PMID- 26409121
OWN - NLM
STAT- MEDLINE
DCOM- 20160818
LR  - 20240324
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Print)
IS  - 0168-3659 (Linking)
VI  - 217
DP  - 2015 Nov 10
TI  - Liposomal doxorubicin extravasation controlled by phenotype-specific transport 
      properties of tumor microenvironment and vascular barrier.
PG  - 293-9
LID - S0168-3659(15)30144-9 [pii]
LID - 10.1016/j.jconrel.2015.09.044 [doi]
AB  - Although nanotherapeutics can be advantageous over free chemotherapy, the 
      benefits of drug vectors can vary from patient to patient based on differences in 
      tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is 
      considered as the major determinant of its efficacy in clinics, recent clinical 
      and basic research indicates that tumor-based PK can provide better 
      representation of therapeutic efficacy. Here, we have studied the role of the 
      tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), 
      delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) 
      tumors. We found that phenotypically different 3LL and 4T1 tumors shared the 
      similar systemic PK, but DOX extravasation in the tumor extravascular tissue was 
      substantially different. Liquid chromatography-mass spectrometry (LC-MS) 
      measurements showed that DOX fluorescence imaged by fluorescence microscopy could 
      be used as a marker to study tumor microenvironment PK, providing an excellent 
      match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic 
      responses can be closely related to the interplay of concentration levels and 
      exposure times in extravascular tissue of tumors. Finally, the computational 
      model of capillary drug transport showed that internalization of drug vectors was 
      critical and could lead to 2-3 orders of magnitude more efficient drug delivery 
      into the extravascular tissue, compared to non-internalized localization of drug 
      vectors, and explaining the differences in therapeutic efficacy between the 3LL 
      and 4T1 tumors. These results show that drug transport and partitioning 
      characteristics can be phenotype- and microenvironment-dependent and are highly 
      important in drug delivery and therapeutic efficacy.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Yokoi, Kenji
AU  - Yokoi K
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Chan, Diana
AU  - Chan D
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Kojic, Milos
AU  - Kojic M
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States; 
      Belgrade Metropolitan University, Research and Development Center for 
      Bioengineering, 3400 Kragujevac, Serbia; Serbian Academy of Sciences and Arts, 
      11000 Belgrade, Serbia.
FAU - Milosevic, Miljan
AU  - Milosevic M
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States; 
      Belgrade Metropolitan University, Research and Development Center for 
      Bioengineering, 3400 Kragujevac, Serbia.
FAU - Engler, David
AU  - Engler D
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Matsunami, Rise
AU  - Matsunami R
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Tanei, Tomonori
AU  - Tanei T
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Saito, Yuki
AU  - Saito Y
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Ferrari, Mauro
AU  - Ferrari M
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States.
FAU - Ziemys, Arturas
AU  - Ziemys A
AD  - The Houston Methodist Research Institute, Houston, TX 77030, United States. 
      Electronic address: aziemys@houstonmethodist.org.
LA  - eng
GR  - U54 CA143837/CA/NCI NIH HHS/United States
GR  - U54 CA151668/CA/NCI NIH HHS/United States
GR  - U54CA143837/CA/NCI NIH HHS/United States
GR  - U54CA151668/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 - 20150925
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Antineoplastic Agents)
RN  - 0 (liposomal doxorubicin)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacokinetics/*therapeutic use
MH  - Cell Line, Tumor
MH  - Doxorubicin/*analogs & derivatives/pharmacokinetics/therapeutic use
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Neoplasms/*drug therapy
MH  - Phenotype
MH  - Polyethylene Glycols/pharmacokinetics/therapeutic use
MH  - Tumor Microenvironment/drug effects
PMC - PMC4623952
MID - NIHMS728320
OTO - NOTNLM
OT  - Computational diffusion model
OT  - Doxorubicin
OT  - Drug vector
OT  - Kinetics
OT  - Liposome
OT  - Nanotherapeutics
EDAT- 2015/09/27 06:00
MHDA- 2016/08/19 06:00
PMCR- 2016/11/10
CRDT- 2015/09/27 06:00
PHST- 2015/04/21 00:00 [received]
PHST- 2015/08/04 00:00 [revised]
PHST- 2015/09/22 00:00 [accepted]
PHST- 2015/09/27 06:00 [entrez]
PHST- 2015/09/27 06:00 [pubmed]
PHST- 2016/08/19 06:00 [medline]
PHST- 2016/11/10 00:00 [pmc-release]
AID - S0168-3659(15)30144-9 [pii]
AID - 10.1016/j.jconrel.2015.09.044 [doi]
PST - ppublish
SO  - J Control Release. 2015 Nov 10;217:293-9. doi: 10.1016/j.jconrel.2015.09.044. 
      Epub 2015 Sep 25.