Conferring biodegradabili
ty
to nanopar
ticles is vi
tally impor
tan
t when nanomedicine applica
tions are being
targe
ted, as
this preven
ts po
ten
tial problems wi
th bioaccumula
tion of byproduc
ts af
ter delivery. In
this work, dex
tran has been modified (and rendered hydrophobic) by par
tial ace
tala
tion. A solid s
ta
te NMR me
thod was firs
t developed
to fully charac
terize
the ace
tala
ted polymers. In a subsequen
t syn
the
tic s
tep, RAFT func
tionali
ty was a
ttached via residual unmodified hydroxyl groups. The RAFT groups were
then used in a living free radical polymeriza
tion reac
tion
to con
trol
the grow
th of hydrophilic PEG-me
thacryla
te chains,
thereby genera
ting amphiphilic comblike polymers. The amphiphilic polymers were
then self-assembled in wa
ter
to form various morphologies, including small vesicles, wormlike rods, and micellar s
truc
tures, wi
th PEG a
t the periphery ac
ting as a nonfouling biocompa
tible polymer layer. The ace
tala
ted dex
tran nanopar
ticles were designed for po
ten
tial doxorubicin (DOX) delivery applica
tion based on
the premise
tha
t in
the cell compar
tmen
ts (endosome, lysozome)
the ace
tala
ted dex
tran would hydrolyze, des
troying
the nanopar
ticle s
truc
ture, releasing
the encapsula
ted DOX.
In-vitro s
tudies confirmed minimal cy
to
toxici
ty of
the (unloaded) nanopar
ticles, even af
ter 3 days, proving
tha
t the hydrolysis produc
ts from
the ace
tal groups (me
thanol and ace
tone) had no observable cy
to
toxic effec
t. An in
triguing ini
tial resul
t is repor
ted
tha
t in vitro s
tudies of DOX-loaded dex
tran-nanopar
ticles (compared
to free DOX) revealed an increased differen
tial
toxici
ty
toward a cancer cell line when compared
to a normal cell line. Efficien
t accumula
tion of DOX in a human neuroblas
toma cell line (SY-5Y) was confirmed by bo
th confocal microscopy and flow cy
tome
try measuremen
ts. Fur
thermore,
the
time dependen
t release of DOX was moni
tored using fluorescence life
time imaging microscopy (FLIM) in SY-5Y live cells. FLIM revealed bimodal life
time dis
tribu
tions, showing
the accumula
tion of bo
th DOX-loaded dex
tran-nanopar
ticles and subsequen
t release of DOX in
the living cells. From FLIM da
ta analysis,
the amoun
t of DOX released in SY-5Y cells was found
to increase from 35%
to 55% when
the incuba
tion
time increased from 3 h
to 24 h.
Keywords:
thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=controlled+radical+polymerization&qsSearchArea=searchText">controlled radical polymerization; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=biodegradable+nanoparticles&qsSearchArea=searchText">biodegradable nanoparticles; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=drug+delivery&qsSearchArea=searchText">drug delivery; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=fluorescence+lifetime+imaging+microscopy+%5C%28FLIM%5C%29&qsSearchArea=searchText">fluorescence lifetime imaging microscopy (FLIM); thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=self%5C-assembled&qsSearchArea=searchText">self-assembled