Combination therapy is an emerging strategy that is under intensive preclinical investigation for the treatment of various diseases. CD98 is highly overexpressed on the surfaces of epithelial cells and macrophages in the colon tissue with ulcerative colitis (UC), which is usually associated with mucosal damage and inflammation. We previously proved that CD98 siRNA (siCD98)-induced down-regulation of CD98 in colitis tissue decreased the severity of UC to a certain extent. In an effort to further improve the therapeutic efficacy, we aim to simultaneously deliver siCD98 in combination with a potent anti-inflammatory agent, curcumin (CUR), using hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant spherical HA-siCD98/CUR-NPs are featured by a desirable particle size (∼246 nm) and slightly negative zeta potential (∼-14 mV). The NPs functionalized with HA are able to guide the co-delivery of drugs to the targeted cells related to UC therapy (colonic epithelial cells and macrophages). Compared to either siCD98- or CUR-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized NPs can exert combinational effects against UC by protecting the mucosal layer and alleviating inflammation both in vitro and in vivo. This study shows the promising capability of the co-delivered siCD98 and CUR for boosting the conventional monotherapy via this novel nanotherapeutic agent, which offers a structurally simple platform for orally administered delivery of drugs to target cells in UC therapy.

Covalent functionalization of azide-modified SiO(2) with well-defined, alkyne-terminated poly(N-isopropylacrylamide) was accomplished by the Cu(I)-catalyzed [3 + 2] Huisgen cycloaddition. The alkyne-terminated RAFT chain transfer agent was first synthesized, and then the alkyne-terminated thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) with different molecular weights were synthesized by the RAFT of NIPAM monomer. The polymerization kinetics and the evolution of number-average molecular weights (M(n)), and polydispersities (M(w)/M(n)), with monomer conversions were investigated. A copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "grafting to" method was used to attach thermoresponsive polymers onto the exterior surface of SiO(2) nanoparticles which produced relatively high grafting density. The as-synthesized hybrid nanoparticles showed thermoresponsive behavior and were characterized by FTIR, XPS, TGA, DLS, and TEM, etc.

A well-defined thermoresponsive poly(ethylene glycol)-block-poly(N-isopropylacrylamide)-block-poly(ε-caprolactone) (PEG(43)-b-PNIPAM(82)-b-PCL(87)) triblock copolymer was synthesized by combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP), and click chemistry. The synthesis included the four steps, and all the structures of the polymers were determined. The thermoresponsive triblock copolymer can disperse in water at room temperature to form core-shell-corona micelles with the hydrophobic PCL block as core, the thermoresponsive PNIPAM block as shell, and the hydrophilic PEG block as corona. At temperatures above the lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PCL core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing.

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