Systemic administration of drugs in tumors is a challenging task due to unorganized microvasculature and nonuniform extravasation. There is an imperative need to understand the transport behavior of drugs when administered intravenously. In this study, a transport model is developed to understand the therapeutic efficacy of a free drug and liposome-encapsulated drugs (LED), in heterogeneous vasculature of human brain tumors. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) data is employed to model the heterogeneity in tumor vasculature that is directly mapped onto the computational fluid dynamics (CFD) model. Results indicate that heterogeneous vasculature leads to preferential accumulation of drugs at the tumor position. Higher drug accumulation was found at location of higher interstitial volume, thereby facilitating more tumor cell killing at those areas. Liposome-released drug (LRD) remains inside the tumor for longer time as compared to free drug, which together with higher concentration enhances therapeutic efficacy. The interstitial as well as intracellular concentration of LRD is found to be 2–20 fold higher as compared to free drug, which are in line with experimental data reported in literature. Close agreement between the predicted and experimental data demonstrates the potential of the developed model in modeling the transport of LED and free drugs in heterogeneous vasculature of human tumors.

References

1.
Pattni
,
B. S.
,
Chupin
,
V. V.
, and
Torchilin
,
V. P.
,
2015
, “
New Developments in Liposomal Drug Delivery
,”
Chem. Rev.
,
115
(
19
), pp.
10938
10966
.
2.
Allen
,
T. M.
, and
Torchilin
,
P. R.
,
2013
, “
Liposomal Drug Delivery Systems: From Concept to Clinical Applications
,”
Adv. Drug Delivery Rev.
,
65
(
1
), pp.
36
48
.
3.
Baxter
,
L. T.
, and
Jain
,
R. K.
,
1989
, “
Transport of Fluid and Macromolecules in Tumors—I: Role of Interstitial Pressure and Convection
,”
Microvasc. Res.
,
37
(
1
), pp.
77
104
.
4.
Baxter
,
L. T.
, and
Jain
,
R. K.
,
1990
, “
Transport of Fluid and Macromolecules in Tumors II. Role of Heterogeneous Perfusion and Lymphatics
,”
Microvasc. Res.
,
40
(2), pp.
246
263
.
5.
Harashima
,
H.
,
Iida
,
S.
,
Urakami
,
Y.
,
Tsuchihashi
,
M.
, and
Kiwada
,
H.
,
1999
, “
Optimization of Antitumor Effect of Liposomally Encapsulated Doxorubicin Based on Simulation by Pharmacokinetic/Pharmacodynamics Modeling
,”
J. Controlled Release
,
61
(
1–2
), pp.
93
106
.
6.
Elkareh
,
A. W.
, and
Secomb
,
T. W.
,
2000
, “
A Mathematical Model for Comparison of Bolus Injection, Continuous Infusion and Liposomal Delivery of Doxorubicin to Tumor Cells
,”
Neoplasia
,
2
(
4
), pp.
325
338
.
7.
Stapleton
,
S.
,
Milosevic
,
M.
,
Allen
,
C.
,
Zheng
,
J.
,
Dunne
,
M.
,
Yeung
,
I.
, and
Jaffray
,
D. A.
,
2013
, “
A Mathematical Model of the Enhanced Permeability and Retention Effect for Liposome Transport in Solid Tumors
,”
PLoS ONE
,
8
(
2
), p.
e81157
.
8.
Goh
,
Y. M. F.
,
Kong
,
H. L.
, and
Wang
,
C. H.
,
2001
, “
Simulation of Delivery of Doxorubicin to Hepatoma
,”
Pharm. Res.
,
18
(
6
), pp.
761
770
.
9.
Arifin
,
D. Y.
,
Lee
,
K. Y. T.
,
Wang
,
C. H.
, and
Smith
,
K. A.
,
2009
, “
Role of Convective Flow in Carmustine Delivery to a Brain Tumor
,”
Pharm. Res.
,
26
(
10
), pp.
2289
2302
.
10.
Soltani
,
M.
, and
Chen
,
P.
,
2011
, “
Numerical Modeling of Fluid Flow in Solid Tumors
,”
PLoS One
,
6
(
6
), p.
e20344
.
11.
Zhan
,
W.
,
Gedroyc
,
W.
, and
Xu
,
X. Y.
,
2014
, “
Effect of Heterogeneous Microvasculature Distribution on Drug Delivery to Solid Tumour
,”
J. Phys. D: Appl. Phys.
,
47
(
47
), p.
475401
.
12.
Magdoom
,
K. N.
,
Pishko
,
G. L.
,
Kim
,
J. H.
, and
Sarntinoranont
,
M.
,
2012
, “
Evaluation of a Voxelized Model Based on DCE-MRI for Tracer Transport in Tumor
,”
ASME J. Biomech. Eng.
,
134
(9), p.
091004
.
13.
Tofts
,
P.S.
,
Brix
,
G.
,
Buckley
,
D. L.
,
Evelhoch
,
J. L.
,
Henderson
,
E .
,
Knopp
,
M. V.
,
Larsson
,
H. B. W.
,
Lee
,
T. Y.
,
Mayr
,
N. A.
,
Parker
,
G. J. M.
,
Port
,
R. E.
,
Taylor
,
J.
, and
Weisskoff
,
R. M.
,
1999
, “
Estimating Kinetic Parameters From Dynamic Contrast-Enhanced T1-Weighted MRI of a Diffusable Tracer: Standardized Quantities and Symbols
,”
J. Magn. Reson. Imaging
,
26
(
4
), pp.
871
880
.https://www.ncbi.nlm.nih.gov/pubmed/10508281
14.
Bhandari
,
A.
,
Bansal
,
A.
,
Singh
,
A.
, and
Sinha
,
N.
,
2017
, “
Perfusion Kinetics in Human Brain Tumor With DCE-MRI Derived Model and CFD Analysis
,”
J. Biomech.
,
59
, pp.
80
89
.
15.
Bhandari
,
A.
,
Bansal
,
A.
,
Singh
,
A.
, and
Sinha
,
N.
,
2017
, “
Transport of Liposomes Encapsulated Drugs in Voxelized Computational Model of Human Brain Tumors
,”
IEEE Trans. Nanobiosci.
,
16
(
7
), pp.
634
644
.
16.
Tofts
,
P. S.
,
1997
, “
Modeling Tracer Kinetics in Dynamic Gd-DTPA MR Imaging
,”
J. Magn. Reson. Imaging,
3
, pp.
91
101
.
17.
Singh
,
A.
,
Haris
,
M.
,
Purwar
,
A.
,
Sharma
,
M.
,
Husain
,
N.
,
Rathore
,
R. K. S.
, and
Gupta
,
R. K.
,
2007
, “
Quantification of Physiological and Hemodynamic Indices Using T1 DCE-MRI in Intracranial Mass Lesions
,”
J. Magn. Reson. Imaging
,
26
(4), pp.
871
880
.
18.
Pintaske
,
J.
,
Martirosian
,
P.
,
Graf
,
H.
,
Erb
,
G.
,
Lodemann
,
K. P.
,
Claussen
,
C. D.
, and
Schick
,
F.
,
2006
, “
Relaxivity of Gadopentetate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (MultiHance) in Human Blood Plasma at 0.2, 1.5 and 3 Tesla
,”
Invest. Radiol.
,
41
(
3
), pp.
213
221
.
19.
Singh
,
A.
,
Rathore
,
R. K. S.
,
Haris
,
M.
,
Verma
,
S. K.
,
Husain
,
N.
, and
Gupta
,
R. K.
,
2009
, “
Improved Bolus Arrival Time and Arterial Input Function Estimation for Tracer Kinetic Analysis in DCE-MRI
,”
J. Magn. Reson. Imaging
,
29
(1), pp.
166
176
.
20.
Tofts
,
P. S.
, and
Kermode
,
A. G.
,
1991
, “
Measurement of the Blood-Brain Barrier Permeability and Leakage Space Using Dynamic MR Imaging
,”
Magn. Reson. Med.
,
17
(2), pp.
357
367
.
21.
Gabizon
,
A.
,
Isacson
,
R.
,
Libson
,
E.
,
Kaufman
,
B.
,
Uziely
,
B.
,
Catane
,
R.
,
Rabello
,
E.
,
Cass
,
Y.
,
Peretz
,
T.
,
Sulkes
,
A.
,
Chisin
,
R.
, and
Barenholz
,
Y.
,
1994
, “
Clinical Studies of Liposome Encapsulated Doxorubicin
,”
Acta Oncol.
,
33
(
7
), pp.
779
786
.
22.
Greene
,
R. F.
,
Collins
,
J. M.
,
Jenkins
,
J. F.
,
Speyer
,
J. L.
, and
Myers
,
C. E.
,
1983
, “
Plasma Pharmacokinetics of Adriamycin and Adriamycinol: Implications for the Design of In Vitro Experiments and Treatment Protocols
,”
Cancer Res.
,
43
(7), pp.
3417
3421
.http://cancerres.aacrjournals.org/content/43/7/3417.short
23.
Eikenberry
,
S.
,
2009
, “
A Tumor Cord Model for Doxorubicin Delivery and Dose Optimization in Solid Tumors
,”
Theor. Bio. Med. Model.
,
6
, p.
16
.
24.
Eliaz
,
R. E.
,
Nir
,
S.
,
Marty
,
C.
, and
Szoka
,
F. C.
,
2004
, “
Determination and Modeling of Kinetics of Cancer Cell Killing by Doxorubicin and Doxorubicin Encapsulated in Targeted Liposomes
,”
Cancer Res.
,
64
(2), pp.
711
718
.
25.
Khalifa
,
A.
,
Dodds
,
D.
,
Rampling
,
R.
,
Paterson
,
J.
, and
Murray
,
T.
,
1997
, “
Liposomal Distribution in Malignant Gliomas: Possibilities for Theraphy
,”
Nucl. Med. Commun.
,
18
, pp.
17
23
.
26.
Hau
,
P.
,
Fabel
,
K.
,
Baumgart
,
U.
,
Rummele
,
P.
,
Grauer
,
O.
,
Bock
,
A.
,
Dietmaier
,
C.
,
Dietmaier
,
W.
,
Dietrich
,
J.
,
Dudel
,
C.
,
Hubner
,
F.
,
Jauch
,
T.
,
Drechsel
,
E.
,
Kleiter
,
I.
,
Wismeth
,
C.
,
Zellner
,
A.
,
Brawanski
,
A.
,
Stienbrecher
,
A.
,
Marienhagen
,
J.
, and
Bogdahn
,
U.
,
2005
, “
Pegylated Liposomal Doxorubicin-Efficacy in Patients With Recurrent High-Grade Gliomas
,”
Am. Can. Soc.
,
100
(
6
), pp.
1199
1207
.
27.
Murray
,
J. D.
,
2012
, “
Glioblastoma Brain Tumours: Estimating the Time From Brain Tumour Initiation and Resolution of a Patient Survival Anomaly After Similar Treatment Protocols
,”
J. Bio. Dyn.
,
6
(
2
), pp.
118
127
.
28.
Anderson
,
D. A.
,
Tannehill
,
J. C.
, and
Pletcher
,
R. H.
,
1984
,
Computational Fluid Mechanics and Heat Transfer
,
Hemisphere
,
New York
, pp.
671
674
.
29.
Abe
,
T.
,
Mizobuchi
,
Y.
,
Nakajima
,
K.
,
Otomi
,
Y.
,
Irahara
,
S.
,
Obama
,
Y.
,
Majigsuren
,
M.
,
Khashbat
,
D.
,
Kagezi
,
T.
,
Nagahiro
,
S.
, and
Harada
,
M.
,
2015
, “
Diagnosis of Brain Tumors Using Dynamic Contrast-Enhanced Perfusion Imaging With a Short Acquisition Time
,”
Springer Plus
,
4
, p.
88
.
30.
Boucher
,
Y.
,
Salehi
,
H.
,
Witwer
,
B.
,
Harsh
,
G. R.
, IV
., and
Jain
,
R. K.
,
1997
, “
Interstitial Fluid Pressure in Intracranial Tumors in Patients and in Rodents
,”
Br. J. Cancer
,
75
, pp.
829
836
.
31.
Guttman
,
R.
,
Leunig
,
M.
,
Feyh
,
J.
,
Goetz
,
A. E.
,
Messmer
,
K.
, and
Kastenbauer
,
E.
,
1992
, “
Interstitial Hypertension in Head and Neck Tumors in Patients: Correlation With Tumor Size
,”
Cancer Res.
,
52
(7), pp.
1993
1995
.http://cancerres.aacrjournals.org/content/52/7/1993.short
32.
Wu
,
Z. N.
,
Da
,
D.
,
Rudoll
,
T. L.
,
Needham
,
D.
,
Whorton
,
A. R.
, and
Dewhirst
,
M. W.
,
1993
, “
Increased Microvascular Permeability Contributes to Preferential Accumulation of Stealth Liposomes in Tumor Tissue
,”
Cancer Res.
,
53
(16), pp.
3765
3770
.http://cancerres.aacrjournals.org/content/53/16/3765.short
33.
Gabizon
,
A.
,
Goren
,
D.
,
Horowitz
,
A. T.
,
Tzemach
,
D.
,
Lossos
,
A.
, and
Siegal
,
T.
,
1997
, “
Long-Circulating Liposomes for Drug Delivery in Cancer Therapy: A Review of Bio-Distribution Studies in Tumor-Bearing Animals
,”
Adv. Drug Delivery Rev.
,
24
(2–3), pp.
337
344
.
34.
Gabizon
,
A.
,
Shmeeda
,
H.
, and
Barenholz
,
Y.
,
2003
, “
Pharmacokinetics of Pegylated Liposomal Doxorubicin, Review of Animal and Human Studies
,”
Clin. Pharm.
,
42
(
5
), pp.
419
436
.
35.
Gabizon
,
A.
,
Catane
,
R.
,
Uziely
,
B.
,
Kaufman
,
B.
,
Safra
,
T.
,
Cohen
,
R.
,
Martin
,
F.
,
Huang
,
A.
, and
Barenholz
,
Y.
,
1994
, “
Prolonged Circulation Time and Enhanced Accumulation in Malignant Exudates of Doxorubicin Encapsulated in Polyethylene-Glycol Coated Liposomes
,”
Cancer Res.
,
54
(4), pp.
987
992
.http://cancerres.aacrjournals.org/content/54/4/987.short
36.
Siegel
,
T.
,
Horowitz
,
A.
, and
Gabizon
,
A.
,
1995
, “
Doxorubicin Encapsulated in Sterically Stabilized Liposomes for the Treatment of a Brain Tumor Model: Bio Distribution and Therapeutic Efficacy
,”
J. Neurosurg.
,
83
(6), pp.
1029
1037
.
You do not currently have access to this content.