PMID- 32335153
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20210711
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Print)
IS  - 0168-3659 (Linking)
VI  - 323
DP  - 2020 Jul 10
TI  - Synergistic drug combinations for a precision medicine approach to interstitial 
      glioblastoma therapy.
PG  - 282-292
LID - S0168-3659(20)30242-X [pii]
LID - 10.1016/j.jconrel.2020.04.028 [doi]
AB  - Glioblastoma (GBM) is a highly aggressive and heterogeneous form of brain cancer. 
      Genotypic and phenotypic heterogeneity drives drug resistance and tumor 
      recurrence. Combination chemotherapy could overcome drug resistance; however, 
      GBM's location behind the blood-brain barrier severely limits chemotherapeutic 
      options. Interstitial therapy, delivery of chemotherapy locally to the tumor 
      site, via a biodegradable polymer implant can overcome the blood-brain barrier 
      and increase the range of drugs available for therapy. Ideal drug candidates for 
      interstitial therapy are those that are potent against GBM and work in 
      combination with both standard-of-care therapy and new precision medicine 
      targets. Herein we evaluated paclitaxel for interstitial therapy, investigating 
      the effect of combination with both temozolomide, a clinical standard-of-care 
      chemotherapy for GBM, and everolimus, a mammalian target of rapamycin (mTOR) 
      inhibitor that modulates aberrant signaling present in >80% of GBM patients. 
      Tested against a panel of GBM cell lines in vitro, paclitaxel was found to be 
      effective at nanomolar concentrations, complement therapy with temozolomide, and 
      synergize strongly with everolimus. The strong synergism seen with paclitaxel and 
      everolimus was then explored in vivo. Paclitaxel and everolimus were separately 
      formulated into fibrous scaffolds composed of acetalated dextran, a biodegradable 
      polymer with tunable degradation rates, for implantation in the brain. Acetalated 
      dextran degradation rates were tailored to attain matching release kinetics (~3% 
      per day) of both paclitaxel and everolimus to maintain a fixed combination ratio 
      of the two drugs. Combination interstitial therapy of both paclitaxel and 
      everolimus significantly reduced GBM growth and improved progression free 
      survival in two clinically relevant orthotopic models of GBM resection and 
      recurrence. This work illustrates the advantages of synchronized interstitial 
      therapy of paclitaxel and everolimus for post-surgical tumor control of GBM.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Graham-Gurysh, Elizabeth G
AU  - Graham-Gurysh EG
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina at Chapel Hill, USA.
FAU - Murthy, Ananya B
AU  - Murthy AB
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina at Chapel Hill, USA.
FAU - Moore, Kathryn M
AU  - Moore KM
AD  - Joint Department of Biomedical Engineering, University of North Carolina at 
      Chapel Hill and North Carolina State University, USA.
FAU - Hingtgen, Shawn D
AU  - Hingtgen SD
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina at Chapel Hill, USA.
FAU - Bachelder, Eric M
AU  - Bachelder EM
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina at Chapel Hill, USA.
FAU - Ainslie, Kristy M
AU  - Ainslie KM
AD  - Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of 
      Pharmacy, University of North Carolina at Chapel Hill, USA; Joint Department of 
      Biomedical Engineering, University of North Carolina at Chapel Hill and North 
      Carolina State University, USA; Department of Microbiology and Immunology, UNC 
      School of Medicine, University of North Carolina, Chapel Hill, NC, USA. 
      Electronic address: ainsliek@email.unc.edu.
LA  - eng
GR  - F32 CA225199/CA/NCI NIH HHS/United States
GR  - R01 NS097507/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200423
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Drug Combinations)
SB  - IM
MH  - Animals
MH  - *Brain Neoplasms/drug therapy
MH  - Cell Line, Tumor
MH  - Drug Combinations
MH  - Drug Synergism
MH  - *Glioblastoma/drug therapy
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Precision Medicine
MH  - Xenograft Model Antitumor Assays
PMC - PMC7453575
MID - NIHMS1589457
OTO - NOTNLM
OT  - Acetalated dextran (Ace-DEX)
OT  - Everolimus
OT  - LN-229
OT  - Paclitaxel
OT  - U87-MG
OT  - mTOR
EDAT- 2020/04/27 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/07/10
CRDT- 2020/04/27 06:00
PHST- 2020/04/13 00:00 [received]
PHST- 2020/04/18 00:00 [accepted]
PHST- 2020/04/27 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/04/27 06:00 [entrez]
PHST- 2021/07/10 00:00 [pmc-release]
AID - S0168-3659(20)30242-X [pii]
AID - 10.1016/j.jconrel.2020.04.028 [doi]
PST - ppublish
SO  - J Control Release. 2020 Jul 10;323:282-292. doi: 10.1016/j.jconrel.2020.04.028. 
      Epub 2020 Apr 23.