Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer.

AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp8-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp8-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp8-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp8-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp8-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells.

[Determination of apparent oil-water partition coefficient of andrographolide and dehydroandrographolide and effect of pH on them].

OBJECTIVE: To determine the apparent n-octanol-water/buffer partition coefficient of andrographolide and dehydroandrographolide. METHODS: The apparent n-octanol-water/buffer partition coefficients of andrographolide and dehydroandrographolide were measured by shaking flask method. The concentrations of andrographolide and dehydroandrographolide were analyzed by HPLC method. RESULTS: The Papp of andrographolide and dehydroandrographolide were 3.90 (log Papp = 0.59) and 19.75 (log Papp = 1. 30) in water at 37 degrees C, respectively. CONCLUSIONS: The apparent n-octanol-buffer partition coefficients of andrographolide and dehydroandrographolide are influenced by pH, and the higher pH may decrease the apparent n-octanol-buffer partition coefficients of them. Andrographolide has the highest partition coefficient in pH6, and dehydroandrogapholide in pH5.

[Study on the quantitative change of anthraquinonoids of Rhei in the preparation of dachengqi].

OBJECTIVE: To study the scientific evidence of the traditional preparation of Dachengqi: "Boiling Aurantii Immaturus and Magnoliae Officinalis first, and then adding Rhei to decoct together. Discarding the dregs, adding Natrii Sulfas into the decoction and drinking the upper solution when the Natrii Sulfas has dissolved completely". METHOD: The concentrations of free and combined anthraquinonoids(emodin, rhein, chrysophanol, physcion) in different decoctions were determined with HPLC method respectively. RESULT: When Natrii Sulfas, Aurantii Immaturus and Magnolias Officinalis are decocted with Rhei in different schemes, the concentrations of anthraquinonoids were changed regularly. CONCLUSION: The scientific evidence of traditional preparation method greatly increased the concentrations of the active components in Dachengqi.