Delivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies

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Authors: Vikash P. Chauhan, Triantafyllos Stylianopoulos, Yves Boucher, and Rakesh K. Jain

Published in: The Annual Review of Chemical and Biomolecular Engineering, vol 2 (2011): 281-98

Introduction

More than 90% of cancer patients die of metastases. In other words, cancer can be considered a systemic disease and requires systemic therapy. This inevitably involves 3 major transport regimes:

  • Vascular transport
  • Transvascular transport
  • Interstitial transport

In addition, we can view tumor as an organ with unusual properties:

  • Accumulated solid stress
  • Abnormal blood vessel networks
  • Elevated interstitial fluid pressure
  • Dense interstitial structure

The heterogeneity of blood distribution and slow flow lead to low and nonuniform perfusion. The transmural pressure gradients are also diminished, limiting the transport mechanism of any drug or its carrier from the blood into the tissue (only through diffusion - inefficient). The drug penetration is also hindered by highly viscoelastic interstitium with tortuous paths and drug sequestration. All these factors result in poor drug delivery.

Transport Regimes

Vascular transport

Supply of drugs via blood into the regions, flow of drug/vehicle, and distribution via vascular network

1. <math>q=\frac{Q}{V}</math>

q=blood perfusion rate

Q=volumetric flow rate (of the blood)

V=tissue volume

2. <math>Q=\frac{\Delta p}{R}</math>

<math>\Delta p =</math>pressure drop

R= resistance

(This has both viscous and geometric components)

3. <math>J_v=QC_v</math>

<math>J_v</math>=flux of drug into tissue from blood vessels

<math>C_v</math>=drug concentration feeding the blood vessel

There is heterogeneity observed in

  • Vascular distribution
  • Flow rates determining volume of distribution

4. Distribution of perfusion rates = <math>Q_jV_j</math>

<math>Q_j=</math>volumetric flow rate into each vessel

<math>V_j=</math>volume of tissue each vessel feeds

Transvascular transport

Flux of drugs across vessel walls and basement membrane

1. <math>J_{t,d}=P_tS_v(C_v-C_i)</math>

<math>J_{t,d}=</math>diffusive flux

<math>C_v=</math>plasma concentration

<math>C_i=</math>interstitial concentration

<math>S_v=</math>vascular surface area

<math>P_t=</math>vascular permeability (constant of proportionality)

2. <math>J_{t,a}=C_vK_tS_v(1-\sigma_s)(\Delta p_t-\sigma \Delta \Pi)</math>

<math>J_{t,a}=</math>convective flux

<math>\Delta p_t=</math>transmural hydrostatic pressure gradient

<math>\sigma=</math>osmotic reflection coefficient

<math>\Delta \Pi=</math>transmural osmotic pressure gradient

<math>K_t=</math>hydraulic conductivity

<math>\sigma_s=</math>solute's reflection coefficient

<math>1-\sigma_s=</math>(constant of proportionality)

Note: <math>P_t</math> and <math>K_t</math> are dependent on biophysical properties of vessel wall and basement membrane (viscoelasticity, porosity, physicochemical properties of drug - size, charge, configuration)

3. <math>J_t=</math>transvascular flux<math>=J_{t,d}+J_{t,a}=K_tS_v(1-\sigma_s)(\Delta p_t-\sigma \Delta \Pi)[\frac{C_ve^{Pe}-C_i}{e^{Pe}-1}]</math>

Pe=<math>P\acute{e}clet number=\frac{LU}{D}=Re_L \cdot S_c</math>

L=characteristic length

U=velocity

D=mass diffusion coefficient

Interstitial transport

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