Synthesis Of Stimulus-responsive Drug Nano-carriers For Controlled-release Of Drugs

The main challenges of traditional periodic method of administration areunstable concentration in medicine system, the short elimination half-life of the drug,low activity ratio and the toxic and side action. Drug controlled carriers succeed solvethese problems and can make the drug system by long-term maintenance drugconcentration in the range of effective concentration with greatly improving theutilization of drugs and medicinal value. Compared to common controlled carriers,the larger relative surface area of nano drug-carriers can obtain better drug controlledrelease rate. Reasonable molecule design can achieve the goal of triggeredintracellular drug release through endocytosis, in order to obtain different controlledrelease rate of drug in different conditions (such as pH, temperature). In addition,nano drug-carriers can realize the targeted therapy in the body circulation. Thischaracteristic is useful for cancer treatment, the size of drug-carriers is the criticalfactor to achieve targeted cancer therapy through EPR effects.In this paper，novel core-shell structured Pluronic-based nanocapsules withthermal-responsive properties were successfully prepared using a modifiedemulsification/solvent evaporation method. The nancapsules were constructedthrough the cross-linking reaction between p-nitrophenyl-activated Pluronic F127andHyaluronic acid (HA)(named Pluronic F127/HA) or Poly(ε-lysine)(PL)(namedPluronic F127/PL) at the organic/aqueous interface. The formation, size and thermalresponsiveness of the nanocapsules were characterized by1H NMR, transmissionelectron microscopy (TEM) and dynamic light scattering (DLS). The resultant shellcross-linked nanocapsules exhibit a larger volume transformation (26times change involume for Pluronic F127/HA and31times for Pluronic F127/PL) over a temperaturerange of4-37°C because of the temperature-related dehydration of cross-linkedPluronic F127polymer chains. The nanocapsules are about72±4nm (polydispersityindex, PDI=0.08) for Pluronic F127/PL (69±5nm, PDI=0.10for PluronicF127/HA) at37°C with narrow size distribution and expand to about226±23nm(PDI=0.34) for Pluronic F127/PL (206±20nm, PDI=0.3) for Pluronic F127/HA) at4°C with broad size distribution in aqueous solutions. The nanocapsules were usedto load and controlled release of Doxorubicin hydrochloride (DOX.HCl) in aqueoussolution. The release curve and release kinetics disclosed that the thermal-responsivehollow nanocapsules are good carries for the drug delivery.In suit forming pH-responsive nanogels were designed and developed based onpoly(ethylene glycol)-block-poly(L-glutamate-tyramine)(PEG-P(LGA-Tyr)) blockcopolymers for efficient loading as well as triggered intracellular release of proteins.Tyramine (Tyr) was chemically conjugated to polyelectrolyte block copolymerpoly(ethylene glycol)-block-poly(L-glutamate)(PEG-PLGA), resulting inPEG-P(LGA-Tyr). These copolymers could be rapidly formed nanogels through theoxidative coupling of tyramine moieties catalyzed by hydrogen peroxide (H2O2) andhorseradish peroxidase (HRP). Remarkably, this cross-linking reaction does notinvolve any toxic catalysts, organic solvent or produce any byproducts. Tyramine andcarboxyl group provided the oxidative coupling crosslinking units andpH-responsiveness of the nanogel, respectively. Dynamic light scattering (DLS)studies showed that these nanogels present different diameters under various pH.FITC-BSA could be efficiently loaded and triggered intracellular released from thenanogel. In vitro release results showed that the release of FITC-BSA was minimalunder physiological conditions but significantly enhanced under acidic pH conditionsunder otherwise the same conditions. These rapidly enzymatically and non-toxicallyin situ forming, pH-sensitive degradable nanogels with carboxyl group have appearedto be highly promising in the further development of protein drug carriers.