Reparation And Characterization Of Resveratral-Polymer Conjugates For Articancer Drug Delivery

At present, the chemotherapy is still one of important methods for cancer therapy, but there are several disadvantages in the treatment for using anti-cancer drugs such as over dose, poor selectivity and obvious side effects. Therefore, it becomes particularly important to set up effective anti-cancer drug delivery system, which could improve the tumor targeting, enhance bioavailability of drugs and solve drug resistance. During the cancer treatment, drug efficacy is not only related to itself, but also closely dependent on the structure and performance of carriers. In view of this, an intelligent drug delivery system with cancer activity was constructed in this paper, and resveratrol (RES) was conjugated to polymer as part of carriers. Response behavior was added to carrier by regulating polymeric composition and structure, the influences of carriers’composition and structure on drug loading content (DLC) and drug loading efficiency(DLE) were investigated; at the same time, the response behavior for drug release and cell uptake were studied deeply. This work provides a new concept for development of effective drug delivery system. The main content and innovation points in this article are as follows:(1) Polyethylene glycol)-resveratrol (PEG-RES) and Polyethylene glycol)-glycine-resveratrol (PEG-Glycine-RES) were designed and synthesized. Compared to RES (23 μg/mL), the water solubility of PEGylated RES was significantly improved, which was 870 mg/mL (PEG-RES) and 930 mg/mL (PEG-Glycine-RES), respectively. The light and acid-base stability have also been improved. More importantly, PEGylated RES still has anti-cancer activity.(2) Bicalutamide (BIC) was selected as model drug, and BIC-loaded PEGylated RES were prepared. The mean size of BIC-loaded PEG-RES and BIC-loaded PEG-Glycine-RES were 112 and 131 nm, respectively, wherein the DLC were 10.1% and 12.5%. Duing to the linking arm of glycine, the RES release from PEG-Glycine-RES was accelerated. During 24 h, the release of RES from PEG-Glycine-RES was 38%, which was higher than that from PEG-RES (17%). After loading BIC, the cytotoxicity of drug-loaded PEGylated RES was obviously enhanced. Finally, PEGylated RES showed good biocompatibility and high cell uptake.(3) Polyethylene glycol)-poly(-1-histidine) (PEG-PHIS) with pH response was synthesized in the experiment, and PEG-Glycine-RES /PEG-PHIS nanoparticles were prepared by dialysis method. Doxorubicin (DOX) was selected as model drug to be studied the drug loading property. When the mass ratio of PEG-Glycine-RES and PEG-PHIS was 1:1, the mean size of nanoparticles was 65 nm, the DLC and DLE were 12.0% and 80%, respectively. At cancer intercellular environment (pH5.5), the DOX release was 80% during 12 h, which was higher than that in normal tissue environment (pH7.4). In addition, pH response nanoparticles significantly enhanced inhibitory effect of cancer cells. Further, the highest inhibition was observed with cytochalasin D, indicating that the most prominent pathway for nanoparticles uptake was macropinocytosis.(4) RGDfK-PEG-PLA-RES was synthesized, and RGDfK-PEG-PLA-RES/CS nanoparticles (targeting RES nanoparticles) were prepared by dialysis methods. Paclitaxel (PTX) was selected as model drug to be investigated the drug loading property. The mean size of targeting RES nanoparticles was 202 nm, the DLC and DLE were 12.5% and 88%, respectively. The PTX release was accelerated at cancer intercellular environment (pH5.5), while the RES release was more completely at high reductant (DTT). Targeting RGDfK could enhance uptake of cancer cells to targeting RES nanoparticles, improve the content of drug in cancer cells and provide more effectively materials to kill cancer cells.(5) Poly(ethyleneimine)-resveratrol (PEI-RES) was synthesized with three different RES grafting rate, and the RES grating rate was 10%,30% and 60%. The mean size of PEI-RES was 100 nm. With the increasing of RES grating rate, the protein resistance of PEI-RES was improved. PEI-RES exhibited proton buffering capacity, which was similar to PEI. Under the low RES grafting rate, the cell toxicity of PEI-RES10% was weaker than that of PEI, while the cell toxicity of PEI-RES was higher than that of PEI with high RES grafting rate. Flow cytometry and confocal microscope showed that the gene transfection of PEI-RES was higher than PEI at low N/P ratio, indicating that grafting RES to PEI could improve the gene transfection of PEI.