PMID- 22829966
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121002
LR  - 20220330
IS  - 2044-5385 (Electronic)
IS  - 2044-5385 (Linking)
VI  - 2
IP  - 4
DP  - 2012 Apr
TI  - Rationally engineered nanoparticles target multiple myeloma cells, overcome 
      cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo.
PG  - e64
LID - 10.1038/bcj.2012.10 [doi]
AB  - In the continuing search for effective cancer treatments, we report the rational 
      engineering of a multifunctional nanoparticle that combines traditional 
      chemotherapy with cell targeting and anti-adhesion functionalities. Very late 
      antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow 
      stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In 
      our design, we used micellar nanoparticles as dynamic self-assembling scaffolds 
      to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, 
      simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was 
      conjugated to the nanoparticles through an acid-sensitive hydrazone bond. 
      VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure 
      for generating precisely controlled number of targeting functionalities. The 
      nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. 
      Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks 
      and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame 
      CAM-DR, and were more efficacious than Dox when MM cells were cultured on 
      fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles 
      preferentially homed to MM tumors with  approximately 10 fold more drug accumulation and 
      demonstrated dramatic tumor growth inhibition with a reduced overall systemic 
      toxicity. Altogether, we demonstrate the disease driven engineering of a 
      nanoparticle-based drug delivery system, enabling the model of an integrative 
      approach in the treatment of MM.
FAU - Kiziltepe, T
AU  - Kiziltepe T
FAU - Ashley, J D
AU  - Ashley JD
FAU - Stefanick, J F
AU  - Stefanick JF
FAU - Qi, Y M
AU  - Qi YM
FAU - Alves, N J
AU  - Alves NJ
FAU - Handlogten, M W
AU  - Handlogten MW
FAU - Suckow, M A
AU  - Suckow MA
FAU - Navari, R M
AU  - Navari RM
FAU - Bilgicer, B
AU  - Bilgicer B
LA  - eng
PT  - Journal Article
DEP - 20120420
PL  - United States
TA  - Blood Cancer J
JT  - Blood cancer journal
JID - 101568469
PMC - PMC3346680
OTO - NOTNLM
OT  - VLA-4
OT  - cell-adhesion-mediated drug resistance
OT  - drug delivery
OT  - multiple myeloma
OT  - nanoparticle
OT  - selective targeting
EDAT- 2012/07/26 06:00
MHDA- 2012/07/26 06:01
PMCR- 2012/04/01
CRDT- 2012/07/26 06:00
PHST- 2012/02/22 00:00 [received]
PHST- 2012/02/28 00:00 [accepted]
PHST- 2012/07/26 06:00 [entrez]
PHST- 2012/07/26 06:00 [pubmed]
PHST- 2012/07/26 06:01 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - bcj201210 [pii]
AID - 10.1038/bcj.2012.10 [doi]
PST - ppublish
SO  - Blood Cancer J. 2012 Apr;2(4):e64. doi: 10.1038/bcj.2012.10. Epub 2012 Apr 20.