Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 10

abnormal vasculature, altered extracellular matrix components, interstitial fluid
pressure, and tumor cell density. All of these aspects affect drug distribution and
thereby the cytotoxicity of the treatment.

2.2.1 Transcytosis

Transcytosis is equivalent to the small-intestine transporter systems where macro-
molecules pass the endothelium barrier bound to a specific carrier through a
receptor-mediated transcellular mechanism. A well characterized pathway is that
mediated by albumin. Albumin is the most abundant protein found in plasma and
can function as a cargo chaperone binding to many substrates in the plasma, facili-
tating their delivery across the endothelial barrier. The albumin-molecule complex
interacts with the cell-surface glycoprotein (gp60) receptor which subsequently
binds to protein caveolin-1 triggering the formation of transcytotic vesicles (cave-
olae). These phenomena have an important clinical impact on drug uptake and
efficacy. One example is Abraxane, a Cremophor® free albumin-bound 130-nm
particle formulation of the chemotherapeutic agent paclitaxel which has been
shown to improve paclitaxel tumor cell penetration with reduced side effects
(Desai et al. 2006 ).

2.2.2 Vasculature Permeability and Models for Passive Drug Transport

Across the Endothelium

The vascular endothelium is a semi-permeable barrier which controls the passage
of macromolecules and fluids in the interstitial space assuring tissue fluid homeo-
stasis. Interactions between endothelial cells and pericytes, or integrin-mediated
interactions with extracellular matrix (ECM) proteins, such as collagen IV,
fibronectin and laminin, activates signaling pathways, keeping the endothelium
quiescent and leading to stable vessels with controlled junctions and permeability.
The passive extravasation of molecules across the endothelium occurs by diffusion
and convection through two primary mechanisms: paracellular and transcellular
routes. In the paracellular route, small molecules (<3 nm), such as urea and glucose,
can pass the endothelium barrier through junctions between cells, moving down a
concentration gradient. The transcellular pathway instead mediates the transport of
large molecules (>3 nm), such as plasma proteins (Mehta and Malik 2006 ). For
example, albumin exploits the receptor-mediated caveolae pathway as well as
transiently formed transcellular channels. This architecture can be altered during
disease states in which inflammatory mediators, such as VEGF (vascular endothelial
growth factor) and thrombin, alter the organization of intercellular junctions and
interactions between cells and ECM, creating intercellular gaps which allow the
uncontrolled flow of plasma protein and liquids across the endothelium, causing
swelling and immunological responses.