PMID- 28549971
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20181202
IS  - 1873-3476 (Electronic)
IS  - 0378-5173 (Linking)
VI  - 527
IP  - 1-2
DP  - 2017 Jul 15
TI  - TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and 
      their dry powder and metered-dose inhaler formulations.
PG  - 171-183
LID - S0378-5173(17)30458-1 [pii]
LID - 10.1016/j.ijpharm.2017.05.046 [doi]
AB  - The regulation of genes utilizing the RNA interference (RNAi) mechanism via the 
      delivery of synthetic siRNA has great potential in the treatment of a variety of 
      lung diseases. However, the delivery of siRNA to the lungs is challenging due to 
      the poor bioavailability of siRNA when delivered intraveneously, and difficulty 
      in formulating and maintaining the activity of free siRNA when delivered directly 
      to the lungs using inhalation devices. The use of non-viral vectors such as 
      cationic dendrimers can help enhance the stability of siRNA and its delivery to 
      the cell cytosol. Therefore, in this work, we investigate the ability of a 
      triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) 
      dendrimer (G4NH(2)-TPP) to enhance the in vitro transfection efficiency of siRNA 
      in a model of the pulmonary epithelium and their aerosol formulations in 
      pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). 
      Complexes of siRNA and G4NH(2)-TPP were prepared with varying TPP densities and 
      increasing N/P ratios. The complexation efficiency was modulated by the presence 
      of the TPP on the dendrimer surface, allowing for a looser complexation compared 
      to unmodified dendrimer as determined by gel electrophoresis and polyanion 
      competition assay. An increase in TPP density and N/P ratio led to an increase in 
      the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing 
      lung alveolar epithelial (A549) cells. G4NH(2)-12TPP dendriplexes (G4NH(2) PAMAM 
      dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at 
      N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the 
      potential of TPP-dendriplexes for pulmonary use, we also developed micron 
      particle technologies for both pMDIs and DPIs and determined their aerosol 
      characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol 
      microparticles encapsulating 12TPP-dendriplexes were shown to be effective in 
      producing aerosols suitable for deep lung deposition for both pMDI formulations 
      (fine particle fraction of 50-53%) and DPI formulations (fine particle fraction 
      of 39%) with no impact on the in vitro gene knockdown efficiency of the siRNA. 
      This work demonstrates the potential benefits of utilizing TPP-conjugated 
      dendrimers in the formation of dendriplexes for siRNA delivery to the pulmonary 
      epithelium and their aerosol formulation for local delivery to the lungs using 
      portable inhalers.
CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
FAU - Bielski, Elizabeth
AU  - Bielski E
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA; Department of Pharmaceutics, School of Pharmacy & 
      Department of Chemical and Life Science Engineering, School of Engineering, 
      Virginia Commonwealth University, Richmond, VA, 23284, USA.
FAU - Zhong, Qian
AU  - Zhong Q
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA; Department of Pharmaceutics, School of Pharmacy & 
      Department of Chemical and Life Science Engineering, School of Engineering, 
      Virginia Commonwealth University, Richmond, VA, 23284, USA.
FAU - Mirza, Hamad
AU  - Mirza H
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA.
FAU - Brown, Matthew
AU  - Brown M
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA.
FAU - Molla, Ashura
AU  - Molla A
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA.
FAU - Carvajal, Teresa
AU  - Carvajal T
AD  - Department of Agricultural & Biological Engineering, Purdue University, West 
      Lafayette, IN, 47907, USA.
FAU - da Rocha, Sandro R P
AU  - da Rocha SRP
AD  - Department of Chemical Engineering and Materials Science, Wayne State University, 
      Detroit, MI, 48202, USA; Department of Pharmaceutics, School of Pharmacy & 
      Department of Chemical and Life Science Engineering, School of Engineering, 
      Virginia Commonwealth University, Richmond, VA, 23284, USA. Electronic address: 
      srdarocha@vcu.edu.
LA  - eng
PT  - Journal Article
DEP - 20170523
PL  - Netherlands
TA  - Int J Pharm
JT  - International journal of pharmaceutics
JID - 7804127
RN  - 0 (Aerosols)
RN  - 0 (Dendrimers)
RN  - 0 (PAMAM Starburst)
RN  - 0 (Powders)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Administration, Inhalation
MH  - Aerosols
MH  - Dendrimers/*chemistry
MH  - Epithelium/*drug effects
MH  - Humans
MH  - Lung/*drug effects
MH  - Metered Dose Inhalers
MH  - Nanoparticles/*chemistry
MH  - Powders
MH  - RNA, Small Interfering/*administration & dosage
OTO - NOTNLM
OT  - Dendriplexes
OT  - Dry powder inhalers (DPIs)
OT  - Inhalation therapy
OT  - PAMAM dendrimers
OT  - Pressurized metered dose inhalers (pMDIs)
OT  - Short interfering RNA (siRNA)
OT  - Triphenylphosphonium (TPP) ion
EDAT- 2017/05/28 06:00
MHDA- 2018/01/06 06:00
CRDT- 2017/05/28 06:00
PHST- 2017/01/11 00:00 [received]
PHST- 2017/05/05 00:00 [revised]
PHST- 2017/05/21 00:00 [accepted]
PHST- 2017/05/28 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
PHST- 2017/05/28 06:00 [entrez]
AID - S0378-5173(17)30458-1 [pii]
AID - 10.1016/j.ijpharm.2017.05.046 [doi]
PST - ppublish
SO  - Int J Pharm. 2017 Jul 15;527(1-2):171-183. doi: 10.1016/j.ijpharm.2017.05.046. 
      Epub 2017 May 23.