PMID- 36358597
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221117
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 14
IP  - 21
DP  - 2022 Oct 22
TI  - Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)-A Potential Gene Target for 
      Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid 
      Nanoparticle to Deliver siRNA.
LID - 10.3390/cancers14215179 [doi]
LID - 5179
AB  - Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine 
      catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor 
      survival and promoting resistance towards radiation therapy has made it an 
      interesting target for therapy. In this study, we prepared a lipid 
      nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown 
      (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing 
      ionizable DODAP lipid was prepared following a microfluidics mixing method and 
      the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral 
      surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in 
      U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial 
      (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein 
      levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. 
      Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards 
      radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in 
      other brain-relevant cells no significant effect on cytotoxic response, either 
      alone or in combination, was observed. A major roadblock for brain therapeutics 
      is their ability to cross the highly restrictive blood-brain barrier (BBB) 
      presented by the brain microcapillary endothelial cells. Here, we used the BBB 
      circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell 
      culture model. A cadherin binding peptide (ADTC5) was used to transiently open 
      the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These 
      results suggest LNP-siSAT1 may provide a safe and effective method for reducing 
      SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.
FAU - Yathindranath, Vinith
AU  - Yathindranath V
AD  - Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB 
      R3E 0Z3, Canada.
FAU - Safa, Nura
AU  - Safa N
AD  - Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB 
      R3E 0Z3, Canada.
FAU - Sajesh, Babu V
AU  - Sajesh BV
AD  - Cancer Care Manitoba Research Institute-CCMRI, Winnipeg, MB R3E 0V9, Canada.
FAU - Schwinghamer, Kelly
AU  - Schwinghamer K
AD  - Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 
      66047, USA.
FAU - Vanan, Magimairajan Issai
AU  - Vanan MI
AUID- ORCID: 0000-0003-2015-0615
AD  - Cancer Care Manitoba Research Institute-CCMRI, Winnipeg, MB R3E 0V9, Canada.
AD  - Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB 
      R3T 2N2, Canada.
FAU - Bux, Rashid
AU  - Bux R
AD  - BioMark Diagnostics Inc., Richmond, BC V6X 2W2, Canada.
FAU - Sitar, Daniel S
AU  - Sitar DS
AD  - Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB 
      R3E 0Z3, Canada.
AD  - Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB 
      R3T 2N2, Canada.
AD  - Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, 
      Canada.
FAU - Pitz, Marshall
AU  - Pitz M
AD  - Cancer Care Manitoba Research Institute-CCMRI, Winnipeg, MB R3E 0V9, Canada.
AD  - Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, 
      Canada.
FAU - Siahaan, Teruna J
AU  - Siahaan TJ
AUID- ORCID: 0000-0001-7250-0627
AD  - Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 
      66047, USA.
FAU - Miller, Donald W
AU  - Miller DW
AUID- ORCID: 0000-0003-1952-5635
AD  - Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB 
      R3E 0Z3, Canada.
LA  - eng
PT  - Journal Article
DEP - 20221022
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC9656607
OTO - NOTNLM
OT  - Spermidine/spermine N1-acetyltransferase 1 (SAT1)
OT  - blood-brain barrier (BBB)
OT  - brain drug delivery
OT  - cadherin peptide
OT  - gene therapy
OT  - glioblastoma (GB)
OT  - lipid nanoparticles
OT  - microfluidic mixing
OT  - siRNA
OT  - transient modulation
OT  - tumor sensitization
COIS- The authors declare no conflict of interest.
EDAT- 2022/11/12 06:00
MHDA- 2022/11/12 06:01
PMCR- 2022/10/22
CRDT- 2022/11/11 01:06
PHST- 2022/01/31 00:00 [received]
PHST- 2022/10/17 00:00 [revised]
PHST- 2022/10/19 00:00 [accepted]
PHST- 2022/11/11 01:06 [entrez]
PHST- 2022/11/12 06:00 [pubmed]
PHST- 2022/11/12 06:01 [medline]
PHST- 2022/10/22 00:00 [pmc-release]
AID - cancers14215179 [pii]
AID - cancers-14-05179 [pii]
AID - 10.3390/cancers14215179 [doi]
PST - epublish
SO  - Cancers (Basel). 2022 Oct 22;14(21):5179. doi: 10.3390/cancers14215179.