(442c) Modeling the Mechanism of Drug Transport to Solid Tumors

Abstract

Cancer
has emerged as one of the leading causes of death in humans in both developed
and developing countries [1].  In spite of remarkable advances in cancer
research in the past few decades that enabled early diagnoses of various
cancers and more effective anti-cancer drugs and novel treatment therapies, a
complete understanding of the nature of the origin of cancer is yet to be
realized due to the complex nature of tumor formation and the unpredictable
functionality of the tumor in the human body.

Proliferation
of the tumor cells and the tumor vasculature (blood and nutrient supply
vessel system) differ among different tumors and even among individuals who
have same type of tumor [2].  Such differences pose difficulties in
generalization of the phenomenological factors and also affect effective
transport of these drugs to the tumor [3].  Therefore developing effective drug
delivery mechanisms needs to have a thorough understanding of: (i) the
formation of the tumor, (ii) the biological structure of the tumor, (iii) the
functionality of the tumor at various stages of its proliferation, and (iv) the
physiological barriers in the drug delivery mechanism caused by the tumor.  Additionally,
due to the lethal nature of these treatments and the interactions of these
drugs with other functional cells in the body, it is necessary that the treatments
be implemented in stages and confined to small doses.  

The
transport of effective doses of anti-cancer tumor drugs to solid tumors is
challenging due to the barriers imposed by the tumor vasculature [1].  Furthermore,
drug metabolism, the body's natural removal process, and binding to non-target
cells [4] make complete utilization of the drug impossible.  In addition, both
the physiological configuration (i.e. the size and shape) and the biological
structure of tumor play major roles in drug transport [3], [5], [6], [7].  Thus,
permeability, porosity of the diffusive media (i.e. the composition of
capillary wall, interstitium and tumor, etc.), and inter-cellular interactions
and bindings also contribute significant influences to the transport mechanisms
[7],[8].  In order to quantify the effectiveness of the anti-cancer drug, a
thorough understanding of the mechanisms of drug transport to the tumor is
needed.

When,
blood-borne molecules or particles enter to the tumor vasculature, they reach
the cancer cell via distribution through the vascular compartment, transport
across the micro vascular wall and transport through the interstitial
compartment.  The transport mechanism involves convection, diffusion, or a
combination of both mechanisms. The presence of a concentration gradient causes
diffusion based transport.  The fluid movement caused by the pressure gradient
leads to convective fluid transport where the solute is carried away by solvent
drag.

The
objective of this study is to develop a general computational model that
describes the mechanisms of drug transport to a solid tumor using solute
transport concepts.  Accountability of the changing tumor boundary due to the
change in cell population is

incorporated
in the computational model.  The computational model also considers drug
transport through the vasculature and the interstitium that surrounds the
tumor.  The transport mechanisms depend on the diffusivity of the drug within
the different media,

permeability
of the vessel geometry, compartment pressures, the concentration of the
anti-cancer drug, and other related factors.  The effects of these factors will
be analyzed using a parametric sensitivity analysis.  It will be shown that
computational models that embody the physics of the transport mechanisms can
improve our knowledge about the barriers to effective drug therapies, the
efficacy of the treatment, and the effectiveness of current and future
anti-cancer drugs.

References:

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cellular medicine to solid tumors, Micro-circulation, 1997, vol.4, No.1,
pages1-23.

[2] J. Folkman. Angiogenesis, MCGraw-Hill,
2001,  pages 517-530.

[3] R.K. Jain. Transport of molecules in the
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3039-3051.

[4] A. David, , F.Yuan, , M.Leuing, and R.K.
Jain,. In vivo measurement of targeted     binding in a human tumor xenograft, 
Biophysics, 1997(94), pages 1785-1790 (PNAS).

[5]
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interactions in interstitial diffusion of macromolecules: Cranial vs.
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[6]
B.Rippe, B.I. Rosengren, O. Carlsson , and D. Venturoli. Transendothelial
transport: the vesicle controversy, J. Vascular research, 2002(39) , 
pages 375-390.

[7]
D.Venturoli, and B. Rippe. Transport asymmetry in peritoneal dialysis:
Application of a serial hetero-porous peritoneal membrane model, Am J. Renol
Physiol, 2001(280),

pages
 F599-F606.

[8]
R.K. Jain. Barriers to drug delivery in solid tumors, Scientific American,
1994(271)(1), pages 58-65.