2 research outputs found
pH and Redox Dual Responsive Nanoparticle for Nuclear Targeted Drug Delivery
To mimic the clinic dosing pattern, initially administering
high
loading dose and then low maintenance dose, we designed a novel polyÂ(2-(pyridin-2-yldisulfanyl)Âethyl
acrylate) (PDS) based nanoparticle delivery system. Side chain functional
PDS was synthesized by free radical polymerization. Polyethylene glycol
and cycloÂ(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide was conjugated
to PDS through thiol–disulfide exchange reaction to achieve
RPDSG polymer. RPDSG/DOX, RPDSG nanoparticle loaded with doxorubicin,
was fabricated by cosolvent dialysis method. The size of the nanoparticles
was 50.13 ± 0.5 nm in PBS. The RPDSG/DOX nanoparticle is stable
in physiological condition while quickly releasing doxorubicin with
the trigger of acidic pH and redox potential. Furthermore, it shows
a two-phase release kinetics, providing both loading dose and maintenance
dose for cancer therapy. The conjugation of RGD peptide enhanced the
cellular uptake and nuclear localization of the RPDSG/DOX nanoparticles.
RPDSG/DOX exhibits IC<sub>50</sub> close to that of free doxorubicin
for HCT-116 colon cancer cells. Due to the synergetic effect of RGD
targeting effect and its two-phase release kinetics, RPDSG/DOX nanoparticles
display significantly higher anticancer efficacy than that of free
DOX at concentrations higher than 5 μM. These results suggest
that RPDSG/DOX could be a promising nanotherapeutic for tumor-targeted
chemotherapy
Asialoglycoprotein Receptor-Mediated Gene Delivery to Hepatocytes Using Galactosylated Polymers
Highly
efficient, specific, and nontoxic gene delivery vector is
required for gene therapy to the liver. Hepatocytes exclusively express
asialoglycoprotein receptor (ASGPR), which can recognize and bind
to galactose or N-acetylgalactosamine. Galactosylated polymers are
therefore explored for targeted gene delivery to the liver. A library
of safe and stable galactose-based glycopolymers that can specifically
deliver genes to hepatocytes were synthesized having different architectures,
compositions, and molecular weights via the reversible addition–fragmentation
chain transfer process. The physical and chemical properties of these
polymers have a great impact on gene delivery efficacy into hepatocytes,
as such block copolymers are found to form more stable complexes with
plasmid and have high gene delivery efficiency into ASGPR expressing
hepatocytes. Transfection efficiency and uptake of polyplexes with
these polymers decreased significantly by preincubation of hepatocytes
with free asialofetuin or by adding free asialofetuin together with
polyplexes into hepatocytes. The results confirmed that polyplexes
with these polymers were taken up specifically by hepatocytes via
ASGPR-mediated endocytosis. The results from transfection efficiency
and uptake of these polymers in cells without ASGPR, such as SK Hep1
and HeLa cells, further support this mechanism. Since in vitro cytotoxicity
assays prove these glycopolymers to be nontoxic, they may be useful
for delivery of clinically important genes specifically to the liver