PMID- 14716678
OWN - NLM
STAT- MEDLINE
DCOM- 20040825
LR  - 20181130
IS  - 1099-498X (Print)
IS  - 1099-498X (Linking)
VI  - 6
IP  - 1
DP  - 2004 Jan
TI  - Steric stabilization of poly(2-(dimethylamino)ethyl methacrylate)-based 
      polyplexes mediates prolonged circulation and tumor targeting in mice.
PG  - 64-75
AB  - BACKGROUND: Efficient tumor targeting of polymeric gene transfer systems 
      (polyplexes) represents a major challenge. To establish tumor targeting after 
      intravenous (IV) administration, the circulation lifetime of these systems should 
      be sufficiently long. Since naked polyplexes are rapidly eliminated from the 
      circulation after IV adminstration, strategies have to be developed to improve 
      their pharmacokinetics. METHODS: Complexes of plasmid DNA and 
      poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block 
      copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via 
      PEGylation of preformed complexes (postPEGylation), were evaluated for their 
      physicochemical properties (size and charge) their interactions with blood 
      constituents and transfection activity in vitro. The pharmacokinetics and 
      biodistribution of PEG-polyplexes were studied in mice after IV administration. 
      The degree of accumulation in two subcutaneous (SC) mouse tumors after IV 
      administration was evaluated for the system with the longest circulation time. 
      RESULTS: It is shown that the surface charge of the pDMAEMA-polyplexes was 
      effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG 
      polymers and postPEGylation). The shielding effect was the highest for the 
      postPEGylation method with PEG(20000), yielding polyplexes that hardly show 
      interactions with blood components (i.e. albumin and erythrocytes) and show 
      substantially prolonged circulation time in mice after IV administration. The 
      superior colloidal stability and circulation kinetics of the postPEGylated 
      polyplexes translated into tumor accumulation which amounted to about 3.5% of the 
      injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% 
      of the injected dose per gram tumor tissue in a SC C26 tumor model. CONCLUSIONS: 
      This study shows that postPEGylation of pDMAEMA-based polyplexes is the most 
      attractive method to prepare polyplexes with long circulating properties. Tumor 
      targeting capacity after intravenous administration was demonstrated in two 
      subcutaneous tumor models.
CI  - Copyright 2004 John Wiley & Sons, Ltd.
FAU - Verbaan, F J
AU  - Verbaan FJ
AD  - Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences 
      (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
FAU - Oussoren, C
AU  - Oussoren C
FAU - Snel, C J
AU  - Snel CJ
FAU - Crommelin, D J A
AU  - Crommelin DJ
FAU - Hennink, W E
AU  - Hennink WE
FAU - Storm, G
AU  - Storm G
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Gene Med
JT  - The journal of gene medicine
JID - 9815764
RN  - 0 (Colloids)
RN  - 0 (Drug Carriers)
RN  - 0 (Methacrylates)
RN  - 0 (Nylons)
RN  - 0 (poly(2-(dimethylamino)ethyl methacrylate))
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Adenocarcinoma/genetics/veterinary
MH  - Animals
MH  - Colloids
MH  - DNA/analysis/chemistry
MH  - Drug Carriers
MH  - Female
MH  - *Gene Transfer Techniques
MH  - Infusions, Intravenous
MH  - Methacrylates/*chemistry/*pharmacokinetics
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neoplasms, Experimental
MH  - Nylons/*chemistry/*pharmacokinetics
MH  - Plasmids/*genetics
MH  - Polyethylene Glycols/*chemistry/*pharmacokinetics
MH  - *Transfection
EDAT- 2004/01/13 05:00
MHDA- 2004/08/26 05:00
CRDT- 2004/01/13 05:00
PHST- 2004/01/13 05:00 [pubmed]
PHST- 2004/08/26 05:00 [medline]
PHST- 2004/01/13 05:00 [entrez]
AID - 10.1002/jgm.475 [doi]
PST - ppublish
SO  - J Gene Med. 2004 Jan;6(1):64-75. doi: 10.1002/jgm.475.