PMID- 21245339
OWN - NLM
STAT- MEDLINE
DCOM- 20110330
LR  - 20220408
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 6
DP  - 2011 Feb 8
TI  - Multistage nanoparticle delivery system for deep penetration into tumor tissue.
PG  - 2426-31
LID - 10.1073/pnas.1018382108 [doi]
AB  - Current Food and Drug Administration-approved cancer nanotherapeutics, which 
      passively accumulate around leaky regions of the tumor vasculature because of an 
      enhanced permeation and retention (EPR) effect, have provided only modest 
      survival benefits. This suboptimal outcome is likely due to physiological 
      barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many 
      of these nanotherapeutics are  approximately  100 nm in diameter and exhibit enhanced 
      accumulation around the leaky regions of the tumor vasculature, but their large 
      size hinders penetration into the dense collagen matrix. Therefore, we propose a 
      multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles 
      after they extravasate from leaky regions of the tumor vasculature and are 
      exposed to the tumor microenvironment. The shrunken nanoparticles can more 
      readily diffuse throughout the tumor's interstitial space. This size change is 
      triggered by proteases that are highly expressed in the tumor microenvironment 
      such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing 
      smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a 
      model system for the 10-nm particles because their fluorescence can be used to 
      demonstrate the validity of our approach. In vitro MMP-2 activation of the 
      multistage nanoparticles revealed that the size change was efficient and 
      effective in the enhancement of diffusive transport. In vivo circulation 
      half-life and intratumoral diffusion measurements indicate that our multistage 
      nanoparticles exhibited both the long circulation half-life necessary for the EPR 
      effect and the deep tumor penetration required for delivery into the tumor's 
      dense collagen matrix.
FAU - Wong, Cliff
AU  - Wong C
AD  - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 
      02139, USA.
FAU - Stylianopoulos, Triantafyllos
AU  - Stylianopoulos T
FAU - Cui, Jian
AU  - Cui J
FAU - Martin, John
AU  - Martin J
FAU - Chauhan, Vikash P
AU  - Chauhan VP
FAU - Jiang, Wen
AU  - Jiang W
FAU - Popovic, Zoran
AU  - Popovic Z
FAU - Jain, Rakesh K
AU  - Jain RK
FAU - Bawendi, Moungi G
AU  - Bawendi MG
FAU - Fukumura, Dai
AU  - Fukumura D
LA  - eng
GR  - 1U54-CA119349/CA/NCI NIH HHS/United States
GR  - P01 CA080124-09/CA/NCI NIH HHS/United States
GR  - R01 CA126642-03/CA/NCI NIH HHS/United States
GR  - R01 CA085140-07/CA/NCI NIH HHS/United States
GR  - R01 CA115767-04/CA/NCI NIH HHS/United States
GR  - R01 CA115767-03/CA/NCI NIH HHS/United States
GR  - P01 CA080124-10/CA/NCI NIH HHS/United States
GR  - R01 CA085140-06/CA/NCI NIH HHS/United States
GR  - P01-CA080124/CA/NCI NIH HHS/United States
GR  - R01 CA115767-01A1/CA/NCI NIH HHS/United States
GR  - T32 CA073479-12/CA/NCI NIH HHS/United States
GR  - P01 CA080124/CA/NCI NIH HHS/United States
GR  - P01 CA080124-08/CA/NCI NIH HHS/United States
GR  - T32 CA073479-08/CA/NCI NIH HHS/United States
GR  - T32 CA073479/CA/NCI NIH HHS/United States
GR  - R01 CA115767-02/CA/NCI NIH HHS/United States
GR  - R01 CA126642/CA/NCI NIH HHS/United States
GR  - R01 CA085140-10/CA/NCI NIH HHS/United States
GR  - T32 CA073479-11/CA/NCI NIH HHS/United States
GR  - R01-CA085140/CA/NCI NIH HHS/United States
GR  - R01 CA085140/CA/NCI NIH HHS/United States
GR  - CA126642/CA/NCI NIH HHS/United States
GR  - R01 CA115767-05/CA/NCI NIH HHS/United States
GR  - T32 CA073479-13/CA/NCI NIH HHS/United States
GR  - P01 CA080124-05/CA/NCI NIH HHS/United States
GR  - R01-CA115767/CA/NCI NIH HHS/United States
GR  - R01 CA126642-02/CA/NCI NIH HHS/United States
GR  - R01 CA085140-09/CA/NCI NIH HHS/United States
GR  - R01-CA096915/CA/NCI NIH HHS/United States
GR  - R01 CA126642-02S1/CA/NCI NIH HHS/United States
GR  - R01 CA126642-01A1/CA/NCI NIH HHS/United States
GR  - U54 CA119349/CA/NCI NIH HHS/United States
GR  - P01 CA080124-07/CA/NCI NIH HHS/United States
GR  - T32 CA073479-09/CA/NCI NIH HHS/United States
GR  - T32 CA073479-10/CA/NCI NIH HHS/United States
GR  - P01 CA080124-06A2/CA/NCI NIH HHS/United States
GR  - R01 CA115767/CA/NCI NIH HHS/United States
GR  - P01 CA080124-05S1/CA/NCI NIH HHS/United States
GR  - R01 CA096915/CA/NCI NIH HHS/United States
GR  - R01 CA085140-08/CA/NCI NIH HHS/United States
GR  - R01 CA126642-04/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110118
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - EC 3.4.24.24 (MMP2 protein, human)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
EIN - Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6336
CIN - Nanomedicine (Lond). 2011 Sep;6(7):1156. PMID: 22029058
MH  - Animals
MH  - Cell Line, Tumor
MH  - *Drug Delivery Systems
MH  - Humans
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasms/*drug therapy/metabolism/pathology
MH  - Neovascularization, Pathologic/*drug therapy/metabolism/pathology
MH  - Particle Size
MH  - *Quantum Dots
MH  - Xenograft Model Antitumor Assays
PMC - PMC3038705
COIS- R.K.J. received commercial research grants from Dyax, AstraZeneca, and MedImmune; 
      consultant fees from AstraZeneca/MedImmune, Dyax, Astellas-Fibrogen, Regeneron, 
      Genzyme, MorphoSys, and Noxxon Pharma; and a speaker honorarium from Genzyme. 
      R.K.J. owns stock in SynDevRx. No reagents or funding from these companies were 
      used in these studies. There is no significant financial or other competing 
      interest in the work.
EDAT- 2011/01/20 06:00
MHDA- 2011/03/31 06:00
PMCR- 2011/08/08
CRDT- 2011/01/20 06:00
PHST- 2011/01/20 06:00 [entrez]
PHST- 2011/01/20 06:00 [pubmed]
PHST- 2011/03/31 06:00 [medline]
PHST- 2011/08/08 00:00 [pmc-release]
AID - 1018382108 [pii]
AID - 201018382 [pii]
AID - 10.1073/pnas.1018382108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2426-31. doi: 
      10.1073/pnas.1018382108. Epub 2011 Jan 18.