The Binding Site Barrier Elicited by Tumor-Associated Fibroblasts Interferes Disposition of Nanoparticles in Stroma-Vessel Type Tumors.
The binding site barrier (BSB) was originally proposed to describe the binding behavior of antibodies to cells peripheral to blood vessels, preventing their further penetration into the tumors. Yet, it is revisited herein to describe the intratumoral cellular disposition of nanoparticles (NPs). Specifically, the BSB limits NP diffusion and results in unintended internalization of NPs by stroma cells localized near blood vessels. This not only limits the therapeutic outcome but also promotes adverse off-target effects. In the current study, it was shown that tumor-associated fibroblast cells (TAFs) are the major component of the BSB, particularly in tumors with a stroma-vessel architecture where the location of TAFs aligns with blood vessels. Specifically, TAF distance to blood vessels, expression of receptor proteins, and binding affinity affect the intensity of the BSB. The physical barrier elicited by extracellular matrix also prolongs the retention of NPs in the stroma, potentially contributing to the BSB. The influence of particle size on the BSB was also investigated. The strongest BSB effect was found with small (∼18 nm) NPs targeted with the anisamide ligand. The uptake of these NPs by TAFs was about 7-fold higher than that of the other cells 16 h post-intravenous injection. This was because TAFs also expressed the sigma receptor under the influence of TGF-β secreted by the tumor cells. Overall, the current study underscores the importance of BSBs in the delivery of nanotherapeutics and provides a rationale for exploiting BSBs to target TAFs.
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Lei
L
Miao
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Jay M
JM
Newby
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
C Michael
CM
Lin
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Lu
L
Zhang
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Feifei
F
Xu
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
William Y
WY
Kim
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
M Gregory
MG
Forest
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Samuel K
SK
Lai
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Matthew I
MI
Milowsky
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Sara E
SE
Wobker
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Leaf
L
Huang
binding site barrier; desmoplastic tumor; nanoparticle; stroma-vessel type tumor; tumor-associated fibroblast
Cancer Res. 1992 Oct 1;52(19):5144-53
1327501
Int J Cancer. 2004 Nov 20;112(4):693-700
15382053
Cancer Res. 1992 May 1;52(9 Suppl):2747s-2751s
1563006
Anal Biochem. 2005 Mar 15;338(2):284-93
15745749
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9469-74
15972807
Cancer Lett. 2006 Jul 18;238(2):188-96
16111806
Nat Rev Cancer. 2006 May;6(5):392-401
16572188
Cancer Res. 2006 Jul 1;66(13):6732-40
16818648
Cancer Biol Ther. 2006 Dec;5(12):1640-6
17106243
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3460-5
17307870
J Mol Biol. 2007 Aug 24;371(4):934-47
17602702
Nat Methods. 2007 Oct;4(10):855-60
17767164
Mod Pathol. 2009 Jun;22 Suppl 2:S70-95
19494855
J Biotechnol. 2010 Jul 1;148(1):3-15
20097238
Biomaterials. 2010 May;31(13):3657-66
20138662
Pharm Res. 2010 Nov;27(11):2343-55
20195708
J Control Release. 2010 Aug 3;145(3):178-81
20338200
Nat Nanotechnol. 2010 Jun;5(6):465-72
20383126
Mol Pharm. 2010 Aug 2;7(4):1195-208
20476759
Microvasc Res. 1991 Jan;41(1):5-23
2051954
Biophys J. 2010 Sep 8;99(5):1342-9
20816045
Breast Cancer. 2012 Apr;19(2):170-6
20978953
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7160-5
21474781
Nat Nanotechnol. 2011 Oct 23;6(12):815-23
22020122
J Control Release. 2012 Feb 28;158(1):108-14
22056915
ACS Nano. 2012 May 22;6(5):4483-93
22540892
Nat Med. 2012 Sep;18(9):1359-68
22863786
Biochim Biophys Acta. 2013 Jul;1832(7):1070-8
23123598
Science. 2012 Nov 16;338(6109):903-10
23161990
Biomaterials. 2013 Feb;34(6):1739-46
23211449
Annu Rev Biomed Eng. 2013;15:29-53
23642249
ACS Nano. 2013 Jun 25;7(6):5376-84
23647441
Mol Ther. 2013 Aug;21(8):1559-69
23774791
Cancer Res. 2013 Aug 1;73(15):4862-71
23907638
Clin Cancer Res. 2013 Dec 15;19(24):6943-56
24030704
ACS Nano. 2013 Nov 26;7(11):9896-904
24083505
Nat Mater. 2013 Nov;12(11):958-62
24150413
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18632-7
24167277
Biomaterials. 2014 Mar;35(9):3027-34
24388798
Adv Drug Deliv Rev. 2014 Jul;74:19-27
24462455
Biomaterials. 2014 May;35(16):4688-98
24613050
J Control Release. 2014 May 28;182:90-6
24637468
Cancer Cell. 2014 Jun 16;25(6):735-47
24856585
Cancer Cell. 2014 Jun 16;25(6):719-34
24856586
Cancer Cell. 2014 Jun 16;25(6):711-2
24937454
J Exp Med. 2014 Jul 28;211(8):1503-23
25071162
Biochim Biophys Acta. 2015 Oct;1848(10 Pt B):2703-14
25173780
Clin Cancer Res. 2014 Dec 1;20(23):6083-95
25231403
Cell. 2014 Sep 25;159(1):80-93
25259922
Breast Cancer Res Treat. 2015 Feb;149(3):727-41
25667103
Cancer J. 2015 Jul-Aug;21(4):299-306
26222082
J Control Release. 2015 Nov 10;217:27-41
26285063
Nano Lett. 2015 Oct 14;15(10):6371-8
26389971