PMID- 30538458
OWN - NLM
STAT- MEDLINE
DCOM- 20190107
LR  - 20220330
IS  - 1178-2013 (Electronic)
IS  - 1176-9114 (Print)
IS  - 1176-9114 (Linking)
VI  - 13
DP  - 2018
TI  - Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity.
PG  - 7771-7787
LID - 10.2147/IJN.S187089 [doi]
AB  - PURPOSE: Anticancer drug delivery systems are often limited by hurdles, such as 
      off-target distribution, slow cellular internalization, limited lysosomal escape, 
      and drug resistance. To overcome these limitations, we have developed a stable 
      nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid 
      [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the 
      anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle 
      (SMA-Dox) carrier. MATERIALS AND METHODS: Effects of SMA-tDodSNO and/or in 
      combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial 
      membrane potential, lysosomal membrane permeability, tumor tissue, and tumor 
      growth were studied using in vitro and in vivo model of triple-negative breast 
      cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination 
      with SMA-tDodSNO were measured in cells and tumor tissues. RESULTS: Combination 
      of SMA-tDodSNO and Dox synergistically decreased cell viability and induced 
      apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 microM) 
      significantly enhanced the cellular uptake of SMA-Dox and increased Dox 
      concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal 
      membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 
      40 microM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect 
      was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration 
      of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that 
      SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the 
      control group. SMA-tDodSNO in combination with SMA-Dox resulted in a 
      statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs 
      control), without causing significant toxicity as monitored through body weight 
      loss. CONCLUSION: Taken together, these results suggest that SMA-tDodSNO can be 
      used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a 
      model of TNBC.
FAU - Alimoradi, Houman
AU  - Alimoradi H
AD  - Department of Pharmacology and Toxicology, University of Otago, Dunedin, New 
      Zealand.
FAU - Greish, Khaled
AU  - Greish K
AD  - College of Medicine and Medical Sciences, Department of Molecular Medicine, and 
      Nanomedicine Unit, Princess Al-Jawhara Centre for Molecular Medicine and 
      Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain, 
      khaledfg@agu.edu.bh.
AD  - Department of Oncology, Faculty of Medicine, Suez Canal University, Ismailia, 
      Egypt, khaledfg@agu.edu.bh.
FAU - Barzegar-Fallah, Anita
AU  - Barzegar-Fallah A
AD  - Department of Pharmacology and Toxicology, University of Otago, Dunedin, New 
      Zealand.
FAU - Alshaibani, Lama
AU  - Alshaibani L
AD  - College of Medicine and Medical Sciences, Department of Molecular Medicine, and 
      Nanomedicine Unit, Princess Al-Jawhara Centre for Molecular Medicine and 
      Inherited Disorders, Arabian Gulf University, Manama, Kingdom of Bahrain, 
      khaledfg@agu.edu.bh.
FAU - Pittala, Valeria
AU  - Pittala V
AD  - Department of Drug Science, University of Catania, Catania, Italy.
LA  - eng
PT  - Journal Article
DEP - 20181120
PL  - New Zealand
TA  - Int J Nanomedicine
JT  - International journal of nanomedicine
JID - 101263847
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Maleates)
RN  - 0 (Polystyrenes)
RN  - 0 (S-Nitrosothiols)
RN  - 0 (tert-dodecane S-nitrosothiol)
RN  - 25300-64-5 (styrene-maleic acid polymer)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Doxorubicin/administration & dosage/*pharmacology/therapeutic use
MH  - *Drug Liberation
MH  - Endocytosis
MH  - Female
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Lysosomes/drug effects/metabolism
MH  - Maleates/chemical synthesis/chemistry
MH  - Mice, Inbred BALB C
MH  - Mitochondria/drug effects/metabolism
MH  - Nanoparticles/*chemistry
MH  - Nitric Oxide/*pharmacology
MH  - Permeability
MH  - Polystyrenes/chemical synthesis/chemistry
MH  - S-Nitrosothiols/chemical synthesis/chemistry
MH  - Triple Negative Breast Neoplasms/drug therapy/pathology
PMC - PMC6251458
OTO - NOTNLM
OT  - SMA-tDodSNO
OT  - biologic barriers
OT  - doxorubicin
OT  - nanoparticles
OT  - nitric oxide
OT  - synergistic cytotoxicity
COIS- Disclosure The authors report no conflicts of interest in this work.
EDAT- 2018/12/13 06:00
MHDA- 2019/01/08 06:00
PMCR- 2018/11/20
CRDT- 2018/12/13 06:00
PHST- 2018/12/13 06:00 [entrez]
PHST- 2018/12/13 06:00 [pubmed]
PHST- 2019/01/08 06:00 [medline]
PHST- 2018/11/20 00:00 [pmc-release]
AID - ijn-13-7771 [pii]
AID - 10.2147/IJN.S187089 [doi]
PST - epublish
SO  - Int J Nanomedicine. 2018 Nov 20;13:7771-7787. doi: 10.2147/IJN.S187089. 
      eCollection 2018.