Dual drug delivery of drug
s with different therapeutic effect
s in a
single
sy
stem i
s an effective way to treat a di
sea
se. One of the main challenge
s in dual drug delivery i
s to control the relea
se behavior of each drug independently. In thi
s study, we devi
sed thermo-re
spon
sive polymeric nano
sphere
s that can provide
simultaneou
s and independent dual drug delivery in the re
spon
se to temperature change. The nano
sphere
s ba
sed on chito
san oligo
saccharide conjugated pluronic
F127 grafting carboxyl group were
synthe
sized to deliver kartogenin (KGN) and diclofenac (DCF) in a
single
sy
stem. To achieve the dual drug relea
se, KGN wa
s covalently cro
ss-linked to the outer part of the nano
sphere, and DCF wa
s loaded into the inner core of the nano
sphere. The nano
sphere
s demon
strated immediate relea
se of DCF and
su
stained relea
se of KGN, which were independently controlled by temperature change. The nano
sphere
s treated with cold temperature effectively
suppre
ssed lipopoly
saccharide-induced inflammation in chondrocyte
s and macrophage-like cell
s. The nano
sphere
s al
so induced chondrogenic differentiation of me
senchymal
stem cell
s, which wa
s further enhanced by cold
shock treatment. Biolumine
scence of the fluore
scence-labeled nano
sphere
s wa
s significantly increa
sed after cold treatment
in vivo. The nano
sphere
s suppre
ssed the progre
ssion of o
steoarthriti
s in treated rat
s, which wa
s further enhanced by cold treatment. The nano
sphere
s al
so reduced cyclooxygena
se-2 expre
ssion in the
serum and
synovial membrane of treated rat
s, which were further decrea
sed with cold treatment. The
se re
sult
s sugge
st that the thermo-re
spon
sive nano
sphere
s provide dual-function therapeutic
s po
sse
ssing anti-inflammatory and chondroprotective effect
s which can be enhanced by cold treatment.
sSec_2">Statement of Significance
sp0015">We developed thermo-responsive nanospheres that can provide a useful dual-function of suppressing the inflammation and promoting chondrogenesis in the treatment of osteoarthritis. For a dual delivery system to be effective, the release behavior of each drug should be independently controlled to optimize their desired therapeutic effects. We employed rapid release of diclofenac for acute anti-inflammatory effects, and sustained release of kartogenin, a newly found molecule, for chondrogenic effects in this polymeric nanospheres. This nanosphere demonstrated immediate release of diclofenac and sustained release of kartogenin, which were independently controlled by temperature change. The effectiveness of this system to subside inflammation and regenerate cartilage in osteoarthritis was successful demonstrated through in vitro and in vivo experiments in this study. We think that this study will add a new concept to current body of knowledge in the field of drug delivery and treatment of osteoarthritis.