| 内容提要: |
The extremely low efficient cytosolic release of the internalized
siRNA has emerged recently as a central issue for siRNA delivery, while there
is a lack of guidelines to facilitate the cytosolic release of internalized siRNA.
To address these concerns, we studied the contribution of the pH-sensitive
inner core on handling the cytosolic release of siRNA delivered by a series of
PG-P(DPAx-co-DMAEMAy)-PCB amphiphilic polycation nanomicelles
(GDDC-Ms) with extremely low internalization (<1/4 of lipofactamine
2000 (Lipo2000)). Significantly, just by varying the mole ratio of DPA and
DMAEMA to adjust the initial disassembly pH (pHdis) of the core near to 6.8,
GDDC4-Ms/siRNA could get nearly 98.8% silencing efficiency at w/w = 12
with 50 nM siRNA and ∼78% silencing efficiency at w/w = 30 with a very low
dose of 5 nM siRNA in HepG-2 cell lines, while Lipo2000 only got 65.7% with 50 nM siRNA. Furthermore, ∼98.4% silencing
efficiency was also realized in the hard-to-transfect human acute monoblastic leukemia cell line U937 by GDDC4-Ms/siRNA (at
w/w = 15, 50 nM siRNA), in the inefficient case for Lipo2000. Additionally, the high silencing efficiency (∼80%) in skin tissue in
vivo was discovered. Undoubtedly, the robust potential of GDDC4-Ms in handling the cytosolic release paves a simple but
efficient new way for the design of the nonviral siRNA vector. |