Controllable targeted system based on pH-dependent thermo-responsive nanoparticles.

In this study, a pH-dependent thermo-responsive polymer (poly (N-isopropyl acrylamide-co-methacrylic acid-co-ethyl methacrylate, P(NIPAAm-co-MAA-co-EMA)), which was used as a masking functional module was designed and prepared. Its LCST was pH-dependent, leading to a sensitive isothermal phase transition between the blood and the extracellular environment of solid tumours. This masking polymer had a LCST of 36.4 °C at pH 6.5, and remained hydrophilic at pH 7.4 even when the temperature was increased to 50 °C. The liver-targeted nanoparticles (NPs) were then obtained by co-grafting the masking functional module and the targeting ligands glycyrrhetinic acid (GA) onto the gold nanoparticles (Au NPs). Their surface properties and targeting ability could be switched based on the expanding or shrinking behaviour of the polymers. The shielding/deshielding effect of GA was confirmed by the bovine serum albumin adsorption and cellular uptake. The results indicated that GA could be shielded by the hydrophilic P(NIPAAm-co-MAA-co-EMA) in the normal physiological environment (pH 7.4, 37 °C) and deshielded in the tumour microenvironment of pH 6.5, 40 °C, leading to an increase in cellular uptake as high as 2.3-fold compared with that observed at pH 7.4, 37 °C. More importantly, the ultrasensitive phase transition of the polymer was reversible, which means that the targeting ability of the deshielded Au NPs could be reshielded if they come back to the blood circulation.

Fabrication of thermo-sensitive complex micelles for reversible cell targeting.

To ideally solve the contradiction between enhanced cellular uptake and prolonged blood circulation, reversible targeting polymeric micelles based on the expanding and shrinking behavior of a temperature-responsive polymer were developed. The micelle contained a hydrophobic PCL core and a mixed shell consisting of poly(N-isopropylacrylamide) (PNIPAAm) and biotin-terminated poly(ethylene glycol) (Biotin-PEG), and its targeting ability could be switched on/off by temperature. The cellular uptake of the complex polymeric micelles was studied. The results from a quantitative enzyme-linked immunosorbent assay (ELISA) indicated that the surface biotin content increased by as much as 11.6-fold when the temperature increased above the lower critical solution temperature (LCST). More importantly, the ELISA confirmed that biotin-mediated targeting on the surface was reversibly switched on and off for at least five cycles. In addition, the results from quantitative flow cytometry and confocal spectroscopy indicated that the cellular uptake of the targeted micelles at temperatures above the LCST was much higher than that at temperatures below the LCST. This complex polymeric micelle with reversible targeting property could be a promising alternative for drug delivery.

Shieldable tumor targeting based on pH responsive self-assembly/disassembly of gold nanoparticles.

A new approach to shield/deshield ligands for controllable tumor targeting was reported, which was based on amphiphilic self-assembly and disassembly of gold nanoparticles (Au NPs). Thanks to the excellent pH response of the system, glycyrrhetinic acid (GA) ligands can be buried inside the Au NPs' assembly at normal tissue pH (pH 7.4), while exposed when the nanostructure is disassembled at tumor extracellular pH (pHe 6.8). Hydrophobic GA molecules not only acted as ligands targeting tumor cells but also provided the major interparticle attractive force for Au NPs' assembling. An ordered assembly of Au NPs with regular shape, proper size and ultrasharp pH sensitivity (ΔpH ∼ 0.2) was achieved by fine-tuning of materials modified on Au NPs. Mechanism studies for assembly and disassembly of Au NPs indicated the possibility of a GA shield when the assembly formed, which was further demonstrated by bovine serum albumin absorption and cellular uptake. The assembly/disassembly process was reversible within extrinsic pH changes, which provides a perspective for reversible tumor targeting.

Ethylene glycol oligomer modified-sodium alginate for efficiently improving the drug loading and the tumor therapeutic effect.

The high viscosity of sodium alginate (ALG) causes its insufficient drug loading and limits its application as a drug carrier. In the present work, we synthesized poly(ethylene glycol) oligomer (mOEG)-modified sodium alginate (ALG-mOEG) and characterized its properties as a drug delivery system. Our results showed that ALG-mOEG displayed a greatly reduced viscosity (0.024 Pa s at 2.0 wt%) with a significantly improved drug loading capacity (18.0% (w/w)) compared with unmodified ALG (6.9% (w/w)). In addition, DOX-ALG-mOEG nanoparticles (DOX-ALG-mOEG NPs) with high drug loading were more cytotoxic for HepG2 cells in vitro and showed a higher antitumor activity in vivo compared with the control group (DOX-ALG NPs) at the same dose of DOX. DOX-ALG-mOEG NPs inhibited HepG2 proliferation in vitro with an IC50 value of 220.0 ng mL-1 and reduced tumor growth in vivo by 75.6%, while DOX-ALG NPs showed activities of 443.9 ng mL-1 and 62.7%, respectively. Meanwhile, we did not observe the "accelerated blood clearance (ABC)" phenomenon in these mOEG-modified ALG nanoparticles. In view of most biologic and chemical molecules used for the biological function being hydrophobic, we thought the ALG-mOEG scaffold also might serve as an efficient long-duration carrier for other hydrophobic molecules with minimal immunogenicity.