extracellular fluid (ECF). Fig. 1. Relationship between molecular radius and permeability/surface area product for intact capillaries.

No abstract

Summary Endocervical columnar epithelium with stroma intact, was maintained in organ culture for up to ten days. Many explants showed a progressive dedifferentiation, pyknosis and eventual loss of columnar cells with a gradual replacement of these with metaplastic cells apparently of stromal origin. This was a progression of changes similar to squamous metaplasia seen in vivo. Studies of the surface characteristics of the cultured tissue, with the scanning electron microscope, showed a change of cell type from columnar cells with closely packed micro‐villi, to a flattened squamous type with interdigitating cell boundaries and a mixed surface structure of micro‐ridges and micro‐villi. The significance of these results and the use of this organ culture system as a model in the study of the actiology of cervical malignancy is discussed.

A mathematical model has been developed to optimize tumor targeting with labeled antibodies. The model is compartmental and nonlinear, incorporating saturable binding. Published parameter values have been used in the model, and the resulting stiff differential equations have been solved using FACSIMILE, a computer package that can simulate very stiff differential systems. Results show that successful tumor targeting depends on an optimal combination of antibody dose, affinity, and molecular size. The model has allowed an assessment to be made of the complicated and interrelated dynamic relationships that these factors have on tumor targeting. It has also offered an explanation for previously unsatisfactory results from tumor targeting with labeled antibodies. The structural identifiability of the model parameters is also analyzed and it is shown that, with the prior knowledge of some parameters which is likely in practice, the remaining model parameters are uniquely identifiable.